5th DIA Cell and Gene Therapy Products Symposium in Japan- Regenerative Medicine from Innovation to Industrialization December 10-11, 2020

Challenge to comparability
evaluation and change control ofCell Therapy Product
Kazumi SAWAGUCHI, Ph.D
SanBio Company Limited Regulatory Affairs
注） 弊社ホームページへの掲載にあたり、当日の発表資料を一部改編しています©2020 SanBio Company Limited

0Disclaimer

本資料に掲載されている当社の計画、戦略、判断などのうち、過去の歴史的事実以外のものは当社の将来の見通しに関する現時点での見解であり、当社が現在入手可能な情報・仮定および判断に基づいて作成されています。従って、将来、実際に公表される結論、成果、業績等は、将来の事業環境の変化等を含む様々な要素によって変動する可能性があります。

本資料には、当社の開発情報その他の事業情報が含まれていますが、それらは宣伝や広告、医学的アドバイスの提供を目的とするものではありません。
本資料に掲載された情報につきましては、予告なく変更される可能性があります。本資料に基づいて被ったいかなる損害についても、当社及び情報提供者は一切責任を負いかねます。
サンバイオ株式会社©2020 SanBio Company Limited1What is SB623

SB623 are modified allogeneic mesenchymal
stromal cells(MSC) transiently transfected withhuman Notch-1 intracellular domain
Implantation of SB623 cells in the peri-infarct
region
Method of SB623 Implant
Injector©2020 SanBio Company Limited

2

SanBio: History
Development

Corporate
Non-clin.

2001

Feb

2002

Nov Technical transfer from YOKOHAMA TLO KK(SB623)

2010

May SB623 Phase I/IIa IND (US)2013Feb

2014

2015

Lab

Established Sanbio, Inc. in the US (California)

Established SanBio KK in JapanMay SB623 Phase IIb（Indication A) IND (US)Jan Reversal JP-US parent-Child（JP subsidiary as Parents Comp.）
AprCMOClinicalBasic Research
Process Development

Plant A

Non-GLP【US】
Phase I/IIa
Plant B

GLP

ProcessDevelopment

Listed on Mothers

2016

MarIND (JP)2020

NovPresent【US】
Phase IIa
(Ind.A)【JP/US/EU】
PhaseII(Ind.B)
Plant C

※POC: Proof of Concept©2020 SanBio Company Limited3

Allogeneic Approach
Select Allogeneic Model in Order to Make RM Available to All PatientsAutologous

AllogeneicDonor

Regenerate

Obtain cells

From healthy donor

Cell culture
Cellmedicine
Obtain cells

Mass production

From each patient

PatientPatients

A service model

A product model©2020 SanBio Company Limited

4Image of Manufacturing Process of SB623
Large Scale Production of Cells Derived From Bone Marrow

Cryopreserved
SB623 Cells

Bone Marrow Aspirate
Expression Vector

NICD 17879 bp

MSC Cells in CF10Isolation and Expansion

Transfectionand Selection©2020 SanBio Company Limited

Expansion of SB623
in CF105Image of Product development and Quality control strategy setting⚫ It is difficult to grasp all the quality of cell therapy product by the Spec., as theinformation is limited.
⚫ The idea of quality control by controlling raw materials and manufacturing processes isimportant.

Image of current Bio product

Image of Cell therapy product

Change Material/Process

ChangeMaterial/Process
Material/Process
ChangeIn-processcontrol
In-process
In-processcontrol
control

Characterization

Characterization
Characterization

Spec.

Spec.
Spec.
Ref. R.Maruyama et.al Perspectives and practical strategies for obtaining approval / reviewing products forregenerative medicine / gene therapy products, Science & Technology, 2020.9 P 186©2020 SanBio Company Limited6Strategy of Scale-up Manufacturing from Lab to CPC
It Takes Time to Develop Large Scale Production TechnologyTechnology
transfer fromuniversities (1year)

Scale-up (1-2 years)

Optimization of condition
Preparation for
GMP/GCTP
manufacturing(1 year)

Small-scale optimization (1-2 years)

Evaluation of cell source
Type and dose of reagents
Type and concentration of culture medium
Inoculation density of cells
Culture conditions
Frequency and number of passages
Evaluation and selection of preservation medium
Freezing method
Unfreezing method

GMP/GCTP manufacturing（2 years）

Preparation of standard
operating procedure
Establishment ofmanufacturing recordsystem
Validation of evaluation
systemTechnology transferAssay system
Manufacturing process

Manufacturing of GM/CTP
training
Establishment of manufacturing
record system
 Scale up

GM/CTP preliminary
manufacturing
GM/CTP manufacturing

Quality check and QA system (2-3 years)

Cell characterization
Examination/establishment of product specification
Development of evaluation system
Product Profile/CQAs/Risk Assessment

Control strategy* GCTP: Good Gene, Cellular, and Tissue-based Manufacturing Practice * CPC: Cell Processing Center©2020 SanBio Company Limited

7Various challenges in the quality of SB623

Raw Materials (Human-derived materials)• Risk of infection/Viral contamination
Scale-up (1-2 years)• Material variability/Donor-to-donorvariability

Process Development••••

Knowledge management from academic field
Comparability for process changes (e.g. scale up)
Limited materials for process evaluation
Identification of CPP (Critical Process Parameter) and CQA (Critical Quality Attribute)

Manufacturing control
••
•
•

GCTP
Aseptic process considerations
Viral safety considerations
Process performance consistency

Analysis• Complex characteristics• Specification (potency assay etc.)©2020 SanBio Company Limited8

Points to consider when transferring or adding CPC to other countries-Reg. Requirement-Raw material-

Material/Equipment-

Transportation-Technic-

Training-

Culture-Communication-Environment-

Scientific progress

Small-scale optimization (1-2 years)
Scale-up (1-2 years)

1st CPC

2nd CPC

3rd CPC

SanBio Lab/CMC/QC Team
* CMC: Chemistry, Manufacturing and Control©2020 SanBio Company Limited

9

Quality characteristics of cell therapy products
Ref. The 16th Congress of the Japanese Society for Regenerative Medicine
PMDA Dr. Oyama 2017

Evaluation item

Identity test

Example of test method(Case by Case depending on the position of the test)

Description, Cell phenotype, Differentiation ability,
Scale-up (1-2 years)
Tumorigenesis etc.

Cell purity test

Cell phenotype, Proliferation abnormality etc.

Process-related Impurities

Manufacturing process-related substances(Serum-related Albumin, Antibiotics, etc.)

Unintended Product-related
physiologically active impurities

Physiologically active substances, etc.

SafetyChromosome abnormality, Soft agar colony forming
ability, Virus, Mycoplasma, Endotoxin, Sterility, etc.
(secured as in-process control)

Potency assay, efficacy test,
Mechanical compatibility

Protein expression, Secretion ability, Differentiation
ability, Cell phenotype, Cell proliferation ability, Cell
survival, Cell/cell interaction etc.

Content

No of cell, Cell viability, etc.

*Quality characteristics related to efficacy and safety can be important quality characteristics, but it is still necessary toorganize and discuss what kind of quality characteristics correspond to each product containing cells.
* We can debate about what quality characteristic items and standard values should be set in the titer test.
©2020 SanBio Company Limited

10Production ratio of various biologically active substance of MSC and SB623

Fold change SB623/MSC
0246810BMP-4 (1-21.6
Scale-upyears)

DKK-1
FGF-7

5.80…

IL-6

3.8

IL-8

3.7

MCP-1

4.7

MMP-1
PDGF-…

VEGF

2.3
1.4
1.8

Quantify various biologically active substance in culture supernatant using antibody array kit.

Can these active substance be subject to “Potency assay”?
Ref: Tate et al, : Cell Transplant 2010; 19(8): 973–984 revised©2020 SanBio Company Limited

11

Setting of Potency AssayScientific
Progress

Biotechnology
Scale-up(1-2 years)
Pharmacology（In vitro/In vivo)

Molecular
Biology

Indication
Clinical（Clinical study)(Clinical research)
MoAs

Physiology

Quality
Method(Reproducibility,Easy, Short time,
Reasonable)
StableSupplyGxPADMECell Biology

Tox

Set the Potency Assay

Cost
effectiveness

Cell
Engineering

Change/add the Potency Assay©2020 SanBio Company Limited

12

Consider to set the specification for Cell therapy productRef. The 16th Congress of the Japanese Society for Regenerative Medicine
PMDA Dr. Oyama 2017

Scale-up (1-2 years)
Release Testing（Specification）

Extended Characterization
Stability Profile

For Cell therapy product1. Cells are alive
2. Quality characteristics are complex, diverse andheterogeneous
3. There are technical restrictions on the implementation ofspecification tests and manufacturing control
4. The specification only confirms an important part of quality
and can only be established on various assumptions.

Points to consider

Process Consistency
・Process Control
・Process Validation
Prior Knowledge

1. Full understanding of quality characteristics (characteristicanalysis)
2. Understanding process variations that lead to quality
fluctuations (quality risk management)
3. Invisible quality parts should be managed as quality
fluctuations from the upstream of the process (quality controlstrategy)©2020 SanBio Company Limited

13

Image of heterogenous, complex and divers

A

Scale-up (1-2 years)

Kyoho〇 Same Spices〇 Same Quality

Kyoho〇 Same Spices? Comparable ?
Color/Maturity/Taste etc.

B
Kyoho

Kyoho

〇 Same Spices
X Different Quality
Taste is different!

CKyohoMuscat©2020 SanBio Company Limited

14

Image of Quality control strategy for SB623

Raw material
quality control

Material quality control
Scale-up (1-2 years)

In-Process Control

Quality bytest

Bone
MarrowIsolateMSC

PassageTransfection

Selection

Harvest andcryopreservation

Verification©2020 SanBio Company Limited

15

Life cycle plan of SB623 from lab to CPC
Ref. IABS, JST(NIBIO), PMDA and WHO joint Workshop Dr.Sato Feb 2015

Scale-up (1-2 years)

SanBio
Lab

CPC A

CPC B

CPC C

Verification

SB623
Pharm.

©2020 SanBio Company Limited

16

Life cycle plan of SB623 from lab to CPC
Ref. IABS, JST(NIBIO), PMDA and WHO joint Workshop Dr.Sato Feb 2015

Scale-up (1-2 years)

SanBio
Lab

CPC A

CPC B

CPC C

Verification

SB623
Pharm.

©2020 SanBio Company Limited17

©2020 SanBio Company Limited

18