Opening P Panel el : Review a and Objectives es Chair: Stephen - - PowerPoint PPT Presentation

Opening P Panel el: Review a and Objectives es

Chair: Stephen Lin (CIRM) Participants: Stephen Sullivan (GAiT), Glyn Stacey (ISCBI), Yoji Sato (Japan NIHS; HESI CT-TRACS), Ngaire Elwood (BMDI; ISCT)

PSC 2019, June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Participants

Director Head of Division of Cell-Based Therapeutic Products, NIHS

Glyn Stacey Yoji Sato Stephen Sullivan

International Liaison Officer Senior Science Officer

Stephen Lin Ngaire Elwood

ISCBI

Director, BMDI Cord Blood Bank

4th Annual Cell Therapy Conference – June 2018

Sessions

1. Learning from the current pluripotent space and the development of international standards 2. Bioanalytics and comparability 3. Tumorigenicity testing 4. Manufacture, Storage, and Shipment

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 3

Ses ession 1, n 1, Par art 1 1 – Learning g from

• m t

the cu current pluripot

• tent s

space ce

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PSC products covered in session:

• ESC-derived Oligodendrocyte Progenitor Cells (allogeneic)
• iPSC-derived Retinal Pigment Epithelial Cells (autologous)
• iPSC-derived Neural Stem Cells (allogeneic)

Takeaways:

• Heterogeneity and stability of PSC products is highly variable
• Understanding science behind cell therapy products is critical
• Demonstrating equivalency of hCTPs is critical

Ses ession 1, n 1, Par art 2 2 – Develop

• pment of
• f i

internation

• nal s

standards

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 5

Highlighted product characterization:

• Genetic stability
• Contamination
• Feeder cells
• Traceability of materials is important

Takeaways:

• There are no regulatory guidelines specific for PSCs and derivatives
• Road map would be helpful

Sessi ssion 2 2 – Bioa

• analytics

cs and c com

• mparability

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 6

Takeaways: Perform the right level of product characterization to ensure product quality Critical quality attributes (CQA) must be controlled within critical process parameters (CPP) Manufacturing changes should be made prior to phase 3 clinical trials Genetic characterization is large topic. Two safety issues: a) potential for residual undifferentiated hPSCs b) Mutations in hPSCs that might lead to transformation of hPSCs or differentiated derivative into tumor cells

Sessi ssion 3 3 – tumor

• rigenici

city t testing

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Takeaways: Animal testing still standard

• All animal models imperfect, but they do provide information on tumorigenic

potential of cells

• Incorporate 3Rs – reduce, refine, replace

Genetic testing

• Genetic testing. Regulatory agencies want it, but it is still informational
• Recommend collection and curation of genomic data
• Data processing (resources and expertise) and interpretation (relevance) remain a

challenging issue for many.

Sessi ssion 4 4 – manufact cture, s stor

• rage, a

and shipment

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Automated cell culture systems

• Reduction of invasive process decisions
• Non-invasive in-process analytics will be important
• Providing high content specificity a highly desired goal of any closed system

Myopathy first condition be treated to get iPSC to the clinic

Clinicians Academia Patients Politicians Regulators Ethicists SMEs Manufacturers Hospitals Investors

Language and coalescence of group vision for the manufacture cell therapies

Cell therapy developers should: (i) support the growth of specialized language that comes with innovation and (ii) use the simplest possible common vocabulary to facilitate community-wide communication.

Beginning with the end in mind, what kind of PSC/iPSC do we want to use in therapies

• Variation can be assessed (new statistical tools)
• Optimally sourced and characterised primary tissue source
• Optimal reprogramming
• Optimally derived through automation, mechanisation in defined media

and matrix conditions

• Robust and consistent during scaling
• Amenable to consistent assaying
• Approved by Regulator for its intended purpose
• Immune matched
• Kill switch included for deviants?
• Comparable lines

PSC/iPSC Comparability

Initial steps towards PSC/iPSC line comparability: (i) selecting and periodically revising Critical Quality Attributes as a community, (ii) selecting what quality assays and what standards to use, and (iii) ensuring quality testing, conducted by different users across the community, is consistent and indicative.

Overview w from me m meeting

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• Key challenges remain in PSC manufacturing
• Sharing experiences and data important
• A mechanism/platform for sharing the data needs to be defined
• Range of new standardisation groups emerging
• More specific global regulatory guidance would be welcome

Output since ce 2018 m meeting

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 14

• Report on IABS 4TH International Conference

Biologicals (2018) 56: 67–83

• Quality control guidelines for clinical grade PSCs
• Regen. Med. (2018) 13(7), 859-866
• Strategic Roadmap to filing a Biologics License Application for PSC products

Biologicals (2019) 59: 68–71

• CT-TRACS/MEASURE position paper on tumorigenicity prepared:
• “Tumorigenicity assessment of cell therapy products: The need for global consensus and

points to consider”. (pre-submission stage)

• Scoping of an International Multisite Study to further evaluate in vitro methods for

tumorigenicity assessment, (initiative open to all interested participants, from the public and private sector.)

• GAiT donor consent guidelines: www.gait.global/donor-consent

Sp Spect ctrum of

• f a

act ctivi vities to m

• make a PSC

PSC therapy prod

• duct

ct

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 15

Primary Donor Material

• No donor eligibility

determination

• Limited material testing

Autologous Allogeneic

• Donor Recruitment and

Appropriate Donor Selection

• Donor consent determination
• Screening and testing

required within 7 days of harvest

iPSC generation

• Traceability of reagents &

materials

• Regulatory approval
• Master Cell Bank
• Testing
• Reprogramming/Gene

Modification/Editing

Final Differentiated Product

• Materials
• Manufacturing process
• Regulatory approval
• Product stability
• Safety Testing
• Efficacy Testing
• Storage
• Final formulation

By building holistic understanding of complete translation process there will be less waste and confusion and will accelerate therapies to the clinic

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 16

International Stem Cell Banking Initiative (ISCBI)

Panel el 2: 2: Pluripot

• tent S

Stem em C Cells a s as Manufac acturing C g Cell Substra rates - Chal allenges E es Encounter ered ed a and F For

• rec

ecas ast

Chair: Wen Bo Wang (Fate Therapeutics)

Participants: Joseph Gold (US City of Hope) Yoji Sato (Japan Institute of Health Sciences ) Glyn Stacey (ISCBI)

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel 2 - Participants

18

Director of Manufacturing, Center for Biomedicine & Genetics Director, UK Stem Cell Bank Head of Division of Cell-Based Therapeutic Products

Glyn Stacey Yoji Sato Joseph Gold

• Sr. VP Technical

Operations

Wen Bo Wang

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Unique Advantages of Human iPSCs

Isolation, Characterization & Selection of a Single iPSC Clone

Unlimited Self- Renewal Potential to Differentiate into 200+ Cell Types Uniform in Composition Precise Engineering Extensive Characterization Master Cell Banks

Single iPSC Clone

Renewable Clonal Cell Line ---> Homogeneous Cell Products

A Single Human Induced Pluripotent Stem Cell (iPSC) Unique starting material for cell therapy

Establishing a New Paradigm in Cellular Engineering

Eliminating stochastic editing variability and heterogeneity associated with pool engineering

Panel 2: Pluripotent Stem Cells as Manufacturing Cell Substrates - Challenges Encountered and Forecast

Stem Cell Processing, Process Monitoring, Quality Control and Cell Preservation:

• Screening and Selection Methods
• Culture Media/GMP Reagents Advances
• Cell Expansion Equipment
• Cell Expansion, Modification, and Differentiation Methods
• Separation Techniques
• Cell Culture Volume Reduction
• Process Automation and Data Analytics
• Monitoring and Feedback Control Technologies
• Cell Attribute Testing and Measurement Technologies
• Fill/Finish and Cryopreservation Technologies

PSC Manufacturing Expert Panels 2019 June 30th 2019, Los Angeles, CA. 21

Panel 2: Pluripotent Stem Cells as Manufacturing Cell Substrates - Challenges Encountered and Forecast

• 1) How to qualify the starting cells to reduce process variation?
• 2) How to understand variation, understand allowable operating

limits, and control variation? how much variation can a manufacturing process encompass before the method requires separate qualification/validation?

• 3) How to demonstrate comparability for process changes?
• 4) What is the biggest challenge for pluripotent stem cell derived

therapies in your view?

PSC Manufacturing Expert Panels 2019 June 30th 2019, Los Angeles, CA. 22

Panel 3 3: Internationa

• nal S

Standa ndardi dization o n of hPS hPSC Manuf ufacturing ng – Ratio tionale le a and R Review o

• f

f Curr rrent S Status s

Chair: Glyn N Stacey (International Stem Cell Banking Initiative, UK)

Participants: Rosario Isasi (U. of Miami, USA), Andreas Kurtz (hPSCreg, Charite Universitatsmedizin Berlin, Germany), Wen Bo Wang (Fate Therapeutics; Standards Coordinating Body, USA), Sheng Lin-Gibson (NIST,

USA)

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel 3 - Participants

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 24

Chief, Biosystems and Biomaterials Division

• Sr. VP Technical

Operations Head, Stem Cell research and Knowledge Mngt. Research Assistant Professor

Glyn Stacey Wen Bo Wang

Director

ISCBI

Rosario Isasi Andreas Kurtz Sheng Lin-Gibson

3 International Standardisation Panel

• How can sharing experiences and data be promoted to drive more efficient progress :
• Clinical trials data
• Standards for consent
• A range of new but different standardization groups exists and are emerging: how can they help the field.
• A map for hPSC stakeholders to understand their roles to best employ them
• Is there a need for new global regulatory guidance specifically addressing hPSC manufacturing issues.
• A standard lexicon for CT with respect to definition and interpretation of terms?
• Focus on areas where regulatory variation occurs such as tumorigenicity
• How do we manage the range of new analytical technologies being utilised for hPSC-based products.
• Hi Content analytics
• Artificial Intelligence such as interrogation of data in multiple datasystems
• ISO TC276 cell manufacturing : hPScs, raw/ancillary materials, transportation, equipment, packaging. Plus

characterization and testing of cells for therapeutic use (count, viability, potency, etc.) - needs input from the hPSC community

• Will automated systems need new standards? What kinds of standards are needed ?
• Reference Materials to ensure the quality of materials (starting materials, reagents/ancillary materials, products)

NB WHO ECBS/NIBSC fixed cells for flow cytometry

• Standards to ensure interoperability of donor consent, hardware, software.

25 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Future: ISO and Automation Standards

26 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 4 4: Defining Quality Parameters of hPSCs

as Manufacturing Intermediates for Therapeutic Development

Chairs: Ngaire Elwood (BMDI), Amanda Mack (Fujifilm CDI) Participants: Thorsten Gorba (IQVIA), Tenneille Ludwig (WiCell), Masayo Takahashi (RIKEN), Wen Bo Wang (Fate)

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel 4 - Participants

28

Ngaire Elwood Director, BMDI Cord Blood Bank Thorsten Gorba

• Sr. Director & Translating

Center Director Masayo Takahashi Project Leader Wen Bo Wang

• Sr. VP Technical

Operations Tenneille Ludwig Director of Distribution, Media Optimization and Core Services Amanda Mack Director iPSC Technologies

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Defining & Refining Quality

• How do we define Quality with respect to both the starting tissues

and hPSCs derived from them?

• What factors can affect Quality?
• Are the Critical Quality Attributes (CQA) for iPSCs published by GAiT (2018)

fit for purpose or needs to change and why?

• What risks/benefits are there to initiating manufacture in GMP from

start to finish vs transitioning a research grade intermediate into GMP?

29 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Quality Testing

• How can we better understand and manage the potential

consequences of tests selected to assess CQAs?

• What can we learn from the Quality Round Testing initiated by GAiT?
• How might potency for PSCs be measure and should it if considered

an intermediate for the production of a final, clinical product?

30 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel anel 5: 5: Outlining a g a roa

• ad map to
• PSC

PSC ce cell t therapy com

• mparability

Chair: Jo Mountford (SNBTS, Edinburgh)

Participants: Micha Drukker (Institute for Stem Cell Research at the Helmholtz Zentrum München) Howard Federov (UCI Health System), Derek Hei (BlueRock Therapeutics)

Panel 5 - Participants

Chief of Manufacturing and Technical Operations Professor of Neurology at UC Irvine; CEO UCI Health System Head of hiPSC Unit, Institute for Stem Cell Research Head of Cellular Therapeutics, Tissues, Cells and Advanced Therapies Directorate

Micha Drukker Howard Federoff Derek Hei Jo Mountford

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 32

Comparability

• Comparability is the regulatory requirement to demonstrate product

equivalence (highly similar) after a process change.

• Such process changes include:
• a media component change,
• a donor/starting material change,
• a manufacturing platform change
• the introduction of a new manufacturing site.
• All changes expected for therapies derived from hiPSC

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 33

Demonstration of comparability is dependent on agreement on the Critical Quality Attributes

• Between iPSC lines derived from different donors (whether

autologous or allogeneic)

• Between those derived by different manufacturers
• Batch-to-batch
• Demonstration of comparability is dependent on agreement on

the Critical Quality Attributes (CQAs), i.e. those physical, chemical, or biological properties that typically, should be within an appropriate limit, range, or distribution needed to ensure quality and safety of the product for its intended use.

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 34

• Regen. Med. (2016) 11(5), 483–492 ISSN 1746-0751
• Product release specifications do not establish full

characterization of the product and therefore whilst ensuring product consistency, form only part of the evidence required to demonstrate comparability

• Attention must be paid to the process instructions

(including standard operating procedures), critical process parameters, in-process controls and critical quality attributes (CQAs) in addition to the product specification to ensure and demonstrate comparability

• Overall, a pragmatic approach to product

characterization is one that would define a ‘window

• f system behavior’, with particular attention to

the definition of the limits, so that a level of biological variability is tolerated but the process as a whole is under control

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 35

Comparability – advice from manufacturers

• Comparability is a big challenge for PSC cell therapies since key

markers/assays may not yet be known.

• Measure predictors of patient risk, refrain from measuring just

because a parameter is measurable – this can give false sense of security, drives up cost with no demonstrable benefit to patient, and takes resources away from other quality testing.

• Begin with the end in mind: safe and efficacious final therapeutic

products require high quality intermediates. Quality is key.

Advice: Test & retain (throughout ?)

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 36

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 37

Biological License Application for a PSC-derived Product

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 38

Summary of key activities under the cellular therapy development path

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Panel 6: 6: T Towards standardized ed tumorigenicity t y testing – challenges and the way f forwar ard

Participants: Andres Bratt-Leal (Aspen Neuroscience), Deborah Ann Hursh (CBER/FDA) Derek Hei (BlueRock Therapeutics), Jane Lebkowski (Regenerative Patch Technologies) Chair: Dr. Yoji Sato, Japan NIHS and CT-TRACS committee member

PSC 2019, June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel 6 - Participants

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA. 41

Head of Division of Cell-Based Therapeutic Products, NIHS

Yoji Sato Andres Bratt-Leal

VP R&D

Derek Hei

Chief of Manufacturing and Technical Operations

Jane Lebkowski

President of R&D

Deborah Ann Hursh

Senior Investigator, CBER/FDA

• HESI CT-TRACS Tumorigenicity WG

Position Paper.

Panel 6: Addressing some of the challenges & needs

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 42

Panel 6: Addressing some of the challenges & needs

Testing methods: How to measure tumorigenicity? [MEASURE studies and CT-TRACS International Multi-Site Studies] Sensitivity: Are detection methods sensitive enough? [MEASURE studies] Need for data generation, data sharing and a platform where these can occur. Translatability of animal models for hPSCs: Can testing human cells in animal models be of any relevance? Interpretation and Predictivity: What test results would be indicative of tumorigenicity risk? (“Go/No Go” decision making)

Thresholds: are we aiming at a “zero tolerance” principle here? (e.g., presence of 1 transformed cell or 1 residual undifferentiated cell means “no go”?)

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 43

Next s steps ps

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 44

Call for participants

• pen

Panel 6: Why tumorigenicity testing? And related challenges

• Risk: cells transformed during the manufacturing process and residual undifferentiated PSC remaining

in the final product may form tumors in patients.

• How is tumorigenicity risk defined? (Risk perception vs. actual risk)
• Challenges & questions:
• Testing methods: How to measure tumorigenicity?

1. Choice of positive/negative controls 2. Sensitivity: Are detection methods sensitive enough? 3. Translatability of animal models for hPSCs: Can testing human cells in animal models be of any relevance? 4. Interpretation and Predictivity: What test results would be indicative of tumorigenicity risk? (“Go/No Go” decision making) 5. Thresholds: are we aiming at a “zero tolerance” principle here? (e.g., presence of 1 transformed cell or 1 residual undifferentiated cell means “no go”?)

• When to test for tumorigenicity?
• Should tumorigenicity testing fall within Quality Testing rather than non-clinical safety testing?

(Theoretically, we cannot discuss the product safety in human, with non-clinical testing without an uncertainty factor for the species difference.)

• Needs:
• Need for data generation, data sharing and a platform where these can occur.

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 45

Pa Panel 7: 7: Towards a automated a and closed h human P Pluripotent Stem C Cell Manufa facture

Participants: Names (affiliation) Chairs: Name (affiliation)

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Participants

Elizabeth Schwarzbach NYSCF Mathilde Girard YposKesi Steven Keizer CCRM Glyn Stacey ISCBI Stephen Lin CIRM Yoji Sato Japan National Institutes of Health Sciences Bill Shingleton Asymptote Koji Tanabe I Peace

Automation of closed iPSC manufacturing

PSC Manufacturing Expert Panels 2019 June 30th 2019, Los Angeles, CA. 48

WHY?

• Remove process variability
• Improve consistency and predictability
• Scale up and out
• Timing
• Cost
• Characterization
• Standardization
• Resourcing
• Aligning efforts

OPPORTUNITIES CHALLENGES

GMP iSPC line - Characterization

PSC Manufacturing Expert Panels 2019 June 30th 2019, Los Angeles, CA. 49

Biological variability Process variability Analytical variability Other variability

• Less important

than others

• This could be reduced by

developing established standard references

• Automation
• Standardised

components (reagents)

• Supply chain
• Just In Time
• Some variability cannot be avoided

in complex biological systems like cells.

• Variability of niche/patient.
• Understanding cell identity and

function

• Biomarkers
• Orthologonal functional assays

UNDERSTAND VARIATION, UNDERSTAND ALLOWABLE OPERATING LIMITS, CONTROL VARIATION Total variability

GMP iSPC line – Level of variability is tolerated, if understood & controlled

PSC Manufacturing Expert Panels 2019 June 30th 2019, Los Angeles, CA. 50

Guiding principles:

• Begin with the end in mind
• Measure twice, cut once
• Timing of implementation is critical
• Pushing to clinic too soon can be

detrimental to outcome

Panel 8

Financial and Logistical Challenges to human Pluripotent Stem Cell Manufacture

Lack of Standards: Clinical Risk & Business Risk

As well as the clinical risk associated with a lack of standards, there are also profound business risks. Standardization activities will reduce risks relating to commercial viability, adaption, and regulation through introduction and promotion of manufacturing and process standards and building a global network.

Market Risk Likelihood Impact Combined score Risk rating Action/Treatment Cell therapies not commercially viable Likely (4) Major (4) 4x4=16 HIGH Poses a serious threat. Requires an immediate action to reduce/mitigate the risk. Low adaptation by market of technology Possible (3) Major (4) 3x4=12 MEDIUM Poses a threat and should be pro-actively managed to reduce/mitigate the risk. Regulatory harmonisation not achieved Possible (3) Moderate (3) 3x3=9 MEDIUM Poses a threat and should be pro-actively managed to reduce/mitigate the risk.

Smart people make new mistakes Complexity of manufacturing often underestimated by other functions Risk of being a blue sky entrant Collaboration vs competition in early market development

Logistics challenges

• Large scale production of PSC cells to make cell therapies

commercially viable is still in its infancy but will be addressed in future projects

• Enough of key reagents and materials of the appropriate grade and

amount.

• Automated, near real-time monitoring of which cellular populations

have been edited

• Improved design of nucleic acid sequences that can predict

expression of genes and off-target effects

• Reduced costs by service providers will greatly accelerate the field

Panel 9 9: Avoiding I Immune Rejection a and Engraftment Fai ailure e - Chal allen enges an es and t the e Way y Forwar ard

Chair: Stephen Sullivan (GAiT) Participants: Anna Falk (KI), Jeanne Loring (Aspen Neuroscience), Ross Okamura (CIRM), Marc Peschanski (Inserm), David Turner (SNBTS)

PSC Manufacturing Expert Panels 2019

June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Panel 9 - Participants

56

Anna Falk Associate Professor

• f Stem Cell Biology

Ross Okamura Senior Science Officer, Discovery and Translation Marc Peschanski Research Director David Tuner Clinical Immunologist Stephen Sullivan International Liaison Officer Jeanne Loring, Chief Scientific Officer, Prof Emeritus

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Immune rejection remains a formidable barrier to successful engraftment/transplantation

• Will stem cells could have a major impact on transplantation beyond

their current use in use in treating blood disorders?

• What are the main strategies we should consider for avoiding

immune rejection and what are the strengths and weakness of each approach?

• Comment on whether these approaches are likely be mutually

exclusive or to be used in combination.

• Comment on the mechanistic complexity graft rejection, T cell

response, NK cell response, macrophages (mHC), tolerance, etc.

57 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Reducing Engraftment Failure

• How can PSC/iPSC manufacturers better understand and manage the

potential consequences of immune rejection?

• How likely will regulatory approval be for different approaches?
• How economically feasible will different approaches be?
• How clinically usability will different approaches be?
• What will the overall clinical impact of each strategy be?

58 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Cl Closing P Panel el: Organizer ers’ Summa mmary

Chairs: Glyn Stacey (ISCBI) and Stephen Lin (CIRM) Participants: Ngaire Elwood (ISCT), Lucilia Mouriès (HESI CT-TRACS), Yoji Sato (NIHS; HESI CT-TRACS), Stephen Sullivan (GAiT)

PSC 2019, June 30th 2019, Los Angeles, CA.

International Stem Cell Banking Initiative (ISCBI)

Closing Panel

Director

Glyn Stacey

ISCBI

Senior Science Officer

Stephen Lin Ngaire Elwood

Director, BMDI Cord Blood Bank

Lucilia Mouriès

Scientific Program Manager Head of Division, Cell- Based Therapeutic Products

Yoji Sato Stephen Sullivan

International Liaison Officer

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Sp Spect ctrum of

• f a

act ctivi vities to m

• make a PSC

PSC therapy prod

• duct

ct

61

Primary Donor Material

• No donor eligibility

determination

• Limited material testing

Autologous Allogeneic

• Donor Recruitment and

Appropriate Donor Selection

• Donor consent determination
• Screening and testing

required within 7 days of harvest

iPSC generation

• Traceability of reagents &

materials

• Regulatory approval
• Master Cell Bank
• Testing
• Reprogramming/Gene

Modification/Editing

Final Differentiated Product

• Materials
• Manufacturing process
• Regulatory approval
• Product stability
• Safety Testing
• Efficacy Testing
• Storage
• Final formulation

PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 2: Pluripotent Stem Cells as Manufacturing Cell Substrates - Challenges Encountered and Forecast

• Understanding and reducing process variation:
• Demonstrating comparability:
• Biggest challenge for pluripotent stem cell derived therapies:

62 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 3: International Standardization

Data sharing

• Clinical: hPSCreg database
• Consents: challenges with EU/GDPR regulations
• Standardization with high content analytics:

63 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 4: Defining Quality Parameters as manufacturing intermediates

• Factors affecting Quality:
• Changes from GAiT report/learning from quality round:
• Risks/benefits initiating manufacture in GMP from start to finish vs transitioning a

research grade intermediate into GMP:

• Potency for PSCs as an intermediate:

64 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 5: Roadmap for comparability

• Donor material:
• Testing:
• Regulatory strategy:

65 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 6 - tumorigenicity

• Diversity of testing methods; no consensus on best practices
• Better characterization of testing methods are critical for the

translation of iPSC-derived products

• Identifying ideal positive control cells for predictivity of clinical safety

is a challenge.

66 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

67

www.hesiglobal.org

HESI Cell Therapy-TRAcking, Circulation and Safety (CT-TRACS) Committee

lmouries@hesiglobal.org

Panel 7 – Automated and closed manufacture

Enabling technology development

• Key aspects of automation:
• First area to focus on:
• Variable that predicts risk for automation development:

68 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 8 – Financial and logistics challenges

• Logistics costs/challenges:
• Autologous vs allogeneic approaches
• Manufacturing:
• Clinical trial design:

69 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

Panel 9 – Immune rejection/engraftment failure

• Impact of stem cells beyond blood disorders:
• Strategies to avoid immune rejection:
• Understand and manage the potential consequences of immune rejection:
• Clinical/economic feasibility of approaches:

70 PSC Manufacturing Expert Panels 2019 - June 30th 2019, Los Angeles, CA.

www.isct-na2019.com

Save the Date! ISCT Returns to the City of Lights in 2020

CT-TRACS CONTACT: Lucilia Mouriès, PhD Scientific Program Manager lmouries@hesiglobal.org Follow us:

www.hesiglobal.org @HESI_Global (#CT_TRACS)

Health & Environmental Sciences Institute (HESI) 740 15th St NW, Suite 600| Washington, DC 20005 www.hesiglobal.org

SAVE THE DATE! Follow-up PSC meeting: 9/27/2019 HESI Offices, Washington DC Let’s keep moving forward!

By building holistic understanding of complete translation process there will be less waste and confusion and will accelerate therapies to the clinic

PSC 2019 Mtg, June 30th 2019, Los Angeles, CA. 74

International Stem Cell Banking Initiative (ISCBI)