gxps - pmda.go.jp · scientific review, gmp/glp/gcp inspection and consultation on the development...

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.


Introduction of PMDA

Pharmaceuticals and Medical Devices Agency (PMDA)

an Incorporated Administrative Agency (IAA)

PMDA’s Safety Triangle

Tokyo, JAPAN


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


Two Acts regulating regenerative medicine & cell therapy

4

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


It may be similar to Hospital exemption

of the EU or PHS 361 in the US

MHLW process PMDA process


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


1. What are GXPs?

2. GTP

3. GMP (=GCTP)

4. Other GxPs

Today’s Topics


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


Purpose of GTP

“to prevent the introduction, transmission,

and spread of communicable diseases by

HCT/P's.”


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


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

10

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


Basic Scientific Issues for

Product Development, Evaluation and Control

Suitability and quality control of raw materials and

manufacture-related substances other than target

cells

11

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


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

12

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


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)

13


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.


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.


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.)

11

Points to Consider for doner eligibility

on Autologous CT & Allogeneic CT


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


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


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


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 .


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.


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.


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.


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

24

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


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.


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.


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)


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)


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


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


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.


The Act on the Safety of


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

32

GMP(GCTP)Cell

processing

Cell

processing

Outsidehospital

GCTP : Good, gene, Cellar and Tissue-based product manufacturing Practice


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


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


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


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


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.


Evaluation of risk in the quality, based on

scientific knowledge, ultimately should be

consequences to patient protection.


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


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.


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.


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.


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”


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


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


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


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


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


Human Embryonic Stem Cells


Guidelines on Ensuring Quality and

Safety of Products Derived from Processing :

Human (Autologous) Somatic Stem Cells


Human (Autologous) iPS-like Cells


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


Thank you for your attention

Daisaku Sato, PhD.Director, Office of Cellular and Tissue-based Products

Pharmaceuticals and Medical Devices Agency (PMDA),

Japan

[email protected]

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!

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