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1Pharmaceuticals and Medical Devices Agency
18 February 2015
Daisaku Sato, PhD
Director, Office of Cellular and Tissue-based Products
Pharmaceuticals and Medical Devices Agency (PMDA), Japan
GXPs
IABS, JST (NIBIO), PMDA and WHO joint Workshop
Disclaimer:The views and opinions expressed in this presentation are those of the presenter and should not necessarily represent the views and opinions of the PMDA.
2Pharmaceuticals and Medical Devices Agency
Introduction of PMDA
Pharmaceuticals and Medical Devices Agency (PMDA)
an Incorporated Administrative Agency (IAA)
PMDA’s Safety Triangle
Tokyo, JAPAN
3Pharmaceuticals and Medical Devices Agency
Two Japanese Regulatory Authorities
Ministry of Health, Labor and Welfare (MHLW)
Planning basic policy, enforcement of administrative
measures based on the law
Marketing authorization of pharmaceuticals and medical devices
Issue emergency safety information and direct product withdrawal
Safety measures for emergent and significant cases
Pharmaceuticals and Medical Devices Agency
(PMDA)
Review, examination and data analysis
Scientific review, GMP/GLP/GCP inspection and consultation on the
development of pharmaceuticals and medical devices for marketing
authorization
Collection, analysis and dissemination of information relating to
quality, efficacy and safety of pharmaceuticals and medical devices 3
4Pharmaceuticals and Medical Devices Agency
Two Acts regulating regenerative medicine & cell therapy
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Regenerative Medicine
All medical technologies using
processed cells which safety and
efficacy have not yet been
established
The Act on Pharmaceuticals and
Medical Devices (PMD Act)*
* Two laws were enacted on 25 November 2014
Production and marketing of
regenerative and cellular
therapeutic products by firms
The Act on the Safety of
Regenerative Medicine
It may be similar to Hospital exemption
of the EU or PHS 361 in the US
MHLW process PMDA process
5Pharmaceuticals and Medical Devices Agency
Regenerative medicine & cell therapy in Japan
Clinical Research using human stem cells
(under the Guideline for Human Stem Cell Clinical Research - since 2006)
Medical care
The Act on the Safety of Regenerative Medicine Pharmaceuticals and Medical Devices Act (PMD Act)
Cellular/Tissue based Products
108 protocols approved (as of November 2014)
2 approved products• JACE (autologous
cultured epidermis)• JACC (autologous
cultured cartilage)2 products under review Process
19 clinical trials initiated
(including 5 gene therapy
products)
(~January 2015)
Academic Research Purpose Product Marketing Authorization
Purpose
Covered by PMDACovered by MHLW
Cancer immunotherapy
Six types of therapy are
currently provided in approved
university hospitals as
“advanced care” * Partially covered by national health
insurance
6Pharmaceuticals and Medical Devices Agency
1. What are GXPs?
2. GTP
3. GMP (=GCTP)
4. Other GxPs
Today’s Topics
7Pharmaceuticals and Medical Devices Agency
What are GXPs?
Broader term of Good Tissue Practice (GTP) is aimed at
source material handling requirement such as:
Source material selection, Donor eligibility
Personnel, procedure
Facility, Equipment, process control
(Contamination prevention / sterility)
Validation
Record keeping, traceability
Storage, shipment, distribution
Reporting
In cellular product manufacturing, the down stream
of GTP regulation may be included in GMP type
regulation
8Pharmaceuticals and Medical Devices Agency
Purpose of GTP
“to prevent the introduction, transmission,
and spread of communicable diseases by
HCT/P's.”
9Pharmaceuticals and Medical Devices Agency
GTP in the regulations
US GTP =
21 CFR 1271 (Donor Eligibility + cGTP)
Japanese GTP =
Minimum requirement of biological ingredients
+
Good gene, Cellular and Tissue-based product
manufacturing Practice (GCTP)
≈ cGMP
≈ biologics GMP
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Final Products
Intermediate(s)
Cell Bank
Cell Line
Cell Collection Selection of Cells that are
Suitable for Reprogramming etc.
Relevant Pluripotency to Differentiate
into the Target Cells, Potency of Self-
Renewal
Potency of Differentiation to Next
Target Cells, Potency of Self-
Renewal, Stability
Relevant Cells Can Be Processed (e.g.
differentiate).to Desired Product
Evaluation of Q/S/E
Characterization、
Constant Supply,
Stability&
Renewal
Inactivation and/or
Elimination of Un-
differentiated Cells
Characteri-
zation,
Stability
Source,
Biological Features
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Quality system to secure consistent
manufacturing of safe and effective
products
GTP is an operational part of quality assurance in a constant and routine manufacturing basis
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Basic Scientific Issues for
Product Development, Evaluation and Control
Suitability and quality control of raw materials and
manufacture-related substances other than target
cells
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Indicate their appropriateness for their intended
use, and if necessary establish their specifications.
Perform proper quality control for these materials.
Prevent the contamination of bacteria, fungi,
viruses, and abnormal prions from biological
materials
12Pharmaceuticals and Medical Devices Agency
Basic Scientific Issues for Product Development, Evaluation and Control
Justification of source and selection of human cells
that serve as raw materials including autologous or
allogeneic donor screening criteria and eligibility
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Justification of source and selection of animal materials that serve
as culture medium, scaffold, etc. in terms of virus
inactivation/removal and ruminant prion transmission
13Pharmaceuticals and Medical Devices Agency
Justification of Source and Selection of Human
Cells that serve as Raw Materials
Select the source and origin of the cells used as raw
materials, and justify the reasons for selecting these
cells.
Autologous or allogeneic somatic cells
Autologous or allogeneic stem cells
Autologous or allogeneic iPS(-like)cells
ES cells
(Any other human cells)
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14Pharmaceuticals and Medical Devices Agency
Principle of Donner eligibility criteria
When collecting human cell / tissue raw material,
depending on the purpose of their use, relevant
bacteria, fungal and viral infection and the like
have been denied through interview, screening
and testing.
The test parameters and method methods used
are appropriate in light of the latest knowledge of
infectious diseases, etc..
The Donor’s presence or absence of experience
that received blood transfusion or transplantation
must be taken into consideration when determining
donor eligibility.
15Pharmaceuticals and Medical Devices Agency
Considering Donner eligibility criteria
According to the test parameters and test
methods, the re-testing and other infection
controls at the right time have been made,
taking into consideration the window period.
However, it does not necessarily require a
donor screening when the donor is the
same person as recipient.
16Pharmaceuticals and Medical Devices Agency
Autologous Human
Cell/Tissue
Infectious status of donor, including infections of HBV, HCV, HIV, and HTLV.
Risk of proliferation or re-activation of virus in manufacturing processes
Robust process control to minimize unevenness of “Custom-Made” products
Limited amount of samples for quality evaluation of products
Allogenic Human Cell/Tissue
History, source, derivation
Donor screening/testing and donor
eligibility
(compatibility with donor qualification
criteria, including ethical and medical
aspects; freedom from the presence
of HBV, HCV, HIV, HTLV and
pulvovirus B19 by screening and
testing; exclusion of potential infection
of CMV, EBV and WNV by testing;
clinical history; experience of blood
transfusion or implanting;genetic etc.) Records of donor
Derivation of cell strain
Cell banking
Viral assay at the final product level
Immunological problems
(eg., rejection, GVHD etc.)
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Points to Consider for doner eligibility
on Autologous CT & Allogeneic CT
17Pharmaceuticals and Medical Devices Agency
Geographic difference
These principles may have been derived
from the experiences of blood transfusion,
so that some different views may exist in
the western world reflecting the different
medical environment
Infectious disease demography
Remunerated/non-remunerated donor
18Pharmaceuticals and Medical Devices Agency
Social and ethical context
The provision of human tissue material
shall be made free of charge. However,
this shall not apply to the compensation
equivalent of transportation expenses and
other actual expenses that occurred upon
the provision of human tissue materials.
In the Japanese regulation
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Other infectious agents
Determine eligibility as a donor, considering the presence
or absence of experience of blood transfusion and
transplantation as well as interviewing anamnesis of the
following listed disease:
Infection by treponema pallidum, chlamydia, neisseria gonorrhoeae,
bacterial such as Mycobacterium tuberculosis
Sepsis
Malignant tumor
Severe metabolic and endocrine disorders
Collagen disease and blood disorders
Liver disease
Transmissible spongiform encephalopathy(TSE) and its suspicion
and other dementia
Specific genetic diseases and family history
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Cell collection, preservation(1)
1. Eligibility of cell/tissue collectors and collecting medical
institutions
Clarify technical requirements for cell/tissue collectors
and collecting medical institutions, handling source
materials
2. Justification of cell/tissue harvest site and collection method
Show the selection criteria and collection method for
collecting site of cells or tissues, clarify that they are
scientifically and ethically appropriate choices.
Regarding cell / tissue collection method, describe and
demonstrate instruments and drugs used, concrete
measures to prevent microbial contamination, mix-up and
cross-contamination .
21Pharmaceuticals and Medical Devices Agency
Cell collection, preservation(2)
3. Prior Informed – consent to Donors
Define the contents of the informed - consent to cells
and tissue donors, including anticipated clinical
applications.
4. protection of personal information of donor
Specifically regulatory and protective measures of
personal information of donors
5. Storage and mix-up prevention measures
Clarify the justification of the storage conditions and
storage period and setting, If the collected cells or
tissues are necessarily to be stored in a certain period.
In addition, explain the means and procedures to
prevent mix-up and confusion.
22Pharmaceuticals and Medical Devices Agency
Elements of Donor informed-consent
(A) Use and application of collected human cell and tissue as raw
materials
(B) Risk and disadvantage expected by the provision of human cell
and tissue
(C) To be a donor is the arbitrary
(D) Right to withdraw the consent
(E) The donor shall not take disadvantage by withdrawal of the consent
of the provision or by non provision of human cell and
(F) Expenses related to the provision of human cell and tissue
(G) Compensation for health damage caused by the provision
(H) Protection of personal information of donor
(I) Patent rights relating to the product derived from the collected
human cell and tissue, copyright and other property rights
(J) Give priority to collection of human cell and tissue materials, not the
cell and tissue diverted from medical treatment, surgery and other
therapeutic treatment.
23Pharmaceuticals and Medical Devices Agency
Recordkeeping
Donner records
The record of donor shall be maintained and stored so
as to verify information required to secure safety of the
cell and tissue as raw material.
In addition, for each experimental sample of the donor
and the patient, the content of information and its
storage measure may depend on the intended use.
24Pharmaceuticals and Medical Devices Agency
Basic Scientific Issues for Product
Development, Evaluation and Control
Justification of source and selection of human cells that serve as raw
materials including autologous or allogeneic donor screening criteria and
eligibility
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Justification of source and selection of animal materials
that serve as culture medium, scaffold, etc. in terms of
virus inactivation/removal and ruminant prion
transmission
25Pharmaceuticals and Medical Devices Agency
The Risk based approach to be taken:
When conducting or evaluating tests on individual product, it is
necessary to take risk based approaches on a case-by-case
basis, in terms of type, characteristics and intended clinical use
of the product in question.
For example: In the use of such an advanced therapeutic product for
treating patients (First-in-Man) with severe and life threatening diseases or
injuries, the risk/risk balance with/without the advanced treatment
should be also taken into account, rather than just discussing unknown
potential risk of a product.
Reflection of scientific progress and accumulation of experience
in relevant field is always encouraged for “unexpected risk”.
Decision making by a patient after extensive IC should be a
crucial element.
26Pharmaceuticals and Medical Devices Agency
Constant revisit on the requirements for the donor
eligibility are needed based on scientific knowledge
For the safe and rapid clinical translation of cellular and tissue based products, source material eligibility requirements are to be revised, based on the latest scientific knowledge on viral safety, the international views on the risk of BSE, etc.
From sound scientific viewpoints, taking into account of characteristics of cellular and tissue based products and their clinical applications.
27Pharmaceuticals and Medical Devices Agency
Example of requirement for biological source materials(Japanese Minimum Requirements for Biological Ingredients)
The purpose
… is to ensure the quality, efficacy and safety of pharmaceutical products, quasi-pharmaceutical products, cosmetics and medical devices (hereafter “pharmaceuticals, etc.”) by establishing standards related to the measures that are required in the event that materials and ingredients used in the manufacturing of these pharmaceuticals, etc. are derived from biological sources (excluding plants) other than the person using the product (including those used during the manufacturing process, such as additives and media components).
MHLW Public Notice No.375 (2014)/No.210 (2003)
28Pharmaceuticals and Medical Devices Agency
Examples of Revisions of requirements(Japanese Minimum Requirements for Biological Ingredients)
1. Countries that can be an origin of ruminant animal-derived
ingredients are expanded to those whose BSE risk became
negligible, according to the latest risk assessment by OIE. (e.g.
Japan and the U.S.)
2. Inactivation and removal of infectious agents from human-
derived ingredients can be omitted, if the reason is justified and
described in the certificate of marketing authorization (e.g.
patient’s serum for culturing an autologous cellular and tissue
based product)
3. the confirmation of the donor animal eligibility and its record as
well as the storage of the record are not required any more, as
long as the therapeutic products have been used at clinical setting
and the animal cell/tissue-based products are produced by culturing
cells derived from a well-characterized cell bank.
MHLW Public Notice No.375 (2014)
29Pharmaceuticals and Medical Devices Agency
Recordkeeping requirement examples in Japan
Record of source information of ingredients derived from allogenic human derived source materials (except using small quantity of albumin as excipient ) :
30 years since the product expiry date
Record for other source materials :
10 years: since the product expiry date
For the product containing the above human derived source materials, The source material specimens must be archived for 10 years since
the expiry date
Medical institutions are required to retain patient record of for 20 years
Japanese GCTP and PMD Act. Ordinance
Taking into account of vCJD window period, like European blood regulations
How long are the source material records retained as a part of GMP(GCTP)?
In the US, 21CFR1271 10 years
30Pharmaceuticals and Medical Devices Agency
Quality System Structure to be
Quality Risk Management/ Knowledge management
Document management system(Product master file, specification, statement, SOPs, record)
Management & Supervision System(release, deviation, change control, self-inspection,
Training/education, complaint management, recall)
Quality control system
(labo. system)
Supplier control system
Manufacturing control system(operation performance of process, Sterility
assurance , Product quality monitoring)
Facility & equipment system(qualification, calibration, maintenance)
Validation / Verification
Product quality review
Reflecting product marketing authorization documents
31Pharmaceuticals and Medical Devices Agency
Consideration for GMP part of GTP
Quality System Requirement for regenerative medical technologies / products, considering the characters of these products; such as raw materials that cannot be sterilized• Quality Risk Management• Manufacturing Control (Sterility assurance,
Prevention of Cross-contamination..)• Quality control (Verification / validation, Quality
review) • Facility requirement
It is necessary to consider whether the risk is manageable,
- not only from the facility point of view,
- but from the effects of the manufacturing operation, such
as the evaluation of performance.
32Pharmaceuticals and Medical Devices Agency
The Act on the Safety of
Regenerative Medicine
PMD Act. (revised PAL)
Example of Japanese GMP(GCTP) regulation
HospitalManufacturer
(Licensed)
Medical technologies using processed cells(except clinical trials under PMD Act. )
Com
missio
n
Cell
collection
Transplant
Cell
Processing
Delivery of cell product
Manufacturer
(Licensed)Obtaining Cell
Regenerative Medical Products
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GMP(GCTP)Cell
processing
Cell
processing
Outsidehospital
GCTP : Good, gene, Cellar and Tissue-based product manufacturing Practice
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Aseptic operation in Manufacturing Control
Sterility assurance of cellular and tissue based products organize sterility assurance and its risk management, based on the
characteristics of the product, equipment and manufacturing operations.
Unique challenges in sterile control of cellular and tissue based product
Difficult to sterilize tissue and cell raw materials themselves, prior to use in the manufacturing process.
Difficult to set the sterilization step in the manufacturing process. High risk of microorganism proliferation if contaminated in the
manufacturing process Unavoidable human intervention may impact consistent contamination
risk in the manufacturing. No methodology of bioburden control has been established
34Pharmaceuticals and Medical Devices Agency
Points to consider in Quality Risk Management
Significance and essence of QRM
QRM will promote understanding of products and
processes, so that you will obtain stronger ability to
assure quality of products manufactured, leading to more
robust quality assurance.
Risk cannot be eliminated
Recognize the risk
Predict, prevent and manage the risk
35Pharmaceuticals and Medical Devices Agency
Understanding of process
Tissue collection↓
cells↓
Primary culture↓
Expansion culture
↓
DifferentiationPurification
↓
Filling↓
Product formulation
Process to obtain / extract the target cells from messy group of cells
Process to propagate only the target cells
Process to make the cells in the formulation
36Pharmaceuticals and Medical Devices Agency
Quality Risk Management Process (ICH Q9)
Quality Risk AssessmentRisk identification
Risk Analysis
Risk Evaluation
Quality Risk ControlAcceptance of risk
Risk reduction
Balance with profit, risk and resources
New risk caused by controling specified
risk
Quality Risk ReviewBuild in review and monitoring system
Review risk acceptance level
in a series of manufacturing processes
37Pharmaceuticals and Medical Devices Agency
Philosophy of Quality Risk Management
From both sides of the equipment and facilities
(hard), quality system (software), set the
achievement level of control, continue to manage it
and to improve, based on whether the potential risk
of individual products is acceptable and
manageable.
To achieve the control level, the philosophy of
GMP/GTP is to implement each documented
quality system in a complementary manner.
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Evaluation of risk in the quality, based on
scientific knowledge, ultimately should be
consequences to patient protection.
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Facility and Equipment
Facility and equipment of cleanliness
controlled area and aseptic operation area
The air conditioning facilities in the aseptic
operation area
The facility for cleaning, disinfection and
sterilization of equipment used in aseptic
areas and for processing waste
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Contamination prevention
Prevention of mix-up and cross-
contamination of human cells during the
manufacturing process is important, so that
the preventive measure measure in process
control should be clarified.
41Pharmaceuticals and Medical Devices Agency
Operational issues for contamination and cross-
contaminations (example 1)
Method of risk reduction for the contamination and
cross-contamination Where it is necessary to handle as a product having an infectivity to
impact on the other product, the dedicated working chamber handling
the products should be considered, unless the validated inactivation
and cleaning procedures were established and carried out.
The necessary measures to prevent contamination and cross
contamination for each step should be carried out in a series of
manufacturing processes., such as inactivation and removal of
bacteria, fungi and viruses,
Cells or tissues harvested from different donors should not be handled
simultaneously in the same location in order to prevent mix-up of the
cells and cross contamination by bacteria, fungi, viruses, etc.,
The necessary measures should be made not to perform improper
storage so as to prevent the risk of mix-up and cross-contamination.
42Pharmaceuticals and Medical Devices Agency
Operational issues for contamination and cross-
contaminations (example 2)
Method of reduction of contamination risk
by mistake As quality control operations of products, in order to
prevent mix-up and cross-contamination of the
samples, to separate the analyte by appropriate labels
and display.
The specimen should be collected from the product, in
the place that was determined in advance, in
accordance with the procedure to prevent
contamination of the collected product or material as
well as to prevent cross contamination of other
products and materials.
43Pharmaceuticals and Medical Devices Agency
More important things
(Knowledge management )
At this point in some site, you have
experienced the followings, don’t you? :
“Ms. X can only culture the cells”
“Dr Y can only identify the target cells”
“Mr Z can only find the result is correct”
“Deviation happened!!, but the test result was
OK, so the batch was OK”
44Pharmaceuticals and Medical Devices Agency
From Knowledge Management to Control Strategy
R&D, clinical trialsProduct
development
Commercial
production
Group
knowledge
Organizational Knowledge
Personal silent
knowledge
・ R&D report・ Knowledge for verification・ Knowledge for validation・ Manufacturing and quality
documentation・ Knowledge for Technical
transfer・ Quality risk management
⇒ Accumulation of Knowledge⇒ Control Strategy
⇒ Manufacturing and quality control
45Pharmaceuticals and Medical Devices Agency
Exploratory Trial Confirmatory Trial
Development
stage
Investigational product
Human subject protection
Level of quality assurance
Requir
ed
assurance
level
In the development phase, quality is also under development. It
would be unreasonable to apply GMP of the commercial product
level. Flexible risk based approach would be more appropriate.
GMP in each stage of development
In an early development
phase, acquired knowledge
is limited, so that
implementable assurance
level may be lower,
however, risk based flexibility
is needed to keep higher level
of assurance
46Pharmaceuticals and Medical Devices Agency
Validation or verification
1. validation or verificationThe purpose is to “validate” the facility and equipment and procedure
at the manufacturing site are giving the expected result, or to “verify ”
they have given the expected result.
The documentation of validation or verification is intended to
allow constant manufacturing of quality compatible products.
⇒ After identified variables, normally the sponsor validates “three
lots” of manufacturing control and quality control methods give the
expected results.(prospective validation)
2. VerificationThe implementation of process validation is difficult
manufacturing process
• Manufacturing experience is limited
• Quantitative limitation of the specimen due to ethical reasons,
• technical limitations
To verify and document manufacturing procedures have given the
expected results for each product for each lot number or batch number
47Pharmaceuticals and Medical Devices Agency
GXPs are not only for quality assurance
in a product life cycle
GTP
GLP (Good Laboratory Practice) for animal study
GCP (Good Clinical Practice) for human clinical
trials
GVP (Good Vigilance Practice) for post-
authorization safety practices including handling
AE reporting and post-authorization studies
48Pharmaceuticals and Medical Devices Agency
System of general guidelines for quality and
safety(pre-clinical) for Human Cell & Tissue-
Based Products since 2000.
Guideline on Ensuring Quality and Safety of Products
Derived from Engineered Human Cells/Tissue
PFSB/MHLW Notification No.1314 Appendix 2 (2000)
Guideline on Ensuring Quality and Safety of Products
Derived from
Processing Human (Autologous) Cells/Tissue
PFSB/MHLW Notification No.0208003 (2008)
Guideline on Ensuring Quality and Safety of
Products Derived from
Processing Human (Allogenic) Cells/Tissue
PFSB/MHLW Notification No.0912006 (2008)
Guidelines on Ensuring Quality and Safety of
Products Derived from Processing :
Human (Allogenic) Somatic Stem Cells
PFSB/MHLW Notification No.0906-3 (2012)
Human (Allogenic) iPS-like Cells
PFSB/MHLW Notification No.0906-5 (2012)
Human Embryonic Stem Cells
PFSB/MHLW Notification No.0906-6 (2012)
Guidelines on Ensuring Quality and
Safety of Products Derived from Processing :
Human (Autologous) Somatic Stem Cells
PFSB/MHLW Notification No.0906-2 (2012)
Human (Autologous) iPS-like Cells
PFSB/MHLW Notification No.0906-4 (2012)
Standard for Biological Ingredients
MHLW Public Notice No.210 (2003)
General Principles for the Handling and Use of
Cells/Tissue-Based Products
PFSB/MHLW Notification No.1314 Appendix1(2000)
Good Tissue Practice
Basic TechnicalRequirements
48
49Pharmaceuticals and Medical Devices Agency
Thank you for your attention
Daisaku Sato, PhD.Director, Office of Cellular and Tissue-based Products
Pharmaceuticals and Medical Devices Agency (PMDA),
Japan
49
Regenerative medicine literature available in English
Hara A. Sato D. Sahara Y. New Governmental Regulatory System for Stem Cell–Based Therapies in
Japan. Therapeutic Innovation & Regulatory Science. 2014; 48(6): 681-688.
Special thanks to our staff members!