Revision of the Guideline on the Impurities in the Medicinal Products with New Active Ingredients TABLE OF CONTENTS I. PFSB/ELD Notification No. 0624001 - Main II. PFSB/ELD Notification No. 0624001 - Attachment containing the annotated text of the Q3B(R) Guideline Explanatory note The PFSB/ELD Notification No. 0624001 refers to and contains the translation into Japanese of the ICH document Q3B(R) "Impurities in New Drug Products (Revised Guideline)" under the Quality topic Q3: Impurities. The Guideline was adopted at the Steering committee and the Expert Working Groups meeting held in February 5, 2003 in Chiba, Japan. The Q3B(R) Guideline was adopted for implementation Step 5 and enforced in Japan by the present PFSB/ELD Notification No. 0624001. The main part of the PFSB/ELD Notification No. 0624001 contains the text enforcing the Q3B(R) Guideline in Japan. The annotated text of the Q3B(R) Guideline contains remarks added by the PFSB/ELD to the translation in Japanese. Here, the remarks are translated in English and placed at the relevant paragraphs of the texts of the Guideline. Main text MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0624001 June 24, 2003 To: Each metropolitan and prefectural Head of Public Health Department (bureau) From: Director Evaluation and Licensing Division Pharmaceutical and Food 　　　Safety Bureau, MHLW Revision of the Guideline on the Impurities in the Medicinal Products with New Active Ingredients 　　　The guidance for the registration applications in regard to the content and qualification of impurities in new drug substances produced by a chemical synthesis is provided in the " Guideline on the Impurities in the Medicinal Products with New Active Ingredients" (Pharmaceutical Bureau Notification No. 539 of June 23, 1997) However, under the agreement of The International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (hereafter the "ICH"), the Guideline for Impurities in New Drug Substances has been revised as indicated in the attached document. Therefore, I request you to direct the relevant organizations under your jurisdiction concerning the items indicated below. In addition to the above, copies of this notification will be sent to the Chairman of the Federation of Pharmaceutical Manufacturers Associations of Japan and the heads of other relevant organizations. Description 1. Application (1) The applications for approval of medicinal products containing new active ingredients submitted after November 1, 2004 have to be prepared pursuant to "Guideline on the Impurities in the Medicinal Products with New Active Ingredients". 2. Notes (important points) (1) As the identification threshold and qualification threshold have been modified and numbers rounded off to the nearest hundred are applied to all cases, we request you to handle the comparison with the threshold, specifications, and analytical rates to create applications for approval of manufacturing (importing) accordingly. (2) The criteria regarding the specifications of impurities are detailed in the "On the Specifications for Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products" (PMSB/ELD Notification No. 568 dated May 1, 2001). Furthermore, refer to the present Guideline for the specifications of impurities. Annotated Attachment Guideline on the Impurities in the Medicinal Products with New Active Ingredients Contents 1. Introduction 1.1 Purpose of the Guideline 1.2 Background 1.3 Coverage of Guideline 2. Description of data that becomes grounds of resolution product management 3. Analytical methods 4. Report of amount of resolution product in lot 5. Resolution product that should be set to standard 6. Confirmation of safety of resolution product 7. Definition of term Appendix 1: Threshold of resolution product in medicine made of new Appendix 2: Example of having shown how to report on amount of resolution product in attached material to judge whether structural decision and confirmation of safety are necessary Appendix 3: Flow chart for structural decision of resolution product and confirmation of safety 1. Introduction 1.1 Purpose of guideline This guideline shows the indicator that is the application for approval concerning the confirmation of the amounts of impurities of the drug product (Hereafter, it is said, "Medicine made of new") manufactured by using the original medicine (Hereafter, it is said, "New drug substance") manufactured from a chemical synthesis method among the drug with new active ingredientss and the safetys. 1.2 Background This guideline is the one that "Guideline concerning impurities of an original medicine of the drug with new active ingredientss" (medicine Shinta No.1216001 on December 16, 2002)(Hereafter, it is said, "ICH-Q3A(R) guideline") is supplemented, and refer to this guideline for a basic idea. Refer to "Residual solvent guideline of the medicine" (medicine Shin No.307 on March 30, 1998)(Hereafter, it is said, "ICH-Q3C guideline") if necessary. 1.3 Coverage of guideline This guideline, Impurity..medicine..resolution..product..medicine..drug additive..directly..container..reaction..product..as follows..both..additionally..resolution..product..say..for.About impurities that exist in the new drug substance, an individual standard need not be targeted in this guideline if the impurities are not resolution products and be set. (Hereafter, it .."Standard of a new medicine and setting of the examination method" (medicine Shin departure No.568 on May 1, 2001)(.. is said, "ICH-Q6A guideline". Refer to). )｡ Impurities or receptacles of the admitted medicine additive origin/Sen ..giving.. system doesn't target ..melting.. impurities that do De in this guideline in the medicine made of new. Moreover, this guideline is not an intention of application to the medicine made of new used at the clinical trial stage. The drug product of the enumerated type is not targeted in this guideline as follows: The medicine of half synthetic medicine that makes a biological preparation, a biotechnology application medicine, peptide, Origonucreotid, a radioactive medicine, the fermentation product, and the fermentation product a raw material, the herbal medicine, and the flora and fauna origin. In addition, impurities whose treating as a problem of GMP with the mixing material from the outside that not is that it is sure to be contained in the medicine made of (1) new originally is a palm body of the more appropriate one, (2) crystal multi type, and (3) original medicine (Enantiomar) are not targeted in this guideline. 2. Description of data that becomes grounds of resolution product management The summary concerning the resolution product admitted in the soundness test while manufacturing the medicine made of new is described to attached material. When describing, it summarizes it based on a chemical evaluation of impurities caused by the interaction with resolution route, drug additive, and direct container/Hodocosen system to which an original medicine in the medicine made of new is presumed. In addition, the summary of the test research executed to detect the resolution product in the medicine made of new is described to attached material. The examination result of the typical lot manufactured in the process of reflecting the lot and the real production manufactured from the development phase is included in this summary. When impurities that originate in impurities and the drug additives of impurities that are not the resolution products , for instance, the original medicine origin are excluded from the object of this report, the grounds are described. Profiles of the typical lot manufactured in the process of reflecting the impurity profile and the real production of lots manufactured from the development phase are compared, and those differences are considered. When (>) exists exceeding a necessary threshold of the structural decision shown in attached paper 1, the resolution product admitted in the soundness test done under the preservation condition described to the application for approval as a storing method decides the structure. The summary of the research that ends unsuccessfully is described to attached material about the resolution product that was not able to decide the structure. The structure need not usually be decided about the resolution product of the level below a necessary threshold of a structural decision (≦). However, the action should be abnormally strong, and the level below a necessary threshold of a structural decision (≦) develop the method by which the resolution product can be analyzed about the resolution product to which it is feared to show toxicity or the pharmacologic action. It is possible to become a reason to select a threshold different from attached paper 1 based on the experience of manufacturing in the process of reflecting the real production a technical factor (For instance, when you use the material of the unrefinement of the animal when the ratio of original medicines to the height of the manufacturing capacity and the drug additive is low or the plant radical fields as a drug additive). 3. Analysis method Data that shows that the analysis method described to the application for approval is the Bali one to have dated, and it is appropriate to detection and the fixed quantity of the resolution product is described to attached material. ("Text concerning analysis method Baridation (execution item)" (Csrishin No.755 on July 20, 1995)Hereafter, it .."Text concerning analysis method Baridation (execution method)" (Csrishin No.338 on October 28, 1997)(.. is said, "ICH-Q2A and Q2B guideline" and. Refer to). )｡In Baridation of the analysis method, it is necessary to show the resolution product especially and to show that the one that the one to set an individual standard doesn't set an individual standard either can be analyzed in the peculiarity. The sample that does to a severe condition appropriate to the drug product is used among the Canadian moisture solution and oxidations with light, heat, humidity, and acid/base for this Baridation. It is necessary to name the identification name to the peak in Cromatogram when the peak (for instance, peaks of impurities that originate in impurities generated when an original medicine and an original medicine are synthesized, the drug additives, and them) is admitted besides the peak of the resolution product as a result of the analysis, and to consider the origin in the description concerning analysis method Baridation of attached material. The quantitation limit of the analysis method should be below a necessary threshold to report (≦). There is a method of comparing the responses of the resolution product in a certain analysis method with the response of an appropriate standard substance or the new drug substance as the one though the content of the resolution product can be measured by various methods. The standard substance used to analyze the resolution product confirms suitable for the use. You may use an original medicine as a standard to estimate the content of the resolution product. You may estimate the content of the resolution product by using an original medicine as a standard if the correction coefficient is applicable or it is estimated more than the amount where the resolution product actually exists even if it is time when it doesn't indicate the value that the ionization gauge coefficient of the resolution product is near the ionization gauge coefficient of an original medicine. In that case, consideration concerning the validity of such assumption is described to attached material though in the judging standard of a resolution product that is structure already-known or unknown and the analysis method, there are often cases to assume, that the ionization gauge coefficient is for instance equal. When the analysis method used by the development phase the analysis method of the application for approval description is different, the difference point is considered, and it describes to attached material. 4. Report of amount of resolution product in lot The analysis result of the resolution product in the lot typical manufactured in the process of reflecting all lots that relate about the medicine made of new used for the clinical trial, the safety test, and the soundness test and the real production is described to attached material. The result of a quantitative examination should not be described by the numerical value, and be described by general marks such as "Agreement" and "Below limit value". It reports on each amount and the gross weight with the analysis method used about all the resolution products admitted at the (>) level that exceeds a necessary threshold (Refer to attached paper 1) to report in these lots. The result is reported up to same number of digits (For instance, to the way of 0.06%) as a necessary threshold to report correspond for less than 1.0%;The result reports even on the first decimal place (For instance, to the way of 1.3%) for 1.0% or more. The result is rounded off by the rule of how to round a usual numerical value (Refer to attached paper 2). It is preferable to show these data by the table form. The resolution product uses and distinguishes an appropriate identification name at the code number or hold time, etc.When a threshold that is higher than a necessary threshold to report on attached paper 1 is used, it is necessary to explain the validity enough. The amount of all the resolution products that exist in the (>) level that exceeds a necessary threshold to report is totaled, and it shows as resolution product gross weight. Cromatogram of a typical lot in which the identification name is named to each peak (data when the analysis methods other than the chromatograph method are used equal with this) is described to attached material with Cromatogram of the examination when analysis method Baridation is done, the long-term storage test, and the accelerated test. If the resolution product profile of an individual lot (for instance, Cromatogram) is demanded, by he or she those who apply are having it can submit. The item that hangs next is described about each lot of the medicine made of new taken up by attached material. - Lot number, amount of mixing of active ingredient, and manufacturing scale - Manufactured date - Manufacturing place - Manufacturing process - Direct container/Hodocosen system - Content of resolution product(amount and resolution product gross weight of individual resolution product) - Usage of lot(for instance, clinical trial and soundness test) - Reference to analysis method used - Lot number of original medicine used to manufacture medicine made of new - Preservation condition of soundness test 5. Resolution product that should be set to standard The resolution product thought to be generation in the preservation condition described to the application for approval as a storing method while manufacturing products on the market to the standard of the medicine made of new is listed. The profile of the resolution product is clarified based on the result of the soundness test, the finding concerning the resolution route, the development research into the drug product, and the lot analysis etc.The resolution product that individually sets the judging standard to the standard of the medicine made of new is selected based on the resolution product admitted in the lot manufactured in the process of reflecting the real production. The one of the structure already-known and the unknown one are included in this guideline, and the resolution product by which these individually set the judging standard is said, "Individual standard setting resolution product". The judgment grounds whether to set an individual standard to each resolution product are shown. Consideration concerning the resolution product profile of the lot manufactured in the process of reflecting the real production is described in this grounds with consideration concerning the resolution product profile admitted in the lot of the development phase used for the safety test and the clinical trial and the soundness test. The resolution product of the structural unknown estimated to be existence at the (>) level that exceeds a necessary threshold of the structural decision shown in attached paper 1 is set to the standard as an individual standard setting resolution product as well as the resolution product of the structure already-known. It is necessary to use the analysis method with quantitation limit/detection limit in which even the level that should control the resolution product can be analyzed about the resolution product to which it is known that the action is abnormally strong or there is toxicity or a pharmacologic action not anticipated. What analysis method you used to estimate the content of the resolution product, and what assumption you put are clearly shown about the resolution product of a structural unknown. The resolution product of a structural unknown to set an individual standard uses and describes an appropriate identification name (for instance, "Unknown material A" and "Unknown material at relative hold time 0.9. " etc.) based on a qualitative characteristic. The general judging standard is assumed about the resolution product that doesn't set an individual standard and, hereafter, a necessary threshold of a structural decision (attached paper 1) is assumed to be (≦). The judging standard of the gross weight of the resolution product is set. The judging standard of the resolution product sets the preservation condition that tries to be set in the application for approval of the amount of an increase and the medicine made of new in the level from which the judging standard of a material concerned (When corresponding) in an original medicine and safety are confirmed and the soundness test and validity term taking it into consideration. Moreover, safety might be not higher than the confirmed levels for the resolution product and not set each judging standard. The judging standard of the resolution product is set when not worrying about safety by the width that can correspond to the change based on the data obtained about the lot of the medicine made of new manufactured in the process of reflecting the real production while manufacturing usually, analyzing, changing, and preserving it. A usually constant change can happen in the manufacturing process, and the management operation is not appropriately done, and there is a Bali possibility of not dating it the manufacturing process of the medicine made of new is when great fluctuations considerably happen to the content of the resolution product between lots (Refer to "Flow chart # 2: the setting of the judging standard of the resolution product in the medicine made of new" of the ICH-Q6A guideline). When the threshold (Refer to attached paper 1) is shown by the numerical value to the second decimal place in this guideline, it is not necessarily the one to mean the accuracy to this level is requested when suitability is judged for the individual standard setting resolution product and the resolution product gross weight. When the above is brought together, the judging standard of the one that it corresponds of items that hang next is set to the standard of the medicine made of new. - Standard setting resolution product of structure already-known according to each - Standard setting resolution product of structural unknown according to each - All other resolution products that do not set individual standard(The judging standard of each resolution product is assumed below a necessary threshold of a structural decision (≦). ) - Gross weight of resolution product 6. Confirmation of safety of resolution product The confirmation of safety is work to collect and to evaluate data necessary to prove the safety of an individual resolution product at the level of the limit value set to the standard or the entire resolution product. The validity of the judging standard of the set resolution product is described to attached material including consideration from the side of safety. It can be thought that safety was confirmed about the resolution product admitted in the lot of the medicine made of new to which it has already been confirmed that it is very safe in the safety test and the clinical trial even as for the level that exists in the lot used for the examination. Therefore, when information on an actual content of the resolution product in a lot concerned at the point used for the safety test and the clinical trial is obtained, it is useful to confirm the safety of the resolution product to describe the information to attached material. It can be thought that safety is confirmed in general when the resolution product is the same as the main metabolic thing admitted by the examination by the animal and the human. When the resolution product at a level that is higher than it exists in the lot of the medicine made of new used for the safety test and the clinical trial is contained, safety can be confirmed by considering it based on the comparison with the amount of the resolution product actually administered in the dosage to which the amount of the resolution product actually administered in the safety test and the medicine made of new are provided. When it is proven that there is no problem even if the resolution product at such a high level is contained, it is necessary to consider it based on the following various factors: The amount of the resolution product to which (1) is administered by the safety test that has already been done and the clinical trial, and it is confirmed that it is safe; (2) Amount of an increase of resolution product;And, the factor that (3) relates to other safetys (When corresponding). It is necessary to examine the addition to confirm safety when there is no data that can confirm safety at the level of the judging standard that tries to be set to the standard though a necessary threshold to confirm safety of showing of the judging standard in attached paper 1 is exceeded about a certain resolution product (Refer to attached paper 3). It might be appropriate to make a necessary threshold to confirm safety higher based on the degree of the anxiety concerning scientific grounds including knowledge concerning the pharmacologic action according to the medicinal effect classification and a clinical experience and safety according to the medicine and to lower. The resolution product of the target for the safety confirmation is contained in the medicine of a certain medicine group or the similar medicine efficacy group, and for instance, it is especially important, and it is appropriate to the confirmation of safety in the patient to lower a necessary threshold to confirm safety so far when having taken part in the side effect. Oppositely, when the anxiety concerning safety is lower than a usual medicine, a necessary threshold to confirm safety may be higher from similar consideration (for instance, knowledge concerning the pharmacologic action according to the patient group of the target for administering and the medicinal effect classification and clinical experience). When a threshold different from attached paper 1 is adopted, the validity is judged case by case. "Flow chart for the confirmation of a structural decision of the resolution product and safety" (attached paper 3) shows how to confirm the safety of the resolution product when the amount of the resolution product exceeds the threshold of attached paper 1. According to circumstances, it might be easier to decrease the amount of the resolution product below the threshold (≦) (For instance, by using protected more container/Hodocosen system or changing the preservation condition) than to make the safety data. Or, to confirm the safety of the resolution product, enough data might be obtained from the science document. It is considered to add the safety test when safety cannot be confirmed by which method and to do. It depends on a lot of factors like the dosage, the administration route, and the administering period a patient group and each target day for administering, etc. what examination for is appropriate to the confirmation of the safety of the resolution product. It might be appropriate to do by using the resolution product that is single Hana though it examines by using the medicine made of new (Or, new drug substance) including the targeted resolution product. This guideline : though it is not the one that it was intended to apply to the medicine made of new used at the clinical trial stage. The threshold shown in this guideline is useful to evaluate the new resolution product admitted in the lot of the medicine made of new manufactured in the process of reflecting the real production in the stage of latter term of development. It is necessary to decide all the structures about the one of the (>) level that exceeds the threshold for which a structural decision of attached paper 1 is necessary about the new resolution product admitted at the stage of latter term of development (Refer to "Flow chart for the confirmation of a structural decision of the resolution product and safety" of attached paper 3). Similarly, it is necessary to confirm safety in case of (>) of the excess of the threshold for which the confirmation of the safety of attached paper 1 is necessary by the level of the resolution product newly admitted. To confirm the safety of the resolution product, it usually examines it in shape to compare lots from which safety has already been confirmed the lot of the medicine made of new (Or, new drug substance) that contains a new resolution product at a typical level. You may examine it by using the resolution product that is single Hana. 7. Definition of term Necessary threshold (Qualification Threshold) to confirm safety: Limit value for which confirmation of (>) for amount of resolution product to exceed the value and safety is needed. Confirmation (Qualification) of safety:Work to collect and to evaluate data necessary to prove safety of individual resolution product at level of limit value set to standard or the entire resolution product. Resolution product (Identified Degradation Product) of structure already-known: Resolution product to which structure is decided. Necessary threshold (Identification Threshold) of a structural decision: The amount of the resolution product exceeds the value (>). Limit value for which decision of structure is needed. Resolution product (Unidentified Degradation Product) of structural unknown: Resolution product that cannot decide structure, and is specified only by qualitative characteristic like relative hold time of chromatograph method. Resolution product (Unspecified Degradation Product) that doesn't set individual standard: Resolution product that is set original judging standard and is not listed individually but is restricted in standard of medicine made of new by general judging standard. Individual standard setting resolution product (Specified Degradation Product): Resolution product that individually is set original judging standard and is listed, and is restricted in standard of medicine made of new. In the standard setting resolution product, the structure is and there are the already-known one and the unknown one, too. New drug substance (New Drug Substance): Material for medical treatment that has not been approved in a certain region or country before. It is called new molecular entity or new chemical entity. It might be easy Tai of the original medicine approved before, and is an ester body or be salts. Development research (Development Studies) into drug product: Research of Bali ..scale improvement, and optimization of manufacturing process of medicine.. done to date it. Impurities (Impurity):The element other than an original medicine or the drug additive among materials included in the drug product. Impurity profile (Impurity Profile): Whole images of impurities that are structure already-known that exists in medicine or unknown. Resolution product (Degradation Product): Action of light, heat, pH, and water or drug additives and impurities by which original medicine causes directly and generated chemical change by reaction with container/Hodocosen system while being manufacturing medicine made of new or preserving it. Profile (Degradation Profile) of resolution product: Whole image of resolution product admitted in original medicine or drug product. Necessary threshold (Reporting Threshold) to report: Limit value for which (>) for amount of resolution product to exceed the value and report are needed. Attached paper 1:Threshold of resolution product in medicine made of new Threshold for which report is needed The first or less dosage 1) Necessary threshold 2 and 3) of reports ≦ 1g 0.1% > 1g 0.05% Threshold for which structural decision is needed The first or less dosage 1) Necessary threshold 2 and 3) of structural decisions < 1mg Low one either of total intake 5μg during 1.0% or days 1mg ～ 10 mg Low one either of total intake 20μg during 0.5% or days >10 mg ～ 2g Low one either of total intake 2mg0.2% or per days > 2g 0.10% Threshold for which confirmation of safety is needed The first or less dosage 1) Necessary threshold 2 and 3) of safety confirmations < 10 mg Low one either of total intake 50μg during 1.0% or days 10 Low one either of total intake 200μg during mg-100 mg 0.5% or a day >100 Low one either of total intake 3mg mg-2g 0.2% or a day > 2g 0.15% Note 1) Amount of original medicine administered in a day. Note 2) The threshold of the resolution product is shown by percentage of the resolution product contained in an original medicine or total intake (TDI) during a day of the resolution product. When the toxicity of the resolution product is very strong, it might be appropriate to use a threshold that is lower than this. Note 3) Show the scientific validity when you use a threshold that is higher than this. It is one 1) that day maximum dosage was shown in the figure for a horizontal axis as for the threshold of the confirmation of a report of the resolution product in the medicine made of new, a structural decision, and safety. =============================================================== ======= Note 1) Obtain the numerical value of an actual threshold from the table of the threshold of last page. The first or less shown by number of mg of original medicines dosage Threshold of resolution product shown by percentage in original medicine Threshold of report Threshold for which structural decision is necessary Threshold for which confirmation of safety is necessary Closeup: The first or less shown by number of mg of original medicines dosage Threshold of resolution product shown by percentage in original medicine Threshold of report Threshold for which structural decision is necessary Threshold for which confirmation of safety is necessary Threshold of confirmation of report of resolution product in medicine made of new, structural decision, and safety One 1) that the maximum dosage on the first was shown in the figure for horizontal axis =============================================================== Attached paper 2:Example of having shown how to report on amount of resolution product in attached material to judge whether structural decision and confirmation of safety are necessary Dosage 50mg on the first or less "Life" Data Report data One of resolution products Judgment Day total intake(TDI) (%) (%) Threshold of structural decision Threshold of confirmation of safety They are four 5 in (μg. (= of threshold of report ..entering.. value) 0.2% 200μgTDI 0.1%) (Correspond to 0.4%. ) 0.04 The report is unnecessary. 20 Unnecessary Unnecessary 0.2143 0.2 100 Unnecessary Unnecessary 0.349 0.3 1) 150 Necessity Unnecessary 1) 0.550 0.6 1) 300 Necessity 1) necessary Dosage 1.9g on the first or less "Life" Data Report data One of resolution products Judgment Day total intake(TDI) (%) (%) Threshold of structural decision Threshold of confirmation of safety It rounds it off to (mg. (= of threshold of report Done value) 2mgTDI 3mg TDI 0.05%) (Correspond to 0.11%. ) (Correspond to 0.16%. ) 0.049 The report is unnecessary. 1 Unnecessary Unnecessary 0.079 0.08 2 Unnecessary Unnecessary 0.183 0.18 1) 3 Necessity Unnecessary 1 and 2) 0.192 0.19 1) 4 Necessity 1) necessary Note 1) It is thought that it is appropriate to try to request the amount of the resolution product that actually exists when the ionization gauge coefficient of the resolution product is requested after the structure is decided when the value that the value assumed different, and to do the judgment whether the confirmation of safety is necessary over again (Refer to attached paper 1). Note 2) In this case, because value (3mg) obtained by rounding off calculation value (3.42mg) of TDI obtained from the dosage 1.9g and the report data 0.18% on the first or less to same number of digits as the threshold of the safety confirmation doesn't exceed threshold 3mg TDI of the safety confirmation, it is judged that the confirmation of safety is unnecessary though the report data 0.18% exceeds the value 0.16% of the percentage that corresponds to threshold 3mg TDI of the safety confirmation. Attached paper 3:Flow chart for structural decision of resolution product and confirmation of safety The under in consideration of use period of object patient group and medicine The execution of the examination of the record is considered: . Inheritance toxicity examination a (mutation and chromosome aberration)) . General..toxicity..examination..animal..kind..usually. . Other specific toxicity tests when it is necessary Does the content of the resolution product exceed threshold c) of a structural decision? Has the structure been decided? Is the action that becomes a problem clinical admitted? Safety has been confirmed. The examination is unnecessary. Who reports that there is a risk for the human?d) It decreases it to a safe level. A further examination is unnecessary. The examination is unnecessary. It decreases it to a safe level. Is the content of the resolution product decreased and is threshold c) of a structural decision decreased as follows? Does the content of the resolution product exceed threshold c) of the safety confirmation? Is the content of the resolution product decreased and is threshold c) of the safety confirmation decreased as follows? Note a) executes the minimum screening examination (for instance, examination for the inheritance toxicity) if necessary. It is all right though both of the examination that detects the examination and the chromosome aberration that detects the mutation are the examinations of in vitro as the minimum screening examination. When note b) general toxicity examination is executed, one or more examinations to be able to compare the unconfirmed one of safety and the one of the confirmation of safety are scheduled. The examination is executed by the animal kind thought to decide based on related information that can be acquired, and to detect the toxicity of the resolution product easily most for the examination period. It is case by case, and when the single time administering medicine is especially examined, the single time administering examination is allowed. It is thought that the examination period of 90 days is appropriate at most for the short 14 days usually. A threshold of the resolution product with very strong note c) toxicity that is lower than that of this might be suitable. ..note d).. for instance, might not this resolution product be likely to feared the safety to the human in the density that in view of an already-known safety data or chemical constitution, exists? Source: Ministry of Health, Labor and Welfare. Translation: JKS LLC Note concerning the translation of the titles All original documents issued by the Japanese Government, other authorities and industry group are issued only in Japanese, including their titles, table of contents and texts. Translation of the titles in English is provided here solely by the Jouhou Koukai Services. While utmost care has been taken both linguistically and organizationally to reflect into the English translation the language, abbreviations, professional jargon, style and conventions used in the original texts, no claims either expressed or implied are made for completeness and correctness. Some of the conventions used originate from legacy documents earlier translated to English under the supervision of the MHLW. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. The translations here are tentative. In a case of legal dispute, the original texts in Japanese will prevail. The translation, formatting, indexing and hyperlinking of the text are copyrights of the Jouhou Koukai Services LLC Worldwide Copyright (c) 2001-2003 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com Both "medicinal products with new active ingredients" and "new drug substances" are use alternatively in the text. (Note of the translator) PFSB/ELD Notification No. 0624001/June 24, 2003 Japan Regulations Series Copyright (c) 2001-2003 by JKS LLC - 3 - Copyright (c) 2001-2003 by JKS LLC - XX -