Perspectives from CASSS CGTP 2018 · Andrew Weiskopf. Perspectives from CASSS CGTP 2018:...

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Andrew Weiskopf

Perspectives from CASSS CGTP 2018: Manufacturing, Quality, and Regulatory Considerations


• Attendees: 205• Number of regulators: 37• Number of companies

represented: 60

• Number of first-time CASSS meeting attendees: 95

• Number of speakers: 35• Countries represented: 15


Keynote Presentation: Dr. Peter Marks, FDA“Advancing Manufacturing for Advanced Therapies”

• For cell and gene therapies products, the product is the process

• 3 advanced therapy products approved in 2017o KYMRIAH, YESCARTA (CAR-T)o LUXTURNA (in vivo gene therapy)

• Dramatic growth in gene therapy IND applications submitted per yearo 2002: 22 IND applicationso 2017: 106 IND applications


Keynote Presentation: Dr. Peter Marks, FDA“Advancing Manufacturing for Advanced Therapies”• Regenerative Medicine Advanced Therapy (RMAT)

o Expedites development of certain cell therapies, therapeutic tissue engineering products, human cell & tissue products

o Genetically-modified cell therapies & gene therapies producing durable effects can also be included

o Products for serious or life-threatening diseases/conditions which have preliminary clinical evidence to show potential to address unmet medical needs

o Eligible for Fast Track, Priority Review, Accelerated Approval, and expanded options to fulfill post-approval requirements

o As of 30 Jun 2018, 24 products granted RMAT, 15 are orphan Most are cell therapy or cell-based gene therapy products


Keynote Presentation: Dr. Peter Marks, FDA“Advancing Manufacturing for Advanced Therapies”

• Efforts to Improve Manufacturingo FDA collaboration with NIH & NIST to

develop standards for regenerative med

o FDA guidance suite issued during the CASSS conference

• INTERACT Programo To encourage interaction with sponsors

o Replaces the “pre-pre-IND” meeting

• Issues in Manufacturingo Developing and validating processes for

autologous cell therapies

o Need for standards for reproducible production

o Lack of vector manufacturing capacity for lentivirus and AAV

o Productivity of cell lines still unable to meet demand, despite recent improvements


First-in-Human & Early CMC DevelopmentThomas Finn (FDA, USA), Ilona Reischl (BASG, Austria), Sadik Kassim (Mustang Bio)

• Phase 1 emphasis on safety: raw material qualification, sterility, endotoxin, ability to manufacture the product

• “Work backwards”: MOA defines Target Product Profile, which in turn dictates critical quality attributes and process parameters

• Design and characterize process with goal in mind: strive for consistency, understand variability, and control through CQAs and CPPs/KPPs

• Transitioning from “academic” to “commercial” manufacturing: have to maintain product comparability while implementing a scalable, sustainable process (UPenn-to-Novartis, NCI-to-Kite)

• Specifications evolve with product development, but should be meaningful & based on science, even in early phases

• Product characterization is critical to successful development, commit to continually improving analytics and use them

“If you want to accelerate your development, you need to accelerate your manufacturing process development and product characterization.”

–Ilona Reischl


The Uniqueness of mRNA-Based ProductsAndreas Kuhn (BioNTech RNA Pharmaceuticals), Ulrich Blaschke (CureVac AG), Thomas Hinz (PEI, Germany)

• Cancer therapy: patient-specific mRNA drug product coding for a tumor’s neoepitopes, used to induce T-cell immune response

o Prophylactic vaccines, protein replacement therapies also in development

• Manufactured by in vitro transcription vs. a plasmid DNA templateo Impurity profile: truncated mRNAs, residual DNA template, residual enzymes, and

residual E. coli proteins

• Is next-generation sequencing (NGS) an in vitro diagnostic, a companion diagnostic, or just a manufacturing process step?

o In US, NGS clearly falls under “companion diagnostic” regulations, but this is much less clear in EU

• Are mRNA drugs considered gene therapy medicinal products in EU?o EMA/CAT precedent would suggest Yes, but definition is partly based on whether

mRNA is produced in a biological system… what about cell-free systems?


Autologous Supply ChainRichard Heath Coats (FDA, US), Albert Ribickas (Moffitt Cancer Center), Craig Vermeyen (Kite)

• In the US, autologous gene-modified cell therapy products are regulated as biological products that are also drugs: must comply with 21 CFR parts 210-211, parts 600-610, and relevant subparts of 1271

• Clinical centers can form dedicated teams to consolidate expertise and coordinate end-to-end care for patient treatment: physicians, pharmacists, nursing staff/administration, and cell therapy core service

• Shipping validation is critical: understand autologous cell shipment logistics, temperature control, qualification of container system, and simulate real-world conditions to ensure integrity

• Cryogenic shipping presents some unique challenges: dangerous if not correctly controlled, label adhesion issues, packaging integrity must be assured

• Traceability is essential: must maintain patient traceability from collection to administration


Analytical CharacterizationRebecca Cooper (Biogen), Xiaoying Jin (Sanofi), Ilya Shestopalov (bluebird bio)

• Residual host cell DNA analysis of AAV vector productso Challenging due to multiple sources of nucleic acid interference (residual plasmid,

partial product genomes), so PCR primer specificity is very important

o Residual host cell DNA trapped within AAV: must determine levels inside and outside

o Digital droplet PCR (ddPCR) an emerging technology: counting binary fluorescent responses in 20,000 microdroplets, uses less material and more tolerant of matrix interference, but reports results as # of copies/µL instead of pg/µL

• LC-MS characterization of AAV capsid proteinso MS-based identity assays able to differentiate AAV serotypes on basis of VP masses

o Capsid protein deamidation correlated to reduced potency of AAV preparations, could explain differences in product potency between AAV manufacturing platforms

• Characterization of CD34+ gene-modified cell therapy productso Potency measured as function of vector copy number

o ICP-MS of cells with lanthanide-tagged affinity reagents (CyTOF) a useful method for deep phenotyping of drug product, alternative to FACS


Christiane Niederlander, MHRA (UK)Christopher Storbeck, Health Canada

Regulatory Updates from Across the Globe

• 7 gene therapy CTAs approved in first half of 2018, including first CTA for CRISPR gene editing

• CAR-T emerging issues similar to those of other health authorities: chain of custody/identity, qualifying apheresis sites, manufacturing strategy built around QTPP, clear procedures for how to proceed with dosing failed lots

• AAV in vivo gene therapy emerging issues: release specification for empty capsids, matrix approach to potency assays, transgene activity test needed later in development

• Present clear knowledge of product and process, well-justified risk-based approach to CQAs and CPPs

• Embracing harmonization through International Pharmaceutical Regulators Programme (IPRP)

• Risk-based approaches to manage risks of the product & process: will dictate extent of data needed in the IMPD dossier

• Early access tools for ATMP developmento PRIME: Eligibility based on non-clinical & clinical data to

show potential to address an unmet medical need.

o Adaptive Pathways: Staggered approval, use of real-world data, involving patients & HTA bodies in development

• Orphan legislation revised: definition of gene therapy updated, ATMP Q&A document issued

• Environmental Risk Assessments (ERAs):

o Gene therapy products are GMOs, regulated by ministries of environment under different definitions and timelines


Denise Gavin, FDA (US)Ofra Axelrod, Israel Ministry of Health

Regulatory Updates from Across the Globe

• 19 CTAs received for review in first half of 2018: most are cell-based therapies, 13/19 from local manufacturers

• First gene therapy approved in 2017 (IMLYGIC –Amgen), 4 more MAAs under review this year

• ATMPs regulated as “biological medicinal products” per Israeli law

o Pharmacists Ordinance amended in 2016 to include ATMPs under regulations

o Follow EU GMP legislation and regulatory framework

• Clinical trials approval overseen by dedicated advisory committee for ATMPs

• “Hospital exemption” permitted only for domestic investigational ATMPs – no imports

• 205 new INDs in first half of 2018: 133 cell therapy products, 82 gene therapy products

• 6 new gene therapy draft guidance documents issued that morning: disease-specific guidances, long-term follow-up for gene therapy subjects, replication competent retrovirus, and gene therapy CMC for INDs

• New CMC draft guidance:

o Recommendations on eCTD submission content

o Definition of drug substance vs. drug product

o Viral vectors used for genetically-modified cell products treated as drug substance, with similar level of detail and GMPs, process validation prior to BLA

o Guidance on cell bank selection, impurity testing, qualification of titer assays, plasmid quality


Strategy & Considerations for Potency AssaysMarcel Hoefnagel (MEB, Netherlands), Phoebe Baldus (Pfizer), Marina Feschenko (Biogen)

• Potency of cell-based products often requires multiple methods during development, some for release testing, others for characterization to control process changes

• EMA guideline on potency testing for cell-based cancer immunotherapies: o Acknowledges complexity of biological mechanisms and variability of starting material

o Assure consistent functional activity of product lots within justified limits, using a bioassay measuring a defined effect that is as close as possible to the MOA

• AAV potency assay matrices: separate methods for in vitro infectivity, transgene expression, and functional activityo Phase 1: Propose infectivity assay for release/stability, other assays for characterization

o Pivotal: Ideally use functional assay for release/stability, expression assay for characterization, drop infectivity unless it does not correlate well with functional assay

• Challenges of not having suitable functional assay for pivotal studies: how to demonstrate efficacy of DP if there’s no good in vitro system?


Process Development, Validation, & VerificationLily Koo (FDA, US), Anthony Thatcher (Novartis), Curran Simpson (RegenXBio)

• Aseptic process simulation: critical for GMP compliance, demonstrate well-controlled handling during process since many ATMPs are not amenable to final sterilization/filtrationo Consider scale, how many concurrent lots being manufactured at the same time, how

many manual steps, how much dependent on operators vs. automation

• Use risk-based approaches to determine which parameters should be studied in process characterization, linkage to CQAs

• For gene-modified cell therapies (CAR-T), critical to build experimental data set with cells from both healthy donors and patients, using normal and “atypical” process conditions for robustness

• Process monitoring & continuous process verification essential to ensuring quality, due to complexity of processes and products

• Short development cycle of AAV gene therapy products requires standard approach to comparability, readiness to implement process improvements, and significant characterization earlier than usual


Late-Stage Development & CommercializationMarcos Timón (AEMPS, Spain), Diane Blumenthal (Spark), Justin McCue (Juno)

• Draft revision to EMA guideline on genetically-modified cell products open for public consultation (until 31 Jul 2019)o New guidance on genome editing protocols, align with new EU GMPs for ATMPs,

clearer GMP expectations for starting materials (vectors, mRNAs, proteins), comparability guidance

• Challenges of fast-moving AAV gene therapy program with limited pre-pivotal manufacturing historyo Build manufacturing database to enable process understanding and specification

setting, limited Phase 1 lots/inventory to conduct comparability vs. pivotal materials, rethink CPPs established in clinical manufacturing due to prior lack of knowledge

• Considerations for validating CAR-T manufacturing processeso Crucial to understand relationship of patient cell variability & final product quality,

build robustness into process to handle very different populations of patient cells

o Generally follow FDA’s process validation guidance, although necessary to accommodate atypical nature of starting materials, risks to process and CQAs dictate different numbers of qualification batches in validation


Critical Starting MaterialsFouad Atouf (USP), Alexandra Beumer Sassi (Voisin Consulting), James Miskin (Oxford BioMedica)

• In US, “ancillary materials” are raw materials that come in contact with cells during processing, but which are not intended to remain in final product: USP <1034>

• Extent of ancillary material qualification on based on risk levelo Low risk: Materials already licensed as drugs, biologics, or medical devices

o High risk: Industrial or research-grade materials which may contain harmful impurities, animal/human-derived components

• In EU, raw materials of biological origin must meet quality requirements per EP 5.2.12o Risk-based assessment of origin, traceability, production steps,

control/removal from final product

• Lentiviral vectors used for in vivo and ex vivo purposes designed to be replication-deficient, but testing for replication competence is essential to ensure safety

“Define early on the various elements of the CGT product and position what is considered Raw Material, Starting Material, Drug Substance, and Drug Product.”

–Alexandra Beumer Sassi


Standards Development for C&GT ProductsJiwen Zhang (Standards Coordinating Body), Rebecca Potts (USP), Samantha Maragh (NIST)

• “Product consistency and lack of standards is possibly the single greatest challenge facing the field.” 2016 survey conducted by AIM

• Standards: documentary, procedural, and/or reference materials

• SCB working on FDA project: Industry and government experts to identify existing standards and gaps, prioritize efforts to establish best practices and guidances

• USP standard for enumeration of CD34+ Cells, USP <127>o Flow cytometry: specific parameters for detection required for accuracy

o Standards described for data interpretation, system suitability ref standard available

• National Institute of Standards & Technology (NIST) actively developing standards for genome editing

o Qualifying genomic assays used to identify on-target vs. off-target locations

o Developing reference materials which mimic genome-edited DNA complexity, for use in qualifying sequencing methods for sensitivity


Comparability Through Development of ATMPsZenobia Taraporewala (FDA, US), Margarida Menezes Ferreira (INFARMED, Portugal), Robert Baffi (BioMarin)

• Comparability should start with product quality data, then advance to non-clinical and clinical studies as appropriate

• Comparability assessment should be holistic: o Extended characterization, testing at critical control points, stability data (including

accelerated or stress), and comparison against historical data to detect CQA “drift”

• Well-controlled, sensitive, quantitative assays are crucial to demonstrating comparability for complex biologics

• Acknowledge and pre-empt challenges whenever possible o Limited manufacturing history, limited inventory of pre-change material, limited

knowledge of CQAs and analytical tools, limited in-process data & stability testing

• Increased understanding of AAV physicochemical attributes and effects on biological activityo Deamidation analysis of capsid proteins, fluorescence spectroscopy for capsid integrity

o Impact of empty capsids on potency

“ICH Q5E on comparability should be considered as broadly applicable [to ATMPs].”

–Margarida Menezes Ferreira


Please join us…

CGTP 201910-12 June 2019

Hyatt Regency BethesdaBethesda, Maryland, USA


Biogen ColleaguesCASSS StaffCGTP 2018 Committee

Acknowledgments

• Bruce Thompson, co-chair• Svetlana Bergelson

• Michael Boyne

• Kathleen Francissen• Andreas Kuhn

• Margarida Menezes Ferreira

• Francis Poulin• Ilona Reischl

• Anthony Ridgway

• Cynthia Riggins• Bryan Silvey

• Dan Takefman

• Karen Bertani

• Stephanie Flores

• Julie Fowle

• Anna Lingel

• Renee Olson

• Catherine Stewart

• Rebecca Cooper

• Marina Feschenko

• Jesse Hernandez

• Mary Beth Pelletier

• John Pieracci

• Sara Potter

• Jessica Sloan

• Mark Tie

…and many thanks to all of our speakers and attendees!

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