Provisional Translation (as of March 2010) ∗

PFSB/ELD (Iyakushin) Notification No.0213001

February 13, 2003

To: Directors of Pharmaceutical Affairs Divisions

Prefectural Governments

From: Director of Evaluation and Licensing Division,

Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare

Basic Principles of Biological Safety Evaluation Required for

Application for Approval to Manufacture (Import) Medical Devices

Among data to be submitted when applying for approval to manufacture (import) medical devices,
the data relating to biological safety have been handled according to the PAB/MDD (Yakuki)
Notification No.99, dated June 27, 1995, “Guidelines for Biological Tests Required for Application
for Approval to Manufacture (Import) Medical Devices.” However, the guidelines have been
abolished, and the basic principles for risk evaluation of adverse biological effects (toxic hazards)
and biological safety evaluation have newly been stipulated as shown in the attached sheets.
Accordingly, you are requested to provide your guidance to relevant business parties and
organizations under your jurisdiction.

This Notification shall apply to medical devices for which applications for approval are to be
submitted on and after April 1, 2003; however, the risk evaluation of adverse biological effects
(toxic hazards) and testing for that purpose may be performed, based on this Notification, with
respect to medical devices for which applications for approval are to be submitted from February 13,
2003 onwards.

Please note that copies of this Notification will be sent to the Board Chairperson of the Japan
Association for the Advancement of Medical Equipment; the Chairman of the Japan Federation of
Medical Devices Associations; the Chairman of Medical Devices and Diagnostics Subcommittee,
the American Chamber of Commerce in Japan; and the Chairman of the Medical Equipment
Committee, the European Business Council in Japan.

∗
This English version of the Japanese Notification is provided for reference purposes only. In the event
of any inconsistency between the Japanese original and the English translation, the former shall prevail.

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 Basic Principles for Biological Safety Evaluation

1. Purpose
This document, as a tool for safety evaluation of medical devices prior to marketing, provides
basic principles for risk evaluation of adverse biological effects (toxic hazards) and biological
safety evaluation/test.

2. Definitions
Definitions of terminology utilized in this document shall be as follows:
1) Material
Refers to a material for medical devices or a material used in the manufacturing processes
for medical devices (including test/inspection process and sterilization process), such as
synthetic or natural polymer compounds, metals, alloys, ceramics and other chemical
substances.
2) Finished product
Refers to a post-test/inspection medical device ready for shipment and, in the case of a
sterile product, refers to a product after sterilization. However, in the event that the shipped
product is to be processed and prepared for use, “finished product” is a product in a state
where it is actually used.
3) Hazard
Refers to a factor that may cause adverse effects on human health, such as genotoxicity,
sensitization or chronic systemic toxicity.
4) Risk
Refers to a probability and a degree of such a hazard that causes an adverse effect on
human health.

3. Adoption of International Standards

As a rule, biological safety evaluation of medical devices shall be performed in compliance
with the ISO 10993 “Biological Evaluation of Medical Devices” series as international
standards. Specifically, based on the framework and principles of ISO 10993-1 “Evaluation and
Testing,” the necessary evaluation items shall be selected corresponding to the nature and
duration of contact of individual medical devices with the body. In addition, safety evaluation is
conducted through the selection of appropriate test methods for each evaluation item by
referring to the guidelines for test methods described in the ISO 10993-2 and other parts.

The test method guidelines in the ISO 10993 series generally include lists of multiple test
methods for each evaluation item. For those test methods indicated, it is not clearly specified
how to apply a given test method to each medical device or how to use the results obtained
using such test methods when evaluating each medical device. Before conducting the tests,
therefore, it is important to select an appropriate test method based on the following clauses 4 to
8.

The international standards have been continuously revised according to the development of
science and technology. Accordingly, an appropriate test method must be selected, considering
the most current international standards at the time when testing is conducted.

4. Principles of Biological Safety Evaluation

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1) Biological safety evaluation of materials or medical devices must be carried out using risk
analysis techniques specified in ISO 14971 “Medical Devices - Application of Risk
Management to Medical Devices.” The intended use/intended purpose and the safety
properties of a medical device must be clarified, known or foreseeable hazards must be
identified, and the risk of each hazard must be anticipated. If such a risk analysis technique
is employed, its positive results represent detection and identification of some hazards and
do not necessarily mean non-conformity of the medical device. The safety of such medical
device must be evaluated through continued risk analyses.

2) Biological safety evaluation must be comprehensively carried out based on the results of
safety tests conducted in accordance with this Notification and the following information,
test results for safety evaluation items specific to such medical device, the latest relevant
scientific literature and other non-clinical studies and clinical experiences (including post-
marketing surveillances), taking the risk-benefit profile into consideration.
a) Information relating to materials
b) Information relating to contaminants generated from materials or during the
manufacturing processes or their residues
c) Information relating to leachable substances (for example, qualitative and quantitative
chemical properties of the substances leached from the finished product)
d) Information relating to biodegradation
e) Information relating to other components and their interactions in a finished product
f) Properties and characteristics of the finished product

3) Biological safety evaluation must be conducted by experienced specialists with sufficient

education and training.

4) If the case falls under any of the following conditions, biological safety evaluation must be
performed, however, the necessity to carry out re-tests or add test items must be considered
thoroughly. For example, if the amount of leached substances is negligible from a
toxicological standpoint or if their toxicity is known and acceptable, it is not necessarily
required to conduct the re-tests.
a) Change of suppliers or any change in the specifications of the materials used for the
product.
b) Any change in the materials, formulation, manufacturing processes, sterilization or
primary packaging of finished products.
c) Any change observed in the finished products during the storage period.
d) Any change in the intended use of the finished products.
e) Any evidence that the product may cause adverse events.

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5. Selection of Evaluation Items
1) Items to be evaluated for the biological safety of each medical device shall be selected by
following the requirements specified in ISO 10993-1. As a general rule, evaluation must be
made for the items shown in Table 1, depending on the categorization in accordance with
the nature of body contact and the duration of contact as described below. When evaluation
is made for a medical device that does not fall into any of the categories, the closest
category should be selected. If multiple categories for the duration of contact apply to the
medical device, the item that corresponds to the category with the longer duration should be
evaluated. When there are categories applicable to multiple regions of contact, the items that
correspond to each category should be evaluated.

i) Categorization by Nature of Body Contact of Medical Device

a) Non-contact devices: Medical devices that do not contact the patient’s
body directly or indirectly
b) Surface devices:
〇 Skin Medical devices that contact intact skin surfaces
only
〇 Mucous membranes Medical devices that contact intact mucous
membranes such as oral cavity, esophagus and
urethra
〇 Breached or compromised surfaces
Medical devices that contact breached or
otherwise compromised skin or mucous
membranes
c) External communicating devices
〇 Blood path, indirect Medical devices that contact blood path at one
point and serve as a conduit for drug entry into
the vascular system
〇 Tissue, bone, or dentin Medical devices that contact tissue, bone, or
pulp and dentin system
〇 Circulating blood Medical devices that contact circulating blood
d) Implant devices
〇 Tissue or bone Medical devices that contact tissue and/or bone
〇 Blood Medical devices that principally contact blood

ii) Categorization by duration of contact

〇 Limited contact Medical devices with a contact duration of less
than 24 hours
〇 Prolonged contact Medical devices of which single, multiple or
longer-term use has a contact duration of not less
than 24 hours and up to 30 days
〇 Permanent contact Medical devices of which single, multiple or
long-term use has a contact duration exceeding
30 days

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 2) Evaluation of equivalence to already approved medical devices or evaluation according to
appropriate published literature is acceptable in lieu of the evaluation for the items shown in
Table 1, and it is not necessarily required to conduct all of the test items shown in Table 1.
In this case, however, it is necessary to clearly determine such appropriateness.

3) Table 2 should be referred based on the duration of contact, nature of contact with the
medical device and characteristics of materials, and then it should be considered whether
there is a need to conduct tests regarding chronic toxicity, carcinogenicity,
reproductive/developmental toxicity and biodegradation.

4) As for acute systemic toxicity, subacute toxicity and chronic toxicity, if the implant testing
or simulated use testing includes observation items and biochemical data that are needed for
those toxicity tests, it is possible to use the testing results in lieu of those of such toxicity
tests.

5) The biological safety evaluation with only those items shown in Table 1 or Table 2 may be
insufficient in some cases or in other cases, a simple application of substitute tests may not
be possible, and thus evaluation items must be investigated, taking the properties of the
medical device into account adequately. For example, the below mentioned tests are
insufficient for tooth pulp stimulation testing for composite resin or contact lens trials. It is
necessary to conduct the evaluation on immunotoxicity if the immunotoxicity is suspected
from the results of toxicity tests and other data. Also, it may be difficult to simply apply the
below mentioned tests to cell/tissue engineered medical devices.

6. Test Methods
1) In the guidelines for test methods specified in the ISO 10993 series, various test methods for
each evaluation item are listed in parallel, but which test method should be selected from
among them is not indicated. When there are multiple test methods for a given evaluation
item, selection must be done taking into account the principles, sensitivity, selectivity,
quantitative capability, and reproducibility of the test methods as well as application method
and limitation of test samples, with respect to the significance of the biological safety
evaluation for the medical device in question. For example, the following items should be
considered as to tests for cytotoxicity, sensitization and genotoxicity.

a) In the case of cytotoxicity, ISO 10993-5 “Tests for In Vitro Cytotoxicity” includes the
extraction test method (colony method or subconfluent method), the indirect contact
method (agar overlay method, filter diffusion method) and the direct contact method
(direct contact via the subconfluent method). Since the sensitivity, quantitative
capability, etc. of these test methods are varied, in order to detect potential hazards for
risk evaluation, it is necessary to use a quantitative test method with high detection
sensitivity (for example, the extraction test method).

b) Regarding tests for sensitization and genotoxicity, in particular, if the concentration of

leached substances in the test solution is low for some extraction solvents, the volume
of leached substances used in testing is limited, which may lead to false negative
results. The provisions relating to extraction solvents in ISO 10993-12 state that a
stressed extraction method must also be considered to detect potential hazards for risk
evaluation. To evaluate the toxicity of unknown substances contained in a medical
device, a solvent with a high extraction rate must be selected.

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 2) It is not logical to establish a uniform test method nor is it necessary to adhere to a specific
test method. However, it is essential to clarify the basis and justification for the judgment
that the results obtained using the selected test methods meet the requirements for
evaluating safety in clinical use.

7. Test Samples
1) Test samples used in testing for biological safety evaluation of medical devices include
finished products, parts of a finished product and materials. Among them, a suitable test
sample must be selected by investigating its ability to evaluate the safety of a finished
product and by demonstrating scientific justification for the selection.

2) Many medical devices are manufactured by combining multiple materials, and the
manufacturing processes (including the sterilization process) can chemically alter the
materials. If the manufacturing processes chemically alter the materials, testing must be
conducted using test samples taken from the finished product or using simulated test
samples manufactured under the same conditions. If the manufacturing processes do not
alter the materials chemically, testing may be conducted using the materials as the test
sample.

3) When the chemical substances as part of the materials are changed to new chemical
substances but are not chemically altered, and if it is more reasonable to conduct tests on
such chemical substances than tests using the materials or finished product as the test
sample, from a viewpoint of conducting both the tests and the evaluation, the former tests
can replace the latter.

8. Animal Welfare
The treatment of animals used in animal testing is performed according to the Law for the
Humane Treatment and Management of Animals and ISO 10993-2 “Animal Welfare
Requirements.”

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 Table 1 Guidelines for Primary Evaluation

Category Duration of contact Biological test

A: Limited contact

Irritation/intracutaneous

Acute systemic toxicity

(< 24 hours)

Hemocompatibility
Subacute toxicity
B: Prolonged contact

Pyrogenousity
Nature of contact (24 hours - 30 days)

Genotoxicity
Sensitization

Implantation
Cytotoxicity

reactivity
C: Permanent contact
(> 30 days)

Non-contact devices
A 〇 〇 〇
Skin B 〇 〇 〇
C 〇 〇 〇
A 〇 〇 〇
Surface devices Mucous membrane B 〇 〇 〇
C 〇 〇 〇 〇 〇
A 〇 〇 〇
Breached or
B 〇 〇 〇
compromised surface
C 〇 〇 〇 〇 〇
A 〇 〇 〇 〇 〇 〇
Blood path, indirect B 〇 〇 〇 〇 〇 〇
C 〇 〇 〇 〇 〇 〇 〇
External A 〇 〇 〇
communicating Tissue/bone/dentin B 〇 〇 〇 〇
devices C 〇 〇 〇 〇
A 〇 〇 〇 〇 〇 〇
Circulating blood B 〇 〇 〇 〇 〇 〇 〇
C 〇 〇 〇 〇 〇 〇 〇 〇
A 〇 〇 〇
Tissue/bone B 〇 〇 〇 〇
C 〇 〇 〇 〇
Implant devices
A 〇 〇 〇 〇 〇 〇 〇
Blood B 〇 〇 〇 〇 〇 〇 〇 〇
C 〇 〇 〇 〇 〇 〇 〇 〇 〇

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 Table 2 Guidelines for Supplemental Evaluation

Category Duration of contact Biological test

A: Limited contact (< 24 hours)

Chronic toxicity

Carcinogenicity

Biodegradation
developmental
Reproductive/
Nature of contact B: Prolonged contact (24 hours - 30 days)

toxicity
C: Permanent contact (> 30 days)

Non-contact devices
A
Skin B
C
A
Surface devices Mucous membrane B
C
A
Breached or
B
compromised surface
C
A
Blood path, indirect B
C 〇 〇
A
External communicating
Tissue/bone/dentin B
devices
C 〇
A
Circulating blood B
C 〇 〇
A
Tissue/bone B
C 〇 〇
Implant devices
A
Blood B
C 〇 〇