07_ESCMID_draft_EUCAST rules in susceptibility test

ASSESSMENT AND CONTROL OF DNA REACTIVE(MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TOLIMIT POTENTIAL CARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制M7Current Step 4 versiondated 23 June 2014This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.M7Document History 文件历史Current Step 4 version 现行版本第4阶段Legal Notice: This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document.The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制ICH Harmonised Tripartite GuidelineICH三方协调指南Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 5 June 2014, this Guideline is recommended for adoption to the three regulatory parties to ICHASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIALCARCINOGENIC RISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制1. INTRODUCTION概述The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive. The purpose of this guideline is to provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk. This guideline is intended to complement ICH Q3A(R2), Q3B(R2) (Note 1), and ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals (Ref. 3).原料药合成牵涉到使用活性化学物质、试剂、溶剂、催化剂和其它工艺助剂，导致在所有原料药及其制剂中会残留有化学合成或其降解产物、杂质。

growth/no growth detection in micro-wells with
different antibiotics 通过光学扫描仪测量光衰减，
用于在具有不同抗生素的微孔中生长/无生长检测
Direct from Sample直接性
No
Uses redox indicator for detection of growth in
Assistant Professor Animal Disease Research & Diagnostic Laboratory Dept. of Veterinary & Biomedical Sciences
South Dakota State University
Outline 提纲
Overview of Antibiotic Susceptibility Testing (AST) 抗生素敏感性测试（AST）概述
Media (in ml) containing different antibiotics
24 hours
No
tested against pathogen of interest 含有不同抗
生素的培养基（以ml计）针对感兴趣的病原体
进行测试
Antibiotic incorporated into agar plates and
Antibiotic susceptibility testing (AST) 抗生素敏感性试验（AST）
Bacterial identification and antibiotic susceptibility testing play an essential role in patient care and the control of antibiotic resistance mechanisms by: 细菌鉴定和抗生素药敏试验在患者护理和抗生素耐药机制的控制中起着至关重要的作用：

Designation:E1447−09(Reapproved2016)Standard Test Method forDetermination of Hydrogen in Titanium and Titanium Alloys by Inert Gas Fusion Thermal Conductivity/Infrared Detection Method1This standard is issued under thefixed designation E1447;the number immediately following the designation indicates the year of original adoption or,in the case of revision,the year of last revision.A number in parentheses indicates the year of last reapproval.A superscript epsilon(´)indicates an editorial change since the last revision or reapproval.1.Scope1.1This test method applies to the determination of hydro-gen in titanium and titanium alloys in concentrations from0.0006%to0.0260%.1.2The values stated in SI units are to be regarded as standard.No other units of measurement are included in this standard.1.3This standard does not purport to address all of the safety concerns,if any,associated with its use.It is the responsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.For specific hazards,see Section9.2.Referenced Documents2.1ASTM Standards:2C696Test Methods for Chemical,Mass Spectrometric,and Spectrochemical Analysis of Nuclear-Grade Uranium Di-oxide Powders and PelletsE50Practices for Apparatus,Reagents,and Safety Consid-erations for Chemical Analysis of Metals,Ores,and Related MaterialsE135Terminology Relating to Analytical Chemistry for Metals,Ores,and Related MaterialsE1601Practice for Conducting an Interlaboratory Study to Evaluate the Performance of an Analytical MethodE1914Practice for Use of Terms Relating to the Develop-ment and Evaluation of Methods for Chemical Analysis (Withdrawn2016)33.Terminology3.1Definitions—For definitions of terms used in this test method,see Terminology E135and E1914.4.Summary of Test Method4.1The specimen,contained in a small,single-use graphite crucible,is fused under aflowing carrier gas atmosphere. Hydrogen present in the sample is released as molecular hydrogen into theflowing gas stream.The hydrogen is sepa-rated from other liberated gases such as carbon monoxide and finally measured in a thermal conductivity cell.4.2Alternatively,hydrogen is converted to water by passing the gas stream over heated copper oxide and subsequently measuring in an appropriate infrared(IR)cell.4.3This test method is written for use with commercial analyzers equipped to perform the above operations automati-cally and is calibrated using reference materials of known hydrogen content.5.Significance and Use5.1This test method is intended to test for compliance with compositional specifications.It is assumed that all who use this test method will be trained analysts capable of performing common laboratory procedures skillfully and safely.It is expected that the work will be performed in a properly equipped laboratory.6.Interferences6.1The elements ordinarily present in titanium and its alloys do not interfere.7.Apparatus7.1Fusion and Measurement Apparatus—Automatic hydro-gen determinator,consisting of an electrode furnace or induc-tion furnace;analytical gas stream impurity removal systems; auxiliary purification systems and either a thermal conductivity cell hydrogen measurement system or an infrared hydrogen measurement system(Note1).N OTE1—The apparatus and analysis system have been previously described in the Apparatus and Apparatus and Equipment sections of Test1This test method is under the jurisdiction of ASTM Committee E01onAnalytical Chemistry for Metals,Ores,and Related Materials and is the directresponsibility of Subcommittee E01.06on Ti,Zr,W,Mo,Ta,Nb,Hf,Re.Current edition approved Aug.1,2016.Published August2016.Originallyapproved st previous edition approved in2009as E1447–09.DOI:10.1520/E1447-09R16.2For referenced ASTM standards,visit the ASTM website,,orcontact ASTM Customer Service at service@.For Annual Book of ASTMStandards volume information,refer to the standard’s Document Summary page onthe ASTM website.3The last approved version of this historical standard is referenced on.Copyright©ASTM International,100Barr Harbor Drive,PO Box C700,West Conshohocken,PA19428-2959.United StatesMethods C696.Several models of commercial analyzers are available and presently in use in industry.Each has its own unique design characteristics and operational requirements.Consult the instrument manufacturer’s instructions for operational details.7.2Graphite Crucibles—The crucibles are machined from high-purity e the size crucibles recommended by the manufacturer of the instrument.7.3Crucible Tongs—Capable of handling recommended crucibles.7.4Tweezers or Forceps—For contamination-free sample handling.8.Reagents and Materials8.1Acetone,low-residue reagent grade or higher purity. 8.2Sodium Hydroxide on Clay Base,commonly known as Ascarite II.8.3High-Purity Carrier Gas(99.99%)—Argon,nitrogen, or helium(Note2).N OTE2—Carrier gases vary by instrument model and include high-purity argon,nitrogen,and helium.Consult instrument manufacturer’s instructions for proper gas recommendation.8.4High-Purity Tin Metal(Low Hydrogen)—Use the purity specified by the instrument manufacturer.8.5Magnesium Perchlorate,Anhydrone.8.6Molecular Sieve—Characteristics specified by the in-strument manufacturer.8.7Schutze Reagent—Iodine pentoxide over silica gel. 8.8Copper Oxide Wire—To convert hydrogen to water in IR-detection instruments.Characteristics specified by the in-strument manufacturer.9.Hazards9.1For hazards to be observed in the use of this test method, refer to Practices E50.9.2Use care when handling hot crucibles and operating electrical equipment to avoid personal injury by either burn or electrical shock.10.Preparation of Apparatus10.1Assemble the apparatus as recommended by the manu-facturer.10.2Test the furnace and analyzer to ensure the absence of gas leaks and make the required electrical power and water connections.Prepare the apparatus for operation in accordance with the manufacturer’s instructions.Make a minimum of two determinations using a specimen as directed in13.2before attempting to calibrate the system or to determine the blank.11.Sample Preparation11.1Use solid form specimens prepared as directed in11.2. Specimens must be of an appropriate size tofit into the graphite crucible and should not exceed0.30g in weight.11.2Cut the specimen to the approximate size of0.15g to 0.30g(preferably by shearing).For specimens of unknown history or suspected surface contamination,abrade specimen surfaces with a cleanfile to remove contamination.Other methods,such as turning down on a lathe,may be employed for reducing sample size and removing the surface of the sample(Note3).Rinse the sample in acetone,and air dry. Weigh to60.001g.Samples shall be handled only with tweezers or forceps after cleaning and weighing to prevent contamination.N OTE3—Regardless of the method used,the sample must not be allowed to overheat,as this will adversely affect the results of the analysis. Indications that the sample has overheated while being worked may include discoloration of the metal or the sample becoming too hot to handle without tools.12.Calibration12.1Calibration Reference Materials—Select only titanium or titanium alloy reference materials(Note4).N OTE4—Gas dosing:it is satisfactory to calibrate the unit by dosing known volume(s)of hydrogen gas into the detection system.If the instrument has this feature,refer to the manufacturer’s recommended procedure.In this case instrument response must always be verified by analyzing titanium or titanium alloy reference materials.12.2Determination of Crucible/Tin Blank Reading:12.2.1If the instrument is equipped with an electronic blank compensator,adjust to zero,and proceed with the determina-tion of the blank value.12.2.2Make at least three blank determinations as directed in13.2using the weight of tinflux as recommended by the instrument manufacturer(Note5).Use a fresh crucible each time.N OTE5—Flux weight is dependent upon the model of the instrument and the manufacturer’s instruction.Refer to the manufacturer’s instruc-tions and recommendations.12.2.3If the average blank value exceeds0.0000%6 0.0001%,or a standard deviation for the three consecutive values exceeds60.0001%,then determine the cause,make necessary corrections,and repeat12.2.1and12.2.2(Note6).N OTE6—Refer to the instrument manufacturer’s instructions concern-ing the troubleshooting and correction of blank determinations not meeting the above criterion.12.2.4Enter the average blank value in the appropriate mechanism of the analyzer(Note7)according to the manu-facturer’s instruction.This mechanism will electronically com-pensate for the blank value.N OTE7—If the unit does not have this function,the average blank must be subtracted from the total result.12.3Calibration Procedure:12.3.1Prepare at least four0.15g to0.30g specimens(at least one specimen if calibrating by gas dosing)of a titanium hydrogen reference material as directed in11.2.This titanium hydrogen reference material should have a hydrogen content greater than or approximately equal to the unknown samples within the scope of this test method(0.0006%to0.0260%).12.3.2Follow the calibration procedure recommended by the manufacturer.Analyze at least three reference material specimens to determine the calibration slope(Note8).Treat each specimen as directed in13.2before proceeding to the next one(Note9).N OTE 8—For calibration by gas dosing,perform at least three gas dose analyses to determine the calibration slope.Refer to instrument manufac-turer’s instructions.N OTE 9—Some instruments have expanded computer capabilities that allow multi-point calibration which may improve the accuracy and precision of the calibration over the single-point calibration methodology as tested in the current interlaboratory study (ILS).12.3.3Confirm the calibration by analyzing a specimen of titanium hydrogen reference material (Note 10).The ILS used an acceptance criterion where the value fell within the allow-able limits of the certified value.An alternate procedure can be implemented where this value should agree with the certified value within the limits of a prediction interval calculated using Eq 1.The prediction interval is defined as the range of values bounded by the analysis value -p and the analysis value +p .If the prediction interval does not encompass the certified value,determine and correct the cause,and repeat 12.3.1and 12.3.2(Note 11).Either acceptance limit criterion is acceptable for routine operation.N OTE 10—Confirmation of the calibration does not ensure accuracy.The accuracy of this test method is largely dependent upon the absence of bias in the hydrogen values assigned to the reference materials and upon the homogeneity of these materials.N OTE 11—See the instrument manufacturer’s instructions concerning the troubleshooting and correcting of errant calibration.p 5t ·S111=nD·s (1)where:p =one-half the prediction interval,n =number of replicates used in 12.3.2,t =student’s t chosen for the 95%confidence level for nreplicate measurements (for example:t =2.35when n =3,2.13when n =4,2.02,when n =5),ands =standard deviation of n replicates in 12.3.2(Note 12).N OTE 12—Here,s should be comparable to S m ,the repeatability standard deviation,given in Table 1.If s »S m ,there is evidence that the repeatability of the particular instrument is not acceptable for use with this test method.The user should determine and correct the cause,and repeat 12.3.1through 12.3.3.12.3.4Confirm calibration linearity by analyzing a mid-range (Note 13)titanium hydrogen reference material,using the limits stated on the certified value as an acceptance range.Alternatively,analyze at least three specimens of a mid-range(Note 13)titanium hydrogen reference material.Calculate the average and standard deviation(s)of these results.In the absence of bias among the reference materials,the average result for this reference material should agree with the certified value within a prediction interval defined by the repeatability of the measurement system at the mid-range of the calibration (Note 14).This prediction interval may be calculated using Eq 1and the s and n values for the mid-range reference material.If the prediction interval does not encompass the certified value,determine and correct the cause and repeat 12.3.1and 12.3.4(Note 15).N OTE 13—Commercially available reference materials are not always available at the concentration required to have a true mid-point check.The mid-range material must have a hydrogen concentration that is above the limit of detection,but below that of the high calibration point,preferably as close to the mid-point of the calibration curve as possible.N OTE 14—Typically,repeatability standard deviation is a function of the concentration of the pare the values labeled ILS Analyzed Mean in Table 1with the values for Minimum SD (S m )to see a typical trend for laboratories using this test method.If your results are not comparable,investigate and correct the cause.N OTE 15—The presence of bias between the reference material used in 12.3.2and the reference material used in 12.3.4may cause the calibration to appear to be non-linear.This cannot be corrected by making adjust-ments to the instrument.12.3.5One or more continuing calibration verifications must be performed prior to and upon completion of a period of continuous operation,and throughout this period with a pre-determined minimum frequency to be established by each individual test facility.The acceptance range for the verifica-tion material may be the limits stated on the certified value for the reference material,or may be calculated using Eq 1and the s and n values for multiple analyses of the verification material.If a continuing calibration verification indicates an out of calibration condition,stop analysis.Results must be supported by acceptable preceding and subsequent verifications to be reported.12.4Calibration Frequency:12.4.1It is the responsibility of the user to document the frequency of blank determination (12.2.1–12.2.4),routine calibration and confirmation (12.3.2and 12.3.3)and linearity confirmation (12.3.4),and the conditions under which blank determination or recalibration,or both,beyond this frequencyTABLE 1Hydrogen in Titanium Metal Statistical Information AMaterial#Labs Certified Value (µg/g)ILS Analyzed Mean (µg/g)Difference (µg/g)Certified Precision (µg/g)Minimum SD (S m ,Practice E1601)Reproducability SD (S R ,Prac-ticeE1601)ReproducabilityIndex (R,Practice E1601)R rel %BCR 318B 1012.211.40.80.80.44 1.01 2.8324.9CEZUS LH C 11...20.3...... 1.64 2.637.3636.3NBS 352D113227.4 4.62 1.43 1.96 5.4720.0CEZUS TIV25C 11...90.2...... 1.44 5.3114.9016.5NBS 353D 119895.8 2.25 3.42 4.0011.1911.7NBS 354D 11215213.2 1.86 3.36 3.6610.24 4.80NIST 2454E 11...219.5...... 5.8011.3531.7814.5CEZUS HH C10...260.1......4.4511.7232.8012.6A ILS conducted in accordance with Practice E1601,Plan A.BCertified Reference Material:Commission of the European Communities,Community Bureau of Reference.CReference Material:CEZUS,Ugine,France.DStandard Reference Material:National Institute of Standards and Technology,formerly National Bureau of Standards.EStandard Reference Material (under development):National Institute of Standards and Technology.Material is in chip form.is required (examples may include changing reagents,chang-ing gas cylinders or a personnel shift change).13.Procedure13.1Assemble the apparatus and condition it as directed in Section 10.13.2Procedure for Operation:13.2.1Set the analyzer to operate mode.13.2.2Prepare a 0.15-g to 0.30-g specimen as directed in 11.2.13.2.3Place a 0.15-g to 0.30-g specimen in the loading device.If the instrument does not have this feature,refer to the manufacturer’s recommended procedure regarding entry of sample.13.2.4Enter the sample weight as recommended by the manufacturer.13.2.5Place a crucible containing high-purity tin as mea-sured in 12.2.2on the furnace electrode/pedestal assembly and close the furnace.13.2.6Start the analysis cycle according to the manufactur-er’s recommended procedure.14.Calculation14.1The reading will be direct if the blank and weight have been entered correctly into the appropriate portion of the analyzer (Note 16).N OTE 16—If the analyzer does not offer these functions,calculate the hydrogen content by the following method:Dial the sample weight or a multiple of the sample weight on the weight compensator and use thefollowing formula (Eq 2)for the calculation of the result:Hydrogen,%5~A 2B !3CD(2)where:A =sample digital volt meter (DVM)reading,B =blank DVM reading,C =weight compensator setting,andD =sample weight,g.15.Precision and Bias15.1Precision 4—Eleven laboratories cooperated in testing eight samples in triplicate.The data are presented in Table 1.The testing and statistical analysis were performed in accor-dance with the provisions of Practice E1601,Plan A.Six instruments were of the thermal conductivity hydrogen mea-surement system configuration and five instruments were of the infrared hydrogen measurement system configuration.Calibra-tion was performed utilizing a single calibration material (NBS 354,215µg ⁄g 66µg ⁄g).15.2Bias—Information on the accuracy of this test method is incomplete at this time.The accuracy of this test method may be judged by comparing the results obtained from certified reference materials with their certified values for hydrogen.16.Keywords16.1hydrogen;inert gas fusion;titanium;titanium alloysASTM International takes no position respecting the validity of any patent rights asserted in connection with any item mentioned in this ers of this standard are expressly advised that determination of the validity of any such patent rights,and the risk of infringement of such rights,are entirely their own responsibility.This standard is subject to revision at any time by the responsible technical committee and must be reviewed every five years and if not revised,either reapproved or withdrawn.Your comments are invited either for revision of this standard or for additional standards and should be addressed to ASTM International Headquarters.Your comments will receive careful consideration at a meeting of the responsible technical committee,which you may attend.If you feel that your comments have not received a fair hearing you should make your views known to the ASTM Committee on Standards,at the address shown below.This standard is copyrighted by ASTM International,100Barr Harbor Drive,PO Box C700,West Conshohocken,PA 19428-2959,United States.Individual reprints (single or multiple copies)of this standard may be obtained by contacting ASTM at the above address or at 610-832-9585(phone),610-832-9555(fax),or service@ (e-mail);or through the ASTM website ().Permission rights to photocopy the standard may also be secured from the Copyright Clearance Center,222Rosewood Drive,Danvers,MA 01923,Tel:(978)646-2600;/4Supporting data have been filed at ASTM International Headquarters and may be obtained by requesting Research ReportRR:E01-1004.。

的报告策略。
2.铜绿假单胞菌折点(ug/ml)修订
Agent 哌拉西林 哌拉西林－他唑巴坦 替卡西林 替卡西林－克拉维酸 Old (M100-(M100-S21) Susc ≤64 ≤64/4 ≤64 ≤64/2 Int Res ≥128 ≥128/4 ≥128 ≥128/2 New M100M100--S22 Susc ≤16 ≤16/4 ≤16 ≤16/2 Int 32--64 32/4--64/4 32--64 32/2--64/2 Res ≥128 ≥128/4 ≥128 ≥128/2
• 不常规报告AST，除非是门诊病人 •
– 沙门菌病通常是自限性疾病不常规推荐进行抗 生素治疗 在一些情况特殊的病人（如免疫功能受抑、HIV） 与医生讨论是否需要做AST – 保守地，要考虑强调更低的环丙沙星折点。
1.肠杆菌科
肠道外分离的沙门菌药敏报告策略
• 做药敏试验 • 环丙沙星使用新的折点 • 病人伴随出现分离株的应用自粪便分离株
≥31
21--30
≤20
≤0.06
0.12--0.5
≥1
M100-S22,P48
1.肠杆菌科
伤寒沙门菌及肠道外沙门菌环丙沙星药敏试验
• 最好做环丙沙星MIC • 自动化药敏仪器无法给出新折点的最低稀释度——考虑用 • • •
E-Test? 如果用纸片扩散法，考虑同时做萘啶酸和环丙沙星纸片 – 萘啶酸对gyrA酶突变菌株检出效果好 – 环丙沙星对质粒编码的基因突变的菌株检出效果好 染色体介导的gyrA酶基因突变比质粒编码的基因突变致氟 喹诺酮敏感性降低更常见。 其它氟喹诺酮（如左氧）折点仍在评估中。
1.肠杆菌科
Modified Hodge Test (MHT) (Table 2A Supplemental Table 2 and 3)