Update on the regulatory framework for biocidal products in Japan

Keisuke Ozaki, D.V.M., Ph.D., D.J.S.T.P., General Manager, Regulatory Affairs & Chemical Safety Dept.

Environmental Health Division, SUMITOMO CHEMICAL CO., LTD.

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• Japanese Pharmaceutical Affairs Law (JPAL) • Organization for evaluate biocidal products in Japan • Flowchart for evaluation and approval • Good vigilance practice (GVP) • Insecticide Standards of Japan • Biocidal product under Chemical Substance Control

Law (CSCL). • Japan Household Insecticide Industry Association • HHI market overview and typical product type

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Contents

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In Japan, Biocide is regulated under Japanese Pharmaceutical Affairs Law (JPAL), together with pharmaceutical products for human or animals, cosmetics and medical devices.

USA; FIFRA (Federal Insecticide, Fungicide, Rodenticide Act) together with pesticides. EU; BPR (Biocidal Product Regulation)

JPAL has NO TG registration system for biocides, but only product registration (Revised JPAL in 2006).

The Pharmaceutical Affairs Law

Article 1, Objectives This Pharmaceutical Affairs Law contains specifications required to ensure the quality, efficacy and safety of drugs, quasi-drugs, cosmetics and medical devices and its aims is to improve the public health by taking measures necessary to promote the development of drugs and medical devices required for healthcare.

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Ref: Drug Approval and Licensing Procedures in Japan 2006

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The Pharmaceutical Affairs Law

Ref: Drug Approval and Licensing Procedures in Japan 2006

Article 2 Definition of drugs (1) The items listed in the Pharmacopoeia of Japan (JP).

(2) The items (other than quasi-drugs) which are intended for use in the diagnosis, treatment and prevention of disease in humans or animals and which are not classified as devices, dental materials, or medical or sanitary supplies.

Biocidal A.Is are included in this category.

6 Ref: Drug Approval and Licensing Procedures in Japan 2006

Article 2, Quasi-drugs Quasi-drug are products used for the following purpose. They must be substances which act mildly on the human body or the similar substances designated by the MHLW.

(1) Articles intended for the uses specified in the following ①to ③ excluding equipment/instruments etc.(excluding drugs) ① To prevent nausea or other discomfort, or bad breath or body odor. ② To prevent heat rash, festering, etc. ③ To prevent the loss of hair, or to grow or remove hair.

(2) Articles intended for the uses to exterminate or prevent rats, flies, mosquitoes, fleas, etc. in order to ensure the health and hygiene of humans or animals excluding equipment/instruments etc. (excluding drugs)

Generally, biocidal products are included in this category

Classification of insecticides under the Pharmaceutical Affairs Law

1. Quasi-drugs. • Commonly, the products containing pyrethroids are

classified as quasi-drug. (Coil, Mat, LV, Aerosol, One push etc.) • Bait station • Repellent (DEET) 2. Drugs • Others should be classified as drugs. (Fumigant, Total release aerosol)

7 Ref: Drug Approval and Licensing Procedures in Japan 2012

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MHLW

PMDA: Pharmaceuticals and Medical Devices Agency Incorporated administrative agency External agency The third party

Request Report

Ministry of Health, Labour and Welfare

Ref: PMDA profile of services

Pharmaceuticals and Medical Devices Agency (PMDA)

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1. Development history 2. Oversea registration information 3. Comparison with current formualtion 4. Physical & Chemical data, specification, analytical method 5. Stability studies (long-term, accelerated, at other conditions) 6. Toxicological studies Acute, Subacute, Chronic, Reproductive toxicity, Mutagenicity, Sensitization and Metabolism. ★Risk assessment of human health should be discussed 7．Efficacy study From 2005, the registration system for A.I. was disappeared. Therefore, only the product registration system in Japan.

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Data requirement of product containing New A.I.

Ref: Drug Approval and Licensing Procedures in Japan 2012

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Item Study USA EU Japan Item Study USA EU Japan

Acute

Oral – Rats ○ ○ ○ Carcinogenicity

2Y Oral – Rats △ ○

Oral – Dogs ○ 1.5Y Oral – Mice △ ○

Dermal – Rats ○ ○ ○ Neurotoxicity

Acute Oral – Rats ○

Inhalation – Rats ○ ○ ○ 90days Oral – Rats ○

Sub Chronic

30days Oral – Rats ○

Reproduction

Teratogenicity

ICH-Ⅰ – Rats ○

30days Inhalation – Rats ○ ○ ICH-Ⅱ- Rats ○

90days Oral – Rats △ ○ ○ ICH-Ⅲ- Rats ○ ○ ○

90days Oral – Dogs △ ○ ○ ICH-Ⅲ – Rabbits ○ ○ ○

90days Dermal – Rats ○ Two gen – Rats ○ ○

90days Inhalation – Rats △ ○ Irritation

Eye – Rabbits ○ ○ ○

Chronic 1Y Oral – Rats △ ○ ○ Skin – Rabbits ○ ○ ○

1Y Oral – Dogs ○ Sensitization Skin – Guinea pig ○ ○ ○

Muta-genicity

Ames ○ ○ ○ Immunotoxicity Oral – Rats ○

in vitro Mammalian cell ○ ○

Chromosome abberration ○ ○ ○ Metabolism

Single dose – Rats △ ○ ○

in vitro Micronucleus ○ △ ○ Repeated dose – Rats △ ○ ○

in vivo Micronucleus ○

Unscheduled DNA synthesis

△ △ Pharmacology General

Pharmacology ○

Regulatory studies required by Competent Authority - Human health (Toxicology) -

○; Required, △; Conditionally required

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Item Study USA EU Japan Item Study USA EU Japan

Fish toxicity

Acute toxicity – Bluegill ○ ○

Avian toxicity

Acute Oral – Quail ○

Acute toxicity – Carp ○ Dietary toxicity - Quail ○

Early life stage ○ Reproduction ○

Daphnia Acute toxicity ○ ○

Honey bee Acute Contact ○

Whole life stage ○ Acute Oral ○

Marine organism

Acute – Oyster ○ ○ Earthworm Acute ○

Acute – Hyalella azteca ○

E-fate

Hydrolysis ○ ○

Acute – Fathead minnow ○ Aquatic photo degradation ○

Chironomid Bottom sediment △ Gas photo degradation △ ○

Aquatic Organism

Tier I ○ Soil degradation △ ○

Tier II △ ○ Adsorption desorption – Soil ○ ○

Terrestrial organism

Vegetative vigor △ Adsorption coefficient ○

Activated sulge Respiration inhibition ○ Bioaccumula

tion

Bluegill △ ○

Degradation ○ ○ Carp ○

Regulatory studies required by Competent Authority - Environment (Eco toxicity, E-fate) -

○; Required, △; Conditionally required

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Acute/Subacute/Chronic Reproduction Mutagenesis Irritation etc.

Human exposure (Exposure)

Toxicological data (NOAEL)

A.I. concentration in air

Risk assessment of HHI product

𝑴𝑴𝑴𝑴𝑴𝑴 𝒐𝒐 𝑬𝑬𝑬𝒐𝑬𝑬𝑴𝑬 𝑴𝑴𝑬 =𝑵𝑴𝑵𝑬𝑵

𝑬𝑬𝑬𝒐𝑬𝑬𝑴𝑬

MOE > 100 : Safety

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Review timeline of PDMA Product containing

New A.I. Product containing

Existing A.I.

Approval ~ 2 years for New AI ~10 month for Existing AI

submission Applicator

PMDA Inquiries important issue

Expert discussion Review report preparation

MHLW Reviews by drug committees

Judgment

Review & Report

CONFIDENTIAL, ALL RIGHTS RESERVED

Good Vigilance practice (GVP)

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Medical institutions

Company

• Collection/confirmation of information regarding quality, efficacy, and safety of drugs and medical devices

• Analysis • Considering safety

measures • Implementing safety

measures

PMDA

• Corporate hearing ↓

• Data collection/analysis ↓

Discussion with experts

↓ • Reporting the results of

review/ analysis

Medical institutions/General public

MHLW

• Tracking all the information

• Planning/development of safety measures

• Implementation of safety measures

Broad dissemination of information

Including drugs, quasi-drugs

Ref: PMDA profile of services (revised)

Flowchart of Relief Services

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PMDA Minister of MHLW

Medical institutions Pharmacies

Adverse health effects sufferers

Company

Claim for benefits

Notice & Payment

Distribution

Prescribed Purchased

Adverse Drug reaction Contributions

Request for judgment

Notice of judgment

Ref: PMDA profile of services (revised)

Including drugs, quasi-drugs

Insecticide Standards of Japan • Insecticide Standards was first published in 1965. It contains the

specifications and analytical methods of approved active ingredients and products.

• Unlike the Pharmacopoeia of Japan (JP), Insecticide Standards is a semi-official document.

• In fact, the A.I. which specification meets the Insecticide

Standards can be used. • Recently, MHLW intend to revise the Insecticide Standards

(1990) . Adding the Efficacy and Safety Parts into the Insecticide Standards.

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Item (%) Approval Spec.

Insecticide Standard(Draft)

Remark

A.I. content 90.0% min. 90.0～96.0% - Impurity (A) 3.0% max. 7.0% max.

(As total impurities) New unknown impurities other than A to D can be included.

Impurity (B) 1.0% max. Impurity (C) 0.5% max. Impurity (D) 4.0% max.

Insecticide Standard of A.I (example)

• There are no limitation of each impurity content. Therefore, it seems that Insecticide Standards doesn’t pay attention to existing and unknown impurities.

• It is well known that some kinds of impurities have high toxic potential. And the impurities issue is a major point for equivalence.

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• For ensure the product safety, approval specification contains each impurity. Especially, regarding the more than 0.1% impurity, its specification is strictly controlled in EU and US.

• However, in Japan, only the total impurities contents is listed in the Insecticide Standards as a rough specification.

• Therefore, we cannot discuss the A.I equivalency or same product issue based on such insufficient specification of the Insecticide Standard.

• We are now negotiating with the MHLW to ask them to set more

strict specification or list each impurity for ensure the product safety.

Concerning points of Insecticide Standards* (* Only applicable for Biocides in Japan)

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Chemical Substance Control Law (CSCL)

• Authority: Ministry of Economy, Trade and Industry, Ministry of Health, Labour and Welfare, Ministry of the Environment. • Japan version of the REACH. • The unique point of CSCL: • If the CLAIM of insecticide product is for agricultural pest insects,

the product should be regulated by the law of pesticide. • If the CLAIM of insecticide product is for sanitary insect, the

product should be regulated by the law of pharmaceutical. • If the CLAIM of the insecticide product is for the insects such as

ants, wasp, moths, the containing active ingredients same as for hygiene pests fall into Chemical Substance Control Law (just a notification required). 20

Regulation for biocides in Japan

Fly, Mosquito, Cockroach, Flea, Louse, Mite, etc.

Hygiene pests

Grasshopper, Shield bug, Aphid, Thrips, Bark beetle, Skin beetle, Cabbage moth, Beet armyworm, etc.

Agricultural pests

Shield bug, Moth fly, Carpet beetle, Bark beetle, Spider, Slug, Millipede, Wood louse, Ant, Sow bug, Clothes moth

Nauseous insects Clothing insects

Wood attacking insects

Pharmaceutical Affairs Law (Regulatory authority: MHLW)

Chemical Substance Control Law (Just a notification needed.)

Pesticide Legislation (Regulatory authority: MAFF)

Biocide regulation in Japan

Fly, Mosquito, Cockroach, Flea, Louse, Mite, etc.

Hygiene pests

Shield bug, Moth fly, Carpet beetle, Bark beetle, Spider, Slug, Millipede, Wood louse, Ant, Sow bug, Clothes moth

Nauseous insects Clothing insects

Wood attacking insects

Pharmaceutical Affairs Law (Regulatory authority: MHLW)

Chemical Substance Control Law (Just a notification needed.)

・Should be regulated together with more organized law like BPR. ・Competent Authority in Japan shared same concern.

Japan Household Insecticide (HHI) society Established：1971 Objective：Improve the Japan HHI industry. Member：17 companies Action: Development Regulation research Prevail safety information of insecticide for consumer Negotiation with authority HP： http://sacchuzai.jp/index.html

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Product type of biocide in Japanese market

Mosquito Coil Liquid vaporizer Fan device Aerosol(FIK)

Total release aerosol Fumigant

Resin device

Bait station Aerosol(CIK)

Repellent One push aerosol EC or Powder 24

Ref: http://sacchuzai.jp/howto.html

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History of Device improvement

Trend of market Convenience Low temperature ECO friendly

Creating the new market based on the new A. I development.

Resin type product No need to heating and power.

-

2,000

4,000

6,000

8,000

10,000

12,000

75,000

80,000

85,000

90,000

95,000

100,000

105,000

2005CY 2006CY 2007CY 2008CY 2009CY 2010CY 2011CY 2012CY 2013CY

Total

Non registered

Resin

LV

Aerosol (FIK)

Coil

Deet

Smoke

Fruit Fly

Aerosol (CIK)

Meter dose aerosol

Fan

Stationary (herb)

Mat

Trend of formulation in Japanese HHI market （Million JPY）

（Left axis)

（Million JPY）

Confidential

Thank you for your attention

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