w19490 IDENTIFYING THE HEALTH PRODUCTION FUNCTION

以医疗器械作用为主的药械组合产品注册审查指导原则英语Guidance Principles for the Registration Review of Medical Device-Drug Combination Products1. IntroductionMedical device-drug combination products are a category of products that combine a medical device and a drug component to achieve the intended use. The registration review of such products requires a comprehensive assessment of both the device and drug components, as well as the interaction between them. This guidance outlines the key principles and considerations for the registration review of medical device-drug combination products.2. ScopeThis guidance applies to medical device-drug combination products where the device component is the primary mode of action. The principles and considerations outlined in this guidance may also be applicable to other types of combination products, such as those where the drug component is the primary mode of action.3. Regulatory FrameworkThe registration of medical device-drug combination products is subject to the regulatory requirements for both medical devices and drugs. Applicants should ensure compliance with the relevant regulations and guidelines for each component, as well as the specific requirements for combination products.4. Product Identification and ClassificationMedical device-drug combination products should be clearly identified and classified based on the primary mode of action and the intended use. Applicants should provide a detailed description of the product, including the device and drug components, their respective functions, and the intended use of the combination product.5. Quality ConsiderationsThe quality of both the device and drug components should be thoroughly evaluated. This includes the design, manufacturing, and control of the individual components, as well as the compatibility and interactions between them. Applicants should provide comprehensive information on thequality attributes, specifications, and control strategies for the combination product.6. Nonclinical EvaluationNonclinical studies should be conducted to assess the safety and performance of the combination product. This may include studies on the device-drug interaction, the local and systemic effects of the combination, and the potential for any adverse interactions or reactions.7. Clinical EvaluationClinical studies are essential to evaluate the safety and efficacy of the combination product. Applicants should design and conduct clinical trials that assess the overall performance of the combination product, including the device and drug components, and the interaction between them.8. Risk ManagementApplicants should implement a comprehensive risk management plan to identify, assess, and mitigate the potential risks associated with the combination product. This includes the risks related to the device and drugcomponents, as well as the risks arising from the interaction between them.9. Labeling and PackagingThe labeling and packaging of the combination product should provide clear and comprehensive information to healthcare professionals and patients. This includes the instructions for use, any special handling or storage requirements, and any warnings or precautions related to the combination product.10. Postmarket SurveillanceApplicants should establish a robust postmarket surveillance system to monitor the performance and safety of the combination product after it is approved for use. This includes the collection and analysis of adverse event reports, as well as the implementation of any necessary corrective or preventive actions.中文版本:医疗器械作用为主的药械组合产品注册审查指导原则1. 引言医疗器械-药物组合产品是一类将医疗器械和药物组合在一起以实现预期用途的产品。

INSTRUCTIONSINTENDED USEThe BinaxNOW™ COVID-19 Antigen Self Test is a lateral flow immunoassay intended for the qualitative detection of nucleocapsid protein antigen from SARS-CoV-2.This test is authorized for non-prescription home use with self-collected anterior nasal (nares) swab samples from individuals aged 15 years or older or adult collected anterior nasal (nares) swab samples from individuals 2 years or older. This test is authorized for individuals with symptoms of COVID-19 within the first seven days of symptom onset when tested at least twice over three days with at least 48 hours between tests, and for individuals without symptoms or other epidemiological reasons to suspect COVID-19, when tested at least three times over five days with at least 48 hours between tests.The BinaxNOW COVID-19 Antigen Self Test does not differentiate between SARS-CoV and SARS-CoV-2. Results are for the identification of SARS-CoV-2 nucleocapsid protein antigen which is generally detectablein anterior nasal (nares) swabs during the acute phase of infection. Positive results indicate the presence of viral antigens, but clinical correlation with patient history and other diagnostic information is necessary to determine infection status. Positive results do not rule out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. Individuals who test positive with the BinaxNOW COVID-19 Antigen Self Test should self-isolate and seek follow-up care with their physician or healthcare provider as additional testing may be necessary.All negative results should be treated as presumptive and confirmation with a molecular assay, if necessary for patient management, may be performed. Negative results do not rule out SARS-CoV-2 infection and should not be used as the sole basis for treatment or patient management decisions, including infection control measures such as isolating from others and wearing masks. Negative results should be considered in the context of an individual’s recent exposures, history and the presence of clinical signs and symptoms consistent with COVID-19. Individuals who test negative and continue to experience COVID-like symptoms of fever, cough and/or shortness of breath may still have SARS-CoV-2 infection and should seek follow up care from their healthcare provider. Individuals should report their test result through the NAVICA app and provide all results obtained with this product to their healthcare provider in order to receive appropriate medical care. All healthcare providers will report all test results they receive from individuals who use the authorized product to relevant public health authorities in accordance with local, state, and federal requirements using appropriate LOINC and SNOMED codes, as defined by the Laboratory In Vitro Diagnostics (LIVD) Test Code Mapping for SARS-CoV-2 Tests provided by CDC. The BinaxNOW COVID-19 Antigen Self Test is intended for non-prescription self-use and/or, as applicable for an adult lay user testing another person aged 2 years or older in a non-laboratory setting. The BinaxNOW COVID-19 Antigen Self Test is only for use under the Food and Drug Administration’s Emergency Use Authorization. This product has not been FDA cleared or approved.Turn OverTEST KIT COMPONENTS OVERVIEWDo not open any parts before reading instructions.!HOW TO USE THIS TESTSerial testing should be performed in all individuals with negative results; individuals with symptoms of COVID-19and initial negative results should be tested again after 48 hours. Individuals without symptoms of COVID-19, andwith initial negative results, should be tested again after 48 hours and, if the 2nd test is also negative, a 3rd timeafter an additional 48 hours. Y ou may need to purchase additional tests to perform this serial (repeat) testing.If you test negative but continue to have symptoms of COVID-19, and both your first and second tests arenegative, you may not have COVID-19, however you should follow-up with your healthcare provider.If your test is positive, then proteins from the virus that causes COVID-19 have been found in your sample and youlikely have COVID-19.FREQUENTLY ASKED QUESTIONSWhat are the Known and Potential Risks and Benefits of this Test?Potential Risks Include:• Possible discomfort during sample collection.• Possible incorrect test results (see Results section).Potential Benefits Include:• The results, along with other information, can help your healthcare provider make informed recommendationsabout your care.• The results of this test may help limit the spread of COVID-19 to your family and others in your community.For more information on EUAs go here: https:///emergencypreparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergencyuse-authorizationWhat is the Difference Between an Antigen and Molecular Test?There are different kinds of tests for the SARS-CoV-2 virus that causes COVID-19.Molecular tests detect genetic material from the virus. Antigen tests, such as the BinaxNOW COVID-19Antigen Self Test, detect proteins from the virus. Due to the lower sensitivity of antigen tests, there is a higherchance this test will give you a false negative result when you have COVID-19 than a molecular test would.How Accurate is this Test?Clinical studies have shown that antigen tests more accurately determine whether you are infected with the virusthat causes COVID-19 when taken multiple times across several days. Repeat testing improves test accuracy.This serial testing approach is recommended to minimize the risk of incorrect results. For more information on theperformance of the test and how the performance may apply to you, please refer to the performance data in theHealthcare Provider Instructions for Use available at www.globalpointofcare.eifu.abbott.What if I Have a Positive Test Result?A positive result means that it is very likely you have COVID-19 because proteins from the virus that causesCOVID-19 were found in your sample. Y ou should self isolate from others and contact a healthcare provider formedical advice about your positive result.What if I have a Negative Test Result?A negative test result indicates that antigens from the virus that causes COVID-19 were not detected in yoursample. However, if you have symptoms of COVID-19, and your first test is negative, you should test again in48 hours since antigen tests are not as sensitive as molecular tests. If you do not have symptoms and received anegative result, you should test at least two more times with 48 hours in between tests for a total of three tests. Ifyou have a negative result, it does not rule out SARS-CoV-2 infection; you may still be infected and you may stillinfect others. It is important that you work with your healthcare provider to help you understand the next stepsyou should take.What does an Invalid Test Result mean?An invalid result means the test was not able to tell if you have COVID-19 or not. If the test is invalid, a new swabshould be used to collect a new nasal specimen and you should test again with a new test.IMPORTANTDo not use this test as the only guide to manage your illness. Consult your healthcare provider if your symptomspersist or become more severe.Individuals should provide all results obtained with this product to their healthcare provider.LIMITATIONSThe performance of this test was established based on the evaluation of a limited number of clinical specimenscollected between January, 2021, and May, 2022. The clinical performance has not been established for allcirculating variants but is anticipated to be reflective of the prevalent variants in circulation at the time andlocation of the clinical evaluation. Performance at the time of testing may vary depending on the variantscirculating, including newly emerging strains of SARSCoV-2 and their prevalence, which change over time.All COVID-19 antigen test negative results are presumptive and confirmation with a molecular assay may benecessary. If you continue to have symptoms of COVID-19, and both your first and second tests are negative,you may not have COVID-19, however you should follow-up with a healthcare provider.If the test is positive, then proteins from the virus that causes COVID-19 have been found in the sample and youlikely have COVID-19.There is a higher chance of false negative results with antigen tests than with laboratory-based molecular tests dueto the sensitivity of the test technology. This means that there is a higher chance this test will give a false negativeresult in an individual with COVID-19 as compared to a molecular test, especially in samples with low viral load.Incorrect test results may occur if a specimen is incorrectly collected or handled.This test is read visually and has not been validated for use by those with impaired vision or color-impaired vision.WARNINGS, PRECAUTIONS and SAFETY INFORMATION1. For in vitro diagnostic use.2. Wear safety mask or other face covering when collecting anterior nares swab specimen from a child oranother individual.3. Use of gloves is recommended when conducting testing.4. Keep testing kit and kit components out of the reach of children and pets before and after use.5. In the USA, this product has not been FDA cleared or approved but has been authorized by FDA under anEUA.6. This product has been authorized only for the detection of proteins from SARS-CoV-2, not for any otherviruses or pathogens.7. The emergency use of this product is only authorized for the duration of the declaration that circumstancesexist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis ofCOVID-19 under Section 564(b)(1) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or authorization is revoked sooner.8. Incorrect test results may occur if a specimen is incorrectly collected or handled.9. Do not use if any of the test kit contents or packaging is damaged.10. Leave test card sealed in its foil pouch until just before use. Do not use if pouch is damaged or open. Onceopened, the test card should be used immediately.11. Do not dip the swab into the liquid reagent or other liquid before inserting the swab into the nose.12. Do not touch swab tip when handling the swab sample.Testing supplies are provided in each box.Test Kit Contains:Swab Test Card in Pouch Dropper BottleCOV O ID-19 AgCARDorThe NAVICA app allows you to track results for yourBinaxNOW COVID-19 tests.• Compatible smart phone includes Apple iPhone running OperationSystem (iOS): latest major version and two prior major versions(iPhone running iOS v12 or later), and Android Phones: latestmajor version and two prior major versions (Android phone runningAndroid OS v9 or later).• Download the app by scanning the QR code• Create an account• Perform a COVID-19 test (digital instructions available)• Record your result in the appAlternatively go to www.binaxnow-selftest.abbott for digitalinstructions.A positive test result means that the virus that causes COVID-19 was detected in your sample and it is verylikely you have COVID-19 and are contagious. Please contact your doctor/primary care physician or yourlocal health authority immediately and adhere to the local guidelines regarding self-isolation. There is a verysmall chance that this test can give a positive result that is wrong (a false positive result).A negative test result indicates that the virus that causes COVID-19 was not detected in your sample. Anegative result is presumptive, meaning it is not certain that you do not have COVID-19. Y ou may still haveCOVID-19 and you may still be contagious. There is a higher chance of false negative results with antigentests compared to laboratory-based tests such as PCR. If you test negative and continue to experienceCOVID-19-like symptoms, (e.g., fever, cough, and/or shortness of breath) you should seek follow up carewith your health care provider.An invalid result means this test was unable to determine whether you have COVID-19 or not. Re-test witha new swab and new test device. Please contact Technical Support at + 1 833-637-1594.For Use Under an Emergency Use Authorization (EUA) OnlyFor use with anterior nasal swab specimensFor in vitro Diagnostic Use Only13. Do not use kit past its expiration date.14. Do not mix components from different kit lots.15. All kit components are single use items. Do not use with multiple specimens. Do not reuse the used test card.16. Dispose of kit components and patient samples in household trash.17. INVALID RESULTS can occur when an insufficient volume of extraction reagent is added to the test card. Toensure delivery of adequate volume, hold bottle vertically, 1/2 inch above the swab well, and add drops slowly.18. Serial testing should be performed in individuals with negative results at least twice over three days (with48 hours between tests) for symptomatic individuals and three times over five days (with at least 48 hoursbetween tests) for asymptomatic individuals. Y ou may need to purchase additional tests to perform thisserial (repeat) testing.19. An anterior nasal swab sample can be self-collected by an individual age 15 years and older. Children age 2 to15 years should be tested by an adult.20. If you have had symptoms longer than seven days, you should consider testing at least three times over fivedays with at least 48 hours between tests.21. Do not use on anyone under 2 years of age.22. Do not read test results before 15 minutes or after 30 minutes. Results read before 15 minutes or after 30minutes may lead to a false positive, false negative, or invalid result.23. There is a higher chance of false negative results with antigen tests than with laboratory-based molecular tests.This means that there is a higher chance this test will give you a negative result when you have COVID-19.24. The Reagent Solution contains a harmful chemical (see table below). Do not ingest any kit components. Ifthe solution contacts the skin or eye, flush with copious amounts of water. If irritation persists, seek medicallegal-regulatory-and-policy-framework/emergencyuse-authorizationFor the most up to date information on COVID-19, please visit: /COVID19STORAGE and STABILITYStore kit between 35.6-86°F (2-30°C). Ensure all test components are at room temperature before use.The BinaxNOW COVID-19 Antigen Self Test is stable until the expiration date marked on the outer packagingand containers. For information about current expiration dates for at-home OTC COVID-19 diagnostic tests,visit /covid-tests.Read all instructions carefully before performing the test. Failure to follow theinstructions may result in inaccurate test results.Test Card Parts:Top HoleTopINSTRUCTIONS - START HERECarefully read instructions prior to starting test.It is recommended gloves (not provided) also be usedduring testing. See other side for important information.6 drops: False negative result may occur if more Abbott Rapid DiagnosticsTechnical SupportUS+ 1-833-637-1594*****************Abbott Diagnostics Scarborough, Inc.10 Southgate RoadScarborough, Maine 04074 USAwww.globalpointofcare.eifu.abbott© 2023 Abbott. All rights reserved.All trademarks referenced are trademarks of either theAbbott group of companies or their respective owners.IN195150WEB Rev. 6 2023/01BinaxNOW™ANTIGEN SELF TESTCOVID-193x。

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USED RAFT C ONSENSUS G UIDELINED ATAE LEMENTS AND S TANDARDS FORD RUG D ICTIONARIESM5Current Step 2 versiondated 10 May 2005At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Steering Committee to the regulatory authorities of the three ICH regions (the European Union, Japan and the USA) for internal and external consultation, according to national or regional procedures.M5 Document HistoryCurrent Step 2 versionD ATAE LEMENTS AND S TANDARDS FOR D RUG D ICTIONARIESDraft ICH Consensus GuidelineReleased for Consultation on 10 May 2005, at Step 2 of the ICH ProcessTABLE OF CONTENTS1.INTRODUCTION (1)1.1.Objectives of the Guideline (1)1.2Background (2)1.3Scope of the Guideline (2)2.GUIDELINE (2)2.1Medicinal Product and Term Identifiers (2)2.1.1Medicinal Product Identifier (MedID) (2)2.1.2Pharmaceutical Product Identifier (PhPID) (3)2.1.3Controlled Vocabulary Term Identifier (TermID) (4)2.2Controlled Vocabulary (4)2.2.1Background (4)2.2.2Active Ingredients Controlled Vocabulary (5)2.2.3Pharmaceutical Dose Form Controlled Vocabulary (6)2.2.4Routes of Administration Controlled Vocabulary (7)2.2.5Units and Measurements Controlled Vocabulary (9)2.3Data Elements (10)2.3.1Medicinal Product Identifier (12)2.3.2Medicinal Product Administrative Section (12)2.3.3Marketing Authorization Holder/Manufacturer/DistributorSection (14)2.3.4Marketing Authorization Section (15)2.3.5Pharmaceutical Product Section (17)2.3.6Active Ingredient(s) Section (19)2.3.7Pharmaceutical Dose Form Section (22)2.3.8Route of Administration Section (22)2.3.9Maintenance Section (23)3.GLOSSARY (25)4.REFERENCES (27)D ATAE LEMENTS AND S TANDARDS FOR D RUG D ICTIONARIES1. INTRODUCTION1.1. Objectives of the GuidelineIt is desirable for regulators and pharmaceutical industry to engage in an intensive information exchange during the drug development phase, the drug evaluation and approval phase and the post-authorization phase. The standardization of medicinal product information is regarded as one of the key elements of this information flow. However, regulators in the ICH regions and observer countries have established their own procedures and applications with standards that differ in data format, content, language and applied terminology (e.g., terminology used for active ingredients, routes of administration, pharmaceutical dose forms).Due to the lack of a common and harmonized approach, both regulators and pharmaceutical industry are confronted with the following issues:-No possibility to exchange medicinal product information between regulators and industry in a structured and efficient way;-Difficulties in ensuring data consistency and in evaluating and comparing medicinal product-related information across the ICH regions due to the lack of harmonized definitions of terminologies and data sets. This currently impairs pharmacovigilance activities in particular;-For the pharmaceutical industry, major administrative burdens and duplication of efforts requiring substantial human and financial resources to comply with and handle different regional requirements;-Lack of consistency in the use of terminology in the health care community. The objectives of this guideline are to address the issues outlined above by developing harmonized standards that build on the processes currently established in the three ICH regions and the observer countries and to support the population of existing systems/applications with fully reliable regulatory medicinal product information. More specifically, the objectives focus on the development of:-‗Unique identifiers‘ at the level of▪Medicinal products: Medicinal Product Identifiers (MedIDs);▪Pharmaceutical products: Pharmaceutical Product Identifiers (PhPIDs);▪The controlled vocabulary: Terminology Identifiers (TermIDs).-‘Controlled vocabulary’ as a standard for the electronic transmission of core sets of medicinal product information related to the following terminologies: ▪Active ingredients;▪Pharmaceutical dose forms;▪Routes of administration;▪Units and measurements.-‗Data elements’ for the electronic transmission of core sets of medicinal product information based on the following data set:▪Proprietary medicinal product name;▪Active ingredient(s);Data Elements and Standards for Drug Dictionaries▪Pharmaceutical dose form(s);▪Strength of the active ingredient(s);▪Route(s) of administration;▪Marketing authorization holder;▪Marketing authorization number;▪Country of authorization.The ‗Data elements’ have been developed for the electronic transmission of MedIDs and the related core medicinal product information.This guideline does not cover the establishment and maintenance of a drug dictionary.1.2 BackgroundThe lack of internationally harmonized standards related to core sets of medicinal product information and medicinal product terminology is hindering the scientific evaluation and comparison of product data as well as healthcare. This applies in particular to the area of pharmacovigilance, where the exchange and management of medicinal product information in expedited and periodic adverse reaction reports at the international level is a key aspect of ensuring drug safety.This document provides guidance on the harmonized standards that are being proposed by the ICH M5 EWG to facilitate the exchange and practical use of medicinal product data by regulators and pharmaceutical industry.1.3 Scope of the GuidelineThis guideline refers to approved medicinal products. Homeopathic medicinal products and investigational medicinal products are excluded from this guideline. 2. GUIDELINE2.1 Medicinal Product and Term Identifiers2.1.1 Medicinal Product Identifier (MedID)Definition:An identifier assigned to a medicinal product by the regulator of the country/territory of authorization.General Conventions:The regulators in the regions and observer countries have various processes established to identify individual medicinal products. Because medicinal product information is exchanged internationally, worldwide unique medicinal product identifiers (MedIDs) are desirable.Regulators intend to assign MedIDs as follows:▪At the ‘medicinal product level’, which means that a specific medicinal product has only one identifier for different pack sizes.For example, the medicinal product ‗TRADENAME X‘ has the same MedID related to two different presentations; a pack size of 50 tablets and a pack size of 100 tablets.Data Elements and Standards for Drug Dictionariesor▪At ‘medicinal product package level’, which means that for each package presentation of the medicinal product a different MedID is assigned.For example, the medicinal product ‗TRADENAME Y‘ has two different MedIDs for each of the two different presentations available: a MedID for the pack size of 50 tablets and a MedID for the pack size of 100 tablets. Methodology:The world-wide unique MedID is constructed as follows:▪Prefix of the country code of that region followed by▪The regionally-assigned identifier followed by▪An error detection codeThe regionally-assigned identifier refers to the medicinal product level or to the medicinal product package level. As a general rule, the MedID should accompany the exchange of the medicinal product information.Examples:EU-EU/1/2342323/001-KFR-123456-XJP-123456789-YUS-0123456789-ZCA-2323232-V2.1.2 Pharmaceutical Product Identifier (PhPID)Definition:An identifier assigned at the level of the pharmaceutical product based on the active ingredient(s), the strength(s) of the ingredient(s) and the pharmaceutical dose form. Methodology:PhPIDs represent the pharmaceutical product at four levels as defined as follows: -PhPID4 = Ingredient(s) - Strength(s) - Strength unit(s) -Pharmaceutical Dose Form-PhPID3 = Ingredient(s) - Pharmaceutical Dose Form-PhPID2 = Ingredient(s) - Strength(s) - Strength unit(s)-PhPID1 = Ingredient(s)Each PhPID is a unique, non-semantic, alphanumeric code and is derived from the ICH M5 data elements, but is not part of these data elements.Data Elements and Standards for Drug DictionariesExamples:Medicinal products with the same active ingredients, strengths and pharmaceutical dose form share a common PhPID4.Medicinal products with the same active ingredients and pharmaceutical dose form share a common PhPID3.Medicinal products with the same active ingredients and strengths share a common PhPID2.Medicinal products with the same active ingredients share a common PhPID1.2.1.3 Controlled Vocabulary Term Identifier (TermID)Definition:An identifier assigned at the level of each term of the controlled vocabulary (active ingredients, pharmaceutical dose forms, routes of administrations and units and measurements).Methodology:The TermID is a unique, non-semantic, alphanumeric code assigned for each term of the controlled vocabulary.2.2 Controlled Vocabulary2.2.1 BackgroundDifferent regulatory standard terminologies are in place in the ICH regions and observer countries, which makes it difficult to exchange this information at the international level. These terminology differences complicate specifically activities in the area of pharmacovigilance and healthcare and the management of medicinal product information.To address the identified terminology differences, the ICH M5 EWG is developing controlled vocabularies for active ingredient(s), pharmaceutical dose form(s), route(s) of administrations and unit(s) and measurement(s) using the following methodology: -Preparing an inventory of the different regulatory standard terminologies including those defined in the ICH E2B(M) guideline (version 4.4.1 includes the Post Step 4 corrections agreed by the Steering Committee on 5 February 2001);-Analyzing definitions for the different regulatory standard terminologies;-Developing a controlled vocabulary that supports good terminological practice;-Defining mapping procedures to determine unique terms and related synonym terms on the basis of the regional definitions in place;-Mapping the individual terms;-Assigning unique TermIDs.The Active Ingredients Controlled Vocabulary, the Pharmaceutical Dose Forms Controlled Vocabulary, the Routes of Administration Controlled Vocabulary and theData Elements and Standards for Drug Dictionaries Units and Measurements Controlled Vocabulary will be made available on the ICH website.2.2.2 Active Ingredients Controlled VocabularyScope:The Active Ingredients Controlled Vocabulary includes active ingredient terms related to approved medicinal products. Excluded are active ingredients related to homeopathic medicinal products and investigational medicinal products. Definitions:An active ingredient is defined as a substance that alone or in combination with one or more other ingredients produces the intended activity of a medicinal product.A substance is any matter and can be of human, animal, vegetable or chemical (natural, semi-synthetic or synthetic) origin.An active moiety is the portion of the active ingredient that is responsible for the effect.Methodology:A comprehensive list of active ingredient terms has been collected based on the standard terminologies currently used by the EMEA, FDA, MHLW and Health Canada.The active ingredient terms are limited to English language terms, with the exception of herbal active ingredients, for which the Latin language terms and/or Japanese language terms are also included.Within the list, the indication of the provenance of the term (i.e., its source) is also included.An active ingredient TermID will be assigned to each unique term.The following approach will be used for the mapping:-Chemical Abstract Service Number (CAS Number);-Reference Source for each active ingredient name (e.g., USAN, INN, JAN) that is linked to the chemical structure by the organizations;-Chemical name (e.g., following the IUPAC nomenclature).Mapping of synonyms will be performed on the level of both the active moiety and the active ingredient where applicable.Herbal substances will be mapped on the following principles:-Botanical scientific name according to the Latin binomial system (genus + species);-The author (e.g., Linnaeus, abbreviated L.) if known;-The plant parts (if known); and-The process (when applicable, and if known).Herbal preparations will be mapped on the basis of the standardized treatments (for instance extraction, distillation, expression, fractionation, purification, concentrationData Elements and Standards for Drug Dictionariesor fermentation) as described in the official Pharmacopoeias of the three regions. For extractions, the solvent will also be specified.For vaccine antigens the mapping of active substances will be based on the following principles:-Conformity with the pharmacopoeia monograph terminology for vaccine antigens in the regions;-For non-pharmacopoeia active substances, according to the formal Latin/Greek name and/or the disease being protected against.For bacteria and viruses, the strain serotype or other appropriate sub-species the designation will also be mapped with the name of each antigen, if relevant.In addition, the nature of any cellular system(s) used for production, and if relevant the use of recombinant DNA technology (including the use of the expression ‗produced in XXX cells <by recombinant DNA technology>) will be mapped, following the pattern set by the following examples:-‗produced in human diploid (MRC-5) cells‘;-‗produced in Escherichia coli cells by recombinant DNA technology‘;-‗produced in chick-embryo cells‘.The inclusion of a mention of the production process in vaccine active substance names will be mapped at the level of the following terms:-‗live, attenuated‘ (in the case of vaccines containing living micro-organisms);-‗inactivated‘ (in the case of vaccines containing killed micro-organisms). 2.2.3 Pharmaceutical Dose Form Controlled VocabularyScope:The Pharmaceutical Dose Form Controlled Vocabulary includes pharmaceutical dose form terms of standard terminologies in use by the regulators in the ICH regions and observer countries.Definitions:A Dose Form is defined as the physical manifestation [―entity‖] that contains the active and/or inactive ingredients that deliver a dose of the medicinal product. The key defining characteristics of the Dose Form can be the state of matter, delivery method, release characteristics, and the administration site or route for which the product is formulated.A Pharmaceutical Dose Form is the form in which a pharmaceutical product is presented in the medicinal product package as supplied by the marketing authorization holder/manufacturer/distributor.Methodology:A comprehensive list of Dose Form terms has been collected, which includes:-European Pharmacopoeia Standard terms;-United States Pharmacopeia (USP) terms;-Japanese Pharmacopoeia terms;-MHLW terms;-Health Canada terms.Within the list, the indication of the provenance of the term (i.e., its source) will also be included.Tasks to be undertaken include:- A term identifier will be allocated to each term (entry) in the list, enabling linkage with original dose form lists;-Each term will initially be identified as a ―dose form concept‖, pending identification of synonymy;-Synonymous terms will be identified and ―annotated‖ e.g., ―otic drops‖ and ―ear drops‖;-Terms that do not fit (for example, device terms) will be identified and annotated, as will be all terms that do not fit within the agreed definition(for example, dose forms that describe aspects of medication such asstrength or shape or indication);-Each of the ―dose form concepts‖ will be analyzed against the ag reed defining characteristics to create a logical description pattern. Thispattern will assist in the identification of unrecognized synonymy andhence will ensure that the resulting Dose Form concepts are unique andunambiguous. A description logic will enable concepts to be defined by thepattern or ―graph‖ of their relationships with other concepts;-Having analyzed all the ―dose form concepts‖, any concepts found to be sharing an identical ―set‖ of characteristics will again be reviewed;additional ―distinguishing‖ characteristics will be added as appropriate. The dose form description applies to only one concept at a time. Therefore, items that are marketed as packs containing more than one medicinal product will not themselves have a ―combination dose form‖, but each medicinal product within them will have a dose form description. This will avoid terms such as ―pessary + cream‖ or ―powder + solvent‖.2.2.4 Routes of Administration Controlled VocabularyScope:The Routes of Administration Controlled Vocabulary includes routes of administration terms of standard terminologies in use by the regulators in the ICH regions and observer countries and defined in the ICH E2B(M) guideline (version 4.4.1 includes the Post Step 4 corrections agreed by the Steering Committee on 5 February 2001).Definitions:The Route of Administration indicates the part of the body through or into which, or the way in which, the medicinal product is intended to be introduced.In some cases a medicinal product can be intended for more than one route and/or method of administration.Methodology:A comprehensive list of Route of Administration terms has been collected and includes:-European Pharmacopoeia Standard terms;-United States Pharmacopeia (USP) terms;-Health Canada terms;-MHLW terms;-ICH E2B(M) Routes of Administration List.Each term is given an identifier, a description and relationships to other terms within the terminology.Tasks undertaken include:- A term identifier is allocated to each term (entry) in the list, enabling linkage with the original route of administration term lists;-Within the list there is an indication of the provenance of the term (i.e., its source). A formal definition from the source vocabulary is included, wherenecessary.Synonymous terms are id entified and ―annotated‖ e.g., ocular use and ophthalmic use.-The route of administration terms are mapped on the basis of the same or the equivalent meaning for route of administration purposes e.g., ocular,ophthalmic. In specific cases the regional definitions were crosschecked toclarify the meaning;-An adjective is used to describe the route of administration where a suitable adjective is available, e.g., inhalational not inhalation;-The descriptor 'use' is generally not supported unless it adds a specific meaning e.g., ‗oral‘ was used instead of ‗oral use‘;-Where a prefix and a main word in the terms are concatenated, the concatenated word is hyphenated only if the ending of the prefix and thebeginning of the next word were both vowels (a, e, i, o, u);-Where a suitable ICH E2B(M) route of administration term exists, this is used as the basis for the official ICH M5 Route of AdministrationControlled Vocabulary term. Where a suitable ICH E2B(M) route ofadministration term is not available to represent the route concept, a newterm is added to the vocabulary. In either case, the above procedures areapplied;-The Routes of Administration Controlled Vocabulary presents the corresponding terms (translations) applicable in the different regions andin the E2B(M) list as follows:o MedID: e.g., 001;o ICH M5 Route of Administration Term e.g., Auricular (OTIC);o Regional Standard Terms:▪EU e.g., Auricular Use;▪FDA e.g., Auricular (OTIC);▪MHLW e.g., Otological Agent;▪Health Canada e.g., OTIC;▪E2B(M) e.g., Auricular (OTIC).-Where, within one region, two or more terms (e.g., a current term and a historic non-current term) refer to the same route of administration, these terms were specified in sequence and separated by the symbol "/". The preferred or current term is specified as the first term, e.g., ocular use/ophthalmic use for EU or unknown/unassigned for the US;- A draft translation for the ICH M5 Routes of Administration Controlled Vocabulary in Japanese has been included.2.2.5 Units and Measurements Controlled VocabularyScope:The Units and Measurements Controlled Vocabulary includes units and measurements in use by the regulators in the ICH regions and observer countries and defined in the ICH E2B(M) guideline (version 4.4.1 includes the Post Step 4 corrections agreed by the Steering Committee on 5 February 2001).General Conventions:The International System of Units (SI) and the Units and Measurements as described in the E2B(M) guideline, (version 4.4.1 includes the Post Step 4 corrections agreed by the Steering Committee on 5 February 2001) are followed in the ICH regions and observer countries. Additional, region specific units are in use specifically regarding biological and microbiological units.Methodology:A comprehensive list of Units and Measurements has been collected and includes:-International System of Units (SI);-Units and Measurements as described in the E2B(M) guideline1;-Region specific units and measurements (CA, EU, JP, US).Each unit and measurement is given an identifier, a description, a symbol and relationships to other terms within the terminology.Tasks undertaken include:- A term identifier is allocated to each unit and measurement (entry) in the list, enabling linkage with the original unit and measurement entries inthe lists;-Within the list there is an indication of the provenance of the term (i.e., its source) and a formal definition from the source vocabulary is included,where appropriate;-Synonymous entries are identified and ―annotated‖ e.g., %(v/v) and (v/v)%; 1Version 4.4.1 includes the Post Step 4 corrections agreed by the Steering Committee on 5 February 2001-The mapping of Units and Measurements is based on the International System of Units (SI) and its abbreviations and definitions. The definitionsof the SI base units refer to the NIST Special Publication 330 (SP 330);-Lower case has been used for the term description;-Exponents of symbols are not expressed in superscript format; e.g., the symbol ‗m2‘ has been used for square meters;-Some important and widely used units outside the International System have been added with regard to biological and microbiological units.Descriptions of these units and their abbreviations were added asappropriate.2.3 Data ElementsThis chapter describes the data elements for the electronic transmission of a core set of medicinal product information.The data elements as presented in this guideline refer to the consolidated core data sets of medicinal products as defined in the scope of this guideline, chapter 0.These data elements are based on the regional standards already established by these regulators to support the local data collection process and do not replace or supersede the regional standards or legal requirements for data collection between the regulators and pharmaceutical companies.As a result, a medicinal product is characterized in the frame of this guideline as follows:▪ A Medicinal Product has:o One and only one MedID;o One and only one Medicinal Product Name;o One and only one Marketing Authorization Holder;o One and only one Marketing Authorization (number);o One or more Pharmaceutical Products.▪ A Pharmaceutical Product has:o One or more Active Ingredients with a specific strength (the same active ingredient with a different strength is considered a differentpharmaceutical product);o One and only one Pharmaceutical Dose Form;o One or more possible Routes of Administration.In order to facilitate the understanding of the relationship of the data elements described in this chapter, a conceptual model is included as follows:Figure 1 - Conceptual Model of the ICH M5 MedID and Data Element SetThis conceptual model does not define the actual message specifications for the exchange format of MedIDs and the related ICH M5 data elements.The figure provides the relationship between the ICH M5 data elements and the MedID.▪All data elements are grouped as elements or attributes within a section;▪ A section defines a concept which is further described by its data elements or attributes;▪The data elements are flagged as Mandatory2 (M:) or Optional (O:);▪The data elements for which the entry is strictly controlled by a list of values(e.g., ISO Country Code 3166) or by the ICH M5 Controlled Vocabulary are initalics.There are relationships between entities, with a specific cardinality.▪The relationship with cardinality 1..1 means that, for example, a Pharmaceutical Product has precisely one pharmaceutical dose form;▪The relationship with cardinality 1..n means that, for example, a Pharmaceutical Product has one or more Active Ingredients.Each section and each element of the ICH M5 data element set is described in the following paragraphs.2The use of ‘Mandatory’ in the remainder of this document refers to technical and not legal requirements.As a general principle, it should be noted that depending on regional laws and regulations a formal marketing authorization might not be required for certain categories of medicinal products (e.g., certain OTC drugs, ‗grandfather‘ drugs). For these medicinal products the same principles apply as for ‗authorised‘ medicinal products.2.3.1 Medicinal Product Identifier2.3.1.1. Medicinal Product Identifier (MedID)User Guidance:The MedID as defined in chapter 0 of the medicinal product and as presented in the ICH M5 data element set should be provided in this field.As a general rule, the MedID should be maintained in any re-transmission of the same medicinal product information.Type:MandatoryExample:FR-123456-XEU-EU/1/2342323/001-KJP-123456789-YUS-0123456789-ZCA-2323232-V2.3.2 Medicinal Product Administrative Section2.3.2.1 Medicinal Product NameDefinition:The name assigned to a medicinal product as approved by the regulator of the country of authorization.User Guidance:The naming of a medicinal product differs in the ICH regions and observer countries.The full and complete medicinal product name as approved by the regulator of the country or territory of authorization and as appearing on the package of the medicinal product, the container or the package insert should be provided in this field.For medicinal products which do not require prior marketing authorization under regional law, the full and complete medicinal product name as appearing on the package of the medicinal product, the container or the package insert should be provided in this field.Synonyms:Proprietary Medicinal Product Name (ICH E2B(M))Name of the Medicinal ProductProduct NameType:MandatoryExamples:Lithium Carbonate liq. Paediatric Company DABC Tabs 500 Company BVinblastine Sulphate Injection Solution 10mg/mlTri-Product C ForteProduct X Oral GelBRANDX 100 U/ml Concentrate for solution for infusion-Intravenous use Vial (glass) 5 ml (100 U/ml) 1 vial2.3.2.2 Medicinal Product Short NameDefinition:The medicinal product name without the trademark or the name of the marketing authorization holder or any other descriptor (e.g., strength, dosage form, user group, route of administration).User Guidance:The name assigned to a medicinal product as approved by the regulator of the country or territory of authorization, without the trademark or the name of the marketing authorization holder or any other descriptor should be provided in this field.For medicinal products which do not require prior marketing authorization under regional law, the medicinal product name without the trademark or the name of the manufacturer/distributor or any other descriptor should be provided in this field.Synonyms:Trade NameBrand NameScientific NameCommon NameInvented NameType:Optional。

VALIDATION OF COMPENDIAL PROCEDURES 药典方法的验证Test procedures for assessment of the quality levels of pharmaceutical articles are subject to various requirements. According to Section 501 of the Federal Food, Drug, and Cosmetic Act, assays and specifications in monographs of the United States Pharmacopeia and the National Formulary constitute legal standards. The Current Good Manufacturing Practice regulations [21 CFR 211.194(a)] require that test methods, which are used for assessing compliance of pharmaceutical articles with established specifications, must meet proper standards of accuracy and reliability. Also, according to these regulations [21 CFR 211.194(a)(2)], users of analytical methods describedin USP–NF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Recognizing the legal status of USP and NF standards, it is essential, therefore, that proposals for adoption of new or revised compendial analytical procedures be supported by sufficient laboratory data to document their validity.用于评估药品质量的检验方法需要满足不同的要求。

Generic Drug Facilities, Sites, and Organizations Guidance for IndustryU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)September 2016GenericsGeneric Drug Facilities, Sites, and Organizations Guidance for IndustryAdditional copies are available from:Office of Communications,Division of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administration10001 New Hampshire Ave., Hillandale Bldg., 4th FloorSilver Spring, MD 20993-0002Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353Email: druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm7519 Standish Place, Rockville, MD 20855Phone: 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)September 2016GenericsTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.GDUFA SELF-IDENTIFICATION REQUIREMENTS (2)A.Who Is Required to Self-Identify? (3)B.What Information Is Required for Submission? (4)1.D-U-N-S Numbers (4)2. Facility Establishment Identifier (5)3.Additional Information (5)C.What Is the Process for Submitting Self-Identification Information? (5)D.What Is the Penalty for Failing to Self-Identify? (6)iSelf-Identification of Generic Drug Facilities, Sites, andOrganizationsGuidance for Industry1This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.I. INTRODUCTIONThis guidance is intended to assist human generic drug facilities, sites, and organizations by describing how to comply with the self-identification requirement contained in the Generic Drug User Fee Amendments of 2012 (Public Law 112-144, Title III), commonly referred to as GDUFA.Under GDUFA, human generic drug facilities, sites, and organizations are required to submit identification information electronically to FDA annually. FDA is issuing this guidance to help human generic drug facilities, sites, and organizations meet the self-identification requirement. Topics discussed in this guidance include:•which types of generic facilities, sites, and organizations are required to self-identify;•what information is requested;•what technical standards are to be used for electronically submitting the requested information; and•the penalty for failing to self-identify.This guidance also explains generally which types of generic facilities, sites, and organizations will be required to pay user fees.FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.II. BACKGROUNDOn July 9, 2012, GDUFA was signed into law by the President.2 GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry. GDUFA enables FDA to assess user fees to support critical and measurable enhancements to FDA’s generic drugs program. GDUFA will also significantly improve global supply chain transparency by requiring owners of facilities producing generic drug products, active pharmaceutical ingredients (API), and certain other sites and organizations that support the manufacture or approval of these products to electronically self-identify with FDA and update that information annually.Self-identification is required for two purposes. First, it is necessary to determine the universe of facilities required to pay user fees. Second, self-identification is a central component of an effort to promote global supply chain transparency. The information provided through self-identification enables quick, accurate, and reliable surveillance of generic drugs and facilitates inspections and compliance.Most facilities that self-identify are required to pay an annual facility user fee. These include facilities manufacturing, or intending to manufacture, API of human generic drugs and/or finished dosage form (FDF) human generic drugs. Other sites and organizations must self-identify, but are not required to pay the annual facility user fee. These include facilities that solely manufacture positron emission tomography (PET) drugs, or sites and organizations that only perform testing, repackaging, or relabeling operations. Please note that while repackagers are not required to pay user fees, packagers are, in most cases, FDF manufacturers and subject to facility fees.A separate system for the electronic self-identification of generic industry facilities, sites, and organizations was established for GDUFA. Entities required to register and list (under section 510 of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public Health Service Act), and those required to self-identify under GDUFA submit information separately to the respective systems. Each system populates its own database to meet unique requirements and deadlines. The separate GDUFA system uses the same platform and technical standards already familiar to manufacturers required to register and list.III.GDUFA SELF-IDENTIFICATION REQUIREMENTSThe following discussion explains who is required to self-identify, what information is required for submission, and what the process is for submitting self-identification information.2 On October 5, 2012 the President signed into law the FDA User Fee Correction Act of 2012. This act amends GDUFA so that due dates for GDUFA user fees in fiscal year 2013 are not dependent on enactment of an appropriations act.A. Who Is Required to Self-Identify?The following types of generic industry facilities, sites, and organizations are required to self-identify with FDA:1. Facilities3 that manufacture, or intend to manufacture, human generic drug APIs or FDFs,or both.42. Facilities that package the FDF of a human generic drug into the primarycontainer/closure system and label the primary container/closure system.53. Sites that are identified in a generic drug submission and pursuant to a contract with theapplicant remove the drug from a primary container/closure system and subdivide thecontents into a different primary container/closure system.3 GDUFA has defined the term “facility” to identify those businesses required to pay fees and for self-identification. GDUFA defines a facility as a business or other entity under one management, either direct or indirect, at one geographic location or address, engaged in manufacturing or processing an API or an FDF. It does not include a business or other entity whose only manufacturing or processing activities are one or more of the following: repackaging, relabeling, or testing. Separate buildings within close proximity are considered to be at one geographic location or address if the activities in them are closely related to the same business enterprise; are under the supervision of the same local management; and are capable of being inspected by FDA during a single inspection. GDUFA further states that if a business entity would meet the definition of a facility but for being under multiple management, the business or entity is deemed to constitute multiple facilities, one per management entity.4 For purposes of self-identification and payment of fees, GDUFA defines API and FDF manufacturers differently from the way these categories of manufacturers have been defined historically. For example, generic drug manufacturers who mix an API when the substance is unstable or cannot be transported on its own are considered API manufacturers and not FDF manufacturers for self-identification and the payment of GDUFA fees only. GDUFA defines an FDF as:(A) a drug product in the form in which it will be administered to a patient, such as atablet, capsule, solution, or topical application;(B) a drug product in a form in which reconstitution is necessary prior to administration to a patient, such as oralsuspensions or lyophilized powders; or(C) any combination of an active pharmaceutical ingredient (as defined in the statute) with another component ofa drug product for purposes of production of a drug product described in subparagraph (A) or (B).GDUFA defines an API as:(A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended—(i) to be used as a component of a drug; and(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body; or(B) a substance intended for final crystallization, purification, or salt formation, or any combination of thoseactivities, to become a substance or mixture described in subparagraph (A).5 Facilities that package the FDF of a human generic drug into the primary container/closure system and label the primary container/closure system are considered to be manufacturers, whether or not that packaging is done pursuant to a contract or by the applicant itself.4. Bioequivalence (BE)/bioavailability (BA) sites that are identified in a generic drugsubmission and conduct clinical BE/BA testing, bioanalytical testing of samples collected from clinical BE/BA testing, and/or in vitro BE testing.5.Sites that are identified in a generic drug submission and perform testing of one or moreattributes or characteristics of the FDF or the API pursuant to a contract with theapplicant to satisfy a current good manufacturing practice (CGMP) testing requirement(excludes sites that are testing for research purposes only).B.What Information Is Required for Submission?The following information is required to meet the self-identification requirement in GDUFA:1. D-U-N-S NumbersFDA requires Data Universal Numbering System (D-U-N-S) numbers for both the facility or site and the registrant owner of the facility or site if the facility or site is in a different location than the registrant owner location. A D-U-N-S number is required to uniquely identify the registrant (the owner or operator) and each physical location of the business’s facility or site (e.g., branches, divisions, and headquarters).A D-U-N-S number is a unique nine-digit sequence provided by Dun & Bradstreet. TheD-U-N-S number is specific for each site. Each distinct physical location of an entity (e.g., branch, division, and headquarter) would be assigned a different D-U-N-S number.The site-specific D-U-N-S number is a widely recognized business identification tool and serves as a useful resource for FDA in identifying and verifying certain business information submitted by a user.If no D-U-N-S number has been assigned, a business entity may obtain one at no cost directly from Dun & Bradstreet. A new number may be obtained, or an existing number verified, by phone or online. Existing facilities D-U-N-S numbers may also be verified on FDA’s current registration site for drug establishments.6Note: It takes Dun & Bradstreet approximately 30 business days to process a newD-U-N-S number and communicate it via email. A business entity may receive aD-U-N-S number in approximately 10 business days for an expedited service fee. Please note that a business entity may not request or apply for a new D-U-N-S number on behalf of another business entity due to the verification procedures used by Dun & Bradstreet. More information is available at the Dun & Bradstreet web page. See also the step-by-step instructions for obtaining a D-U-N-S number for businesses based either in the United States or abroad.6/scripts/cder/drls/default.cfm2. Facility Establishment IdentifierFacilities must also submit a Facility Establishment Identifier (FEI), a unique identifier designated by FDA to assign, monitor, and track inspections of regulated firms. 7A business entity that has previously obtained an FEI number may verify its FEI number by sending an email request to FDAGDUFAFEIRequest@.Alternatively, business entities that have not previously registered with FDA can obtain an FEI number by sending an email request to FDAGDUFAFEIRequest@. Please type “GDUFA FEI Request” in the subject line and include the following information in the body of the email:Firm NameFacility Address including City, Province, Country, and Mail CodeSize of FirmType of Operation (Manufacturer, Lab, etc.)Type of Industry: DrugsRequests for issuance of FEI numbers associated with GDUFA self-identification are typically processed within 10 to 15 business days.3. Additional InformationFDA requests the name and contact information for the registrant owner and facility information, including name, type of business operation, and contact information. Submitters are also asked to indicate whether they manufacture drugs that are not generic drugs.C.What Is the Process for Submitting Self-Identification Information?The self-identification process is similar to other FDA electronic submission standards. Self-identification files should be formatted in the same electronic messaging standard used for drug registration and listing information and for the content of labeling for abbreviated new drug applications (ANDAs). This standard, known as Health Level Seven Structured Product Labeling (SPL), allows information to be exchanged, searched, and combined with other data sources in a manner that supports health information technology initiatives to improve patient care. Providing Regulatory Submissions in Electronic Format— Drug Establishment Registration and Drug Listing8provides detailed instructions on how to submit information using SPL. FDA also offers tools and information for creating and submitting SPL files. Additional information can be found at /edrls.7 For the Agency’s policy on the assignment of FEIs, please refer to Field Management Directive (FMD) #130, Official Establishment Inventory (OEI) Development and Maintenance, which provides standardized definitions and associated procedures to facilitate consistency of data in the OEI.8 /downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072339.pdfD.What Is the Penalty for Failing to Self-Identify?Although GDUFA provides no explicit penalty for sites and organizations that fail to comply with the self-identification requirement, the failure of a site or organization to comply with the law and self-identify may raise significant concerns about that site. Such failure is a factor that may increase the likelihood of a site inspection prior to approval. FDA does not expect to give priority to completion of inspections that are required simply because sites fail to comply with self-identification requirements.More importantly, under GDUFA, if a facility fails to self-identify, all FDF or API products manufactured at the facility and all FDFs containing APIs manufactured at the facility will be deemed misbranded.9 It is a violation of federal law to ship misbranded products in interstate commerce or to import them into the United States. Such violations can result in prosecution of those responsible, injunctions, or seizures of the misbranded products. Products that are deemed misbranded because of failure of the facility to self-identify are subject to being denied entry into the United States.9 21 U.S.C. §352(aa)FDA Tracking #: 14819 FRDTS # 2013-90 Drafted: ALeboeuf/OGD 11/2/2015Reviewed: DNaik/CDER/OPQ/OS/DQIRAM/DIB 11/3/2015PLoebach/ CDER/OC/OPRO/DRLS 11/4/2015Reviewed: SLevine/OGD 03/28/16Revised: HSchwirck/OGD 04/12/16Reviewed: MNguyen/OGD 04/13/16Cleared: DBeers/OCC 09/2/16Final: ALeBoeuf/OGDP 09/09/16。

WHO Model Formulary for ChildrenBased on the Second Model List of Essential Medicines for Children 2009世界卫生组织儿童标准处方集基于2009年儿童基本用药的第二个标准目录WHO Library Cataloguing-in-Publication Data:WHO model formulary for children 2010.Based on the second model list of essential medicines for children 2009.1.Essential drugs.2.Formularies.3.Pharmaceutical preparations.4.Child.5.Drug utilization. I.World Health Organization.ISBN 978 92 4 159932 0 (NLM classification: QV 55)世界卫生组织实验室出版数据目录：世界卫生组织儿童标准处方集基于2009年儿童基本用药的第二个标准处方集1．基本药物 2.处方一览表 3.药品制备 4儿童 5.药物ISBN 978 92 4 159932 0 (美国国立医学图书馆分类：QV55)World Health Organization 2010All rights reserved. Publications of the World Health Organization can be obtained fromWHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: ******************). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the aboveaddress(fax:+41227914806;e-mail:*******************).世界卫生组织2010版权所有。

欧盟GMP附录15确认和验证欧盟GMP附录15确认和验证ANNEX 15 附件15Qualification and Validation确认和验证Table of Contents 目录1. Qualification and Validation 确认和验证2. Planning for Validation 验证计划3. Documentation 文件4. Qualification 确认5. Process Validation 工艺验证6. Cleaning Validation 清洁验证7. Change Control 变更控制8. Revalidation 再验证9. Glossary 术语表Qualification and Validation 确认和验证Principle 原理1.This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation.1.本附件描述了确认和验证的原理，适用于医药产品的生产者。

Naming requirements for BiosimilarsA Biosimilar Medicinal Product, (also referred to as “biosimilar”) or Follow-on Protein Product (FOPP) as it is called in the United States, is a follow-on version of a previously approved recombinant biotechnology product, which is produced by a different manufacturer after patent expiry of the original. The advent of biosimilars has causeda debate as to whether the current INN (International Non-proprietary Name) systemfor medicines should be revised to assign each biological product a distinct INN. TheINN system was established by the World Health Organization in 1953 to «providehealth professionals with a unique and universally accepted available designated nameto identify each pharmaceutical substance». Novartis believes the INN should continueto identify the active substance and not the medicinal product, which is defined by the active substance together with its formulation.Novartis PositionNovartis Pharmaceuticals and Sandoz, the generic division of Novartis (both hereafter “Novartis”), develop and manufacture, among others, branded and biosimilar biopharmaceuticals, respectively. Novartis is unique among pharmaceutical companies in that it has large investments in both branded and generic drugs, and is therefore not advocating a particular position based on the commercial interests of a particular product. Instead, Novartis strongly supports a balanced position which advocates that the same standards of high quality and science consistently be applied to all medicines, that intellectual property be provided full protection, while recognizing the role that generic and biosimilar drugs can play in the health care system.Novartis supports the existing WHO INN system and its application to all pharmaceutical, including biological, substances as it facilitates clear identification, safe prescription and dispensing of medicines to patients. Novartis believes that the INN should remain to identify the active substance and not the medicinalproduct, which is defined by the active substance together with its formulation. Novartis advocates that only scientifically substantiated criteria should be used to allocate INNs, such as the current criteria for biological substances which are based on their molecular characteristics and distinguish according to e.g. differences in amino acid sequence.The biosimilar concept is based on the recognition that a biosimilar has been systematically developed using state-of-the-art analytical technology and process science combined in sound Quality by Design concepts designed to create a product that matches, i.e. is highly similar to, the reference product. Minor differences in the profiles of product-related substances and impurities (as classified in ICH guideline Q6B on “Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products”) are natural and to be expected. The relevance of such minor differences must be systematically evaluated using information available in the scientific literature as well as state-of-the-art analytical, biological and/or pre-clinical studies. Any such evaluation should follow the principles laid out in ICH guideline Q5E (“Comparability of Biotechnological/ Biological Products Subject to Changes in Their Manufacturing Process”): “The demonstration of comparability does not necessarily mean that the quality attributes […] are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy […].” Finally, safety and efficacy of biosimilar products are confirmed in clinical studies. These have to be designed in line with relevant guidelines or in consultation with the competent authorities.Novartis advocates that, if the main active component(s) is (are) identical and if the biosimilar product is approved to be similar to its reference product in all aspects required for its market authorization, it should be allocated the same INN. As the regulatory authority that evaluates the market authorization application of the biosimilar product possesses the technical expertise and the relevant information, it should equally assess, whether or not the biosimilar substance fulfills the requirements to justify the allocation of the INN used for the reference substance.1. Quality by Design means designing and developing products and manufacturing processes to ensurepredefined quality. In the case of biosimilars, product quality is predefined by the reference product.Novartis supports robust pharmacovigilance and traceability of all medicinal products, including biosimilars. Established procedures that use the distinct brand name of a product and/or the name of its manufacturer/sponsor in combination with the INN, together with the batch and lot number enable the identification of each medicinal product.。

Pedosphere24(1):13–38,2014ISSN1002-0160/CN32-1315/Pc 2014Soil Science Society of China Published by Elsevier B.V.and SciencePressSources and Deficiency Diseases of Mineral Nutrients inHuman Health and Nutrition:A ReviewU.C.GUPTA1,∗1and S.C.GUPTA21Agriculture and Agri-Canada Canada,Crops and Livestock Research Centre,Charlottetown,PE C1A4N6(Canada)2The Department of Plastic Surgery,Loma Linda University,Loma Linda,CA92354(USA)(Received August30,2013;revised December8,2013)ABSTRACTMineral nutrients are fundamentally metals and other inorganic compounds.The life cycle of these mineral nutrients begins in soil,their primary source.Soil provides minerals to plants and through the plants the minerals go to animals and humans;animal products are also the source of mineral nutrients for humans.Plant foods contain almost all of the mineral nutrients established as essential for human nutrition.They provide much of our skeletal structure,e.g.,bones and teeth.They are critical to countless body processes by serving as essential co-factors for a number of enzymes.Humans can not utilize most foods without critical minerals and enzymes responsible for digestion and absorption.Though mineral nutrients are essential nutrients,the body requires them in small,precise amounts.We require them in the form found in crops and they can be classified into three different categories:major, secondary,and micro or trace minerals.This classification is based upon their requirement rather than on their relative importance. Major minerals such as potassium(K)and phosphorus(P)are required in amounts of up to10g d−1.The daily requirement of secondary and micro minerals ranges from400to1500mg d−1and45μg d−1to11mg d−1,respectively.To protect humans from mineral nutrient deficiencies,the key is to consume a variety of foods in modest quantities,such as different whole grains,low fat dairy,and different meats,vegetables and fruits.For insurance purposes,a supplement containing various mineral nutrients can be taken daily.Key Words:deficiency diseases,deficiency symptoms,origin,recommended daily dose,toxicityCitation:Gupta,U.C.and Gupta,S.C.2014.Sources and deficiency diseases of mineral nutrients in human health and nutrition: A review.Pedosphere.24(1):13–38.INTRODUCTIONLike water,carbohydrates,proteins,fats,vitamins and the enzymes required to digest them,mineral nu-trients are also essential to life.Minerals are inorganic substances,present in all body tissues andfluids and their presence is necessary for the maintenance of cer-tain physicochemical processes which are essential to life(Soetan et al.,2010).Over99%of the adult body’s 1000–1200g calcium(Ca)is in the bones and teeth, yet the remainder,less than1%,plays an essential part in the functioning of many diverse vital activities,such as maintenance and functioning of cell membranes and activation of enzymes and hormone secretion(Wise-man,2002).Humans require a number of mineral nu-trients known to play key role in maintaining human health.This investigation will include mineral nutri-ents which have been shown to be essential and of ut-most importance to human health.Silica(Si),tin(Sn) and cobalt(Co)are excluded from discussion as these are in plentiful supply in nature and their deficiency is seldom encountered.Furthermore,the understanding of their roles is less exact.Carbon(C),oxygen(O)and hydrogen(H)are primarily derived from air and water and are not discussed;nitrogen(N),a major mineral, has also been excluded as it is a component of proteins and that is not a part of the objective of this study.Mineral nutrients are the key to the engines we know of as vitamins.No vitamin can be absorbed or can carry out its intended function without the spe-cific minerals in very particular amounts.Minerals are fundamentally metals and other inorganic compounds that provide much of our skeletal structure,e.g.,bones and teeth.In addition,they are critical to countless body processes(Wikipedia Foundation Inc.,2002).Mineral nutrients can be separated into major,se-condary and micro or trace minerals.This classifica-tion is based on their requirement by humans rather than their relative importance.The mineral nutrients included in this study are categorized as follows.Ma-jor:P and K;secondary:calcium(Ca),magnesium (Mg)and sulfur(S);and micro,trace or rare:boron∗1Corresponding author.E-mail:umesh.gupta@agr.gc.ca.14U.C.GUPTA AND S.C.GUPTA(B),chlorine(Cl),chromium(Cr),fluoride(Fl),iodine (I),iron(Fe),manganese(Mn),molybdenum(Mo), nickel(Ni),selenium(Se),sodium(Na),vanadium(V) and zinc(Zn).With ongoing and future research,this list is expected to grow longer.The objective of this review was to report up-to-date information on mineral nutrients,their origin and natural occurrence,sources,daily requirement,func-tions,symptoms associated with their deficiency dis-eases,and their role in human nutrition.NATURAL OCCURRENCE OF MINERALSPlant foods contain almost the entire nutrient mi-nerals and organic nutrients established as essential for human nutrition.Every form of living matter re-quires these inorganic elements or mineral nutrients for their normal life processes(Soetan,2010).Mine-rals are inorganic(non-carbon)containing nutrients and are either positively charged(cation)or nega-tively charged(anion).Mineral nutrients are elements remaining after foods are burned completely to ash (Greene,2000).The primary and the only source of mi-neral nutrients found in plants,animals and humans is soil.The kinds of nutrients found vary depending upon the origin of the soil.For example,B occurs in high concentrations in sedimentary rocks and in clay-rich marine sediment due to the relatively high concentra-tion of B in seawater(Samir et al.,2011).Deposits of B are found in association with volcanic activity and where marshes or lakes have evaporated under arid conditions(Samir et al.,2011).The abundance and diversity of nutrient minerals are controlled directly by their chemistry,in turn de-pendent upon elemental abundance in the earth.The majority of minerals are derived from the earth’s crust (Stipanuk and Caudill,2012).Eight elements in order of decreasing abundance are:O,Si,aluminum(Al),Fe, Mg,Ca,Na and K,which comprise98%of the earth’s crust by weight(Stipanuk and Caudill,2012).Inor-ganic minerals include matter other than plant or ani-mal and do not include C,H and O as in living things.RELATIONSHIP OF MINERAL NUTRIENTS TO HUMAN NUTRITIONMineral nutrients are absolutely essential for good health.Scientists have established that at least28mi-neral elements are indispensable for normal nutrition (Health Lifestyles Inc.,1993).Furthermore,they are even more important than cking vitamins, the body can make some use of minerals,but lacking minerals,vitamins are useless(Health Lifestyles Inc., 1993).The shocking fact is that even if one prides themselves on eating a well-balanced diet,they are probably among the95%of Americans who are lac-king in at least one major mineral nutrient.The root of this problem lies in a mineral-poor earth.As far back as1936,Senate Document No.264warned Ame-ricans that the soils used to grow fruits and vegetables were seriously deficient in needed minerals.Continu-ous cropping and the ravages of pollution were even then robbing the soil of the minerals needed to sustain life(Health Lifestyles Inc.,1993).Unlike the body’s complex organic compounds (carbohydrates,lipids,proteins,vitamins)that are used metabolically in the generation of energy,mine-rals are often found in the form of salts in the body that are inorganic and not metabolized(Carpenter et al.,2013).Minerals constitute about4to6percent of body weight—about one-half as Ca,one-quarter P as phosphates,and the remainder being made up of the other essential minerals that must be derived from the diet(Carpenter et al.,2013).Minerals not only impart hardness to bones and teeth but also function broadly in metabolism,e.g.,as electrolytes in controlling the movement of water in and out of cells,as components of enzyme systems,and as the constituents of many organic molecules(Carpenter et al.,2013).Mineral nutrition in humans is defined as the pro-cess by which substances in foods are transformed into body tissues and provide energy for the full range of physical and mental activities that make up human life(Carpenter et al.,2013).The ultimate goal of nu-tritional science is to promote optimal health and re-duce the risk of chronic diseases,such as cardiovascular disease and cancer,as well as to prevent classic nu-tritional deficiency diseases,such as kwashiorkor and pellagra(Carpenter et al.,2013)MAJOR CROP AND ANIMAL SOURCES AND THEIR RECOMMENDED DAILY DOSESRecommended daily doses of all mineral nutrients stu-diedAll foods contain several mineral nutrients;ho-wever,some are higher in certain minerals than other minerals.The recommended doses vary considerably as established by various agencies related to regulation of mineral nutrients in various foods.A dietary requirement is defined as the lowest con-tinuing intake of a nutrient that,for a specified indica-tor of adequacy,will maintain a defined level of nutri-ture in an individual(Sutherland et al.,1998).An es-sential dietary component is one that the body can not synthesize in sufficient quantities to maintain health.SOURCES AND DEFICIENCY DISEASES OF MINEARL NUTRIENTS15Recommended dietary allowances are based on esti-mates of the dietary requirements,and are designed to prevent deficiency diseases and promote health through an adequate diet(Lenntech,1998).In1996, the Food and Nutrition Board(FNB)began a revi-sion process of the recommended dietary allowances using as criteria specific indicators of adequacy and functional end points for reducing the risk of chronic diseases.Boron is a dietary component,and evidence from animal studies indicates that it is a dietary essential; it can not be synthesized in tissues,and organisms ex-posed to very low levels of B show developmental de-fects(Lenntech,1998).Recommended daily dosages of various mineral nutrients are reported in Table I.It is evident that their amounts vary considerably.BoronThe average B concentration in the earth’s crust is17mg kg−1and most soils fall within the range of 3–100mg kg−1(Samir et al.,2011).In general,these amounts in soils are lower than most essential micronu-trients with the exception of Mo and Se.Deficiency of B has been found to affect the physi-ology of human beings(Shaaban,2010).Boron may be beneficial for bone growth and maintenance,cen-tral nervous system function,and the inflammatory response(Nielsen,2009).The best documented benefi-cial effect of B is on Ca metabolism and utilization,and thus affects bone calcification and maintenance (Nielsen,1998a).The highest B concentration is found in bones,indicating one of the potential benefits in its ability to protect humans from osteoporosis(Nielsen, 1998).It has been reported that B appears to lessen effects of a low Mg-diet on body growth,serum choles-terol and ash concentration in bone,but exacerbate deficiency symptoms,without affecting the Mg or Ca concentration in the serum(Kenny and McCoy,2000).The elevation of endogenous steroid hormones as a result of B supplementation suggests that B may be used as an ergogenic,safe substance for athletes,but needs further investigation(Naghii,1999).Boron sup-plementation also has been found to result in high B absorption efficiency and the elevation of endogenous estrogen suggests a protective role of B in atheroscle-rosis(Naghii and Samman,1997).In humans,there is evidence of homeostatic regulation of B;e.g.,human milk B concentrations are under apparent homeostatic control(Hunt,2007).Boron satisfies the criterion of essentiality and tissue B concentrations during short term variations in intake are maintained by homeo-static mechanisms(Hunt,2007).In most studies it has been found that B affects human steroid hormone levels.Circulating testoste-rones and estradiol levels have been proposed to mo-dify prostate and cancer risk(Wiseman,2002).After controlling for age,race,smoking,body mass index, dietary caloric intake,and alcohol consumption,incre-TABLE IRecommended daily dosages a)of mineral nutrientsMineral nutrient Lenntech(1998)Wikipedia—The Free Balch and Balch(2000)Encyclopedia(2012)Boron(mg)20-3–6Calcium(mg)10001000–13001500–2000(as citrate or ascorbate) Chlorine(mg)3400(in chloride form)2300–3400-Chromium(μg)12035–120150–400(as glucose tolerance factor orpicolinate or polynicotinate)Copper(mg)20.9–22–3Fluoride(mg) 3.54-Iodine(mg)0.150.15100–225Iron(mg)151818–30Magnesium(mg)350400–420750–1000Manganese(mg)52–2.33–10Molybdenum(μg)7545–7530–100(as ascorbate or aspartate) Nickel(mg)<1--Phosphorus(mg)10001000-Potassium(mg)3500350099–500(as citrate)Selenium(μg)3570100–200Sodium(mg)24002400-Sulfur(mg)---Vanadium(mg)<1.8 1.80.2–1(as vanadyl sulfate)Zinc(mg)1511–1530–50a)A range of values from recommended daily intake to maximum recommended daily allowance of daily reference intakes.16U.C.GUPTA AND S.C.GUPTAased dietary B intake was generally associated with a decreased risk of prostate cancer with a dose-response pattern(Cui et al.,2004).When with the high B in-take,low dietary B resulted in significantly poorer performance on tasks emphasizing manual dexterity, eye-hand coordination,attention,perception,encoding and short-term memory,and long-term memory.Col-lectively,the data from these studies indicate that B may play a role in human brain function and cognitive performance,and provide additional evidence that B is an essential nutrient for humans(Penland,1994).One of the reasons why many researchers think B helps treat arthritis is that it is essential for the strengthening of bones.Boron helps metabolize many bone strengthening minerals like Ca,Cu and Mg(Sti-panuk and Caudill,2012).There is also evidence that B provides several health benefits to the brain.It is widely believed that B can positively influence a di-verse set of brain functions including memory,concen-tration,and even hand-eye coordination(Stipanuk and Caudill,2012).Data on dietary B intake by human beings are fairly sparse.Boron is not included in the United States Department of Agriculture nutrient databases,and no comprehensive analytical database exists on the B con-tent of specific foods.In an American study,the B levels were slightly higher in vegetarian adults than in the general population(Rainey et al.,1999).It was stated that the top two B contributors,coffee and milk, are low in B,yet they make up12%of the total B in-take by virtue of the volume consumed.Peanut butter, wine,raisins,apples,pears,grapes,avocados,legumes, peanuts and other nuts are good sources of B(Rainey et al.,1999;Stipanuk and Caudill,2012).Diets low in fruits,vegetables,legumes and nuts may not provide an adequate amount of B.CalciumCalcium is thefifth most abundant element by mass in the earth’s crust.It is everywhere on the planet,and this common mineral provides a number of health benefits to the human body(Stipanuk and Caudill,2012).Most well-known health benefit of Ca is the important part it plays in developing strong bones. Almost all the body’s Ca can be found in the bones and teeth,and there are countless studies which show that proper Ca intake helps young people develop strong bones while keeping the bones of older people strong and healthy.It also helps to prevent and treat a vari-ety of bone-related illnesses,such as osteoporosis(Sti-panuk and Caudill,2012).In addition to fulfilling the needs for Ca ions re-quired in numerous intracellular functions as well as for the regulation of blood clotting(hemostasis),prac-tically all of the body’s remaining Ca exists in skele-tal salts that support the body,enable ambulation, and protect internal organs.Afixed amount of Ca forms the teeth which,after formation,remains static in the oral cavity and which,unlike the bones,do not participate in Ca metabolism(Anderson and Garner, 2011).Following the achievement of peak bone mass in the second or third decade of life,dietary Ca is needed to replace Ca lost from bone tissue as part of the normal dynamic turnover of the skeleton.Adult bone mineral content and bone mineral density are better maintained by an adequate amount of Ca in the diet(Anderson and Garner,2011).Dietary supplement use is associated with a higher prevalence of groups meeting the adequate intake for Ca and vitamin D.Monitoring usual total nutrient in-take is necessary to adequately characterize and evalu-ate the population’s nutritional status and adherence to recommendations for nutrient intake(Bailey et al., 2010).Knowledge of osteoporosis and the importance of dietary intake of Ca and vitamin D did improve after the intervention(Bohaty et al.,2008).Osteoporosis is a painful,disabling illness and its prevention is a lifelong process.Older women may suffer its devastating effects because of these nutrient deficiencies in their diet as young adult women(Bohaty et al.,2008).Epidemio-logical and prospective studies have related vitamin D deficiency not only to osteoporosis but also to cardio-vascular disease,diabetes,cancer,infection and neu-rodegenerative disease(P´e rez-L´o pez et al.,2012).In a study in Japan,an excessive intake of400mg Ca-fortifiedfish sausage,a special health food in Japan, appeared to be a safe means to obtain the daily Ca requirement(Murota et al.,2010).Inadequate sunlight exposure and Ca intake during rapid growth at puberty lead to hypocalcemia,hypovi-taminosis D and eventually to overt rickets(Dahifar et al.,2007).It was concluded that low daily Ca intake and vitamin D acquirement are two important prob-lems in Iranian girls during rapid growth at puberty; therefore,for prevention of overt rickets,Ca and vita-min D supplementation appears to be necessary(Dahi-far et al.,2007).In a study involving the mean daily Ca intake at553mg d−1,along with other minerals in pregnant women,it was found that only Ca intakes were significantly correlated to birth weight(Denguezli et al.,2007).In a US study,milk and milk products were by far the lowest-cost sources of dietary Ca and also were among the lowest-cost sources of riboflavin and vita-SOURCES AND DEFICIENCY DISEASES OF MINEARL NUTRIENTS17min B12(Drewnowski,2011).An intake of approxi-mately1500mg Ca d−1could aid in the management of body and truncal fat.It has been recommended that young adults be encouraged to increase their total Ca intakes to at least the recommended daily allowance of 1000mg d−1for reasons extending beyond bone health (Skinner et al.,2011).The tolerable upper Ca intake level ranges from1000to3000mg d−1,based on Ca excretion or kidney stone formation,and vitamin D from1000to4000international units daily,based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships(Ross et al.,2011).Due to the nutrient synergy of foods,dietary Ca sources should continue to be promoted in nutritional counselling efforts as the optimal method of obtaining adequate Ca(French et al.,2008).Nutrition education should emphasize strategies to decrease the side effects associated with Ca-rich foods and alleviate concerns re-garding the cholesterol and fat content of some Ca-rich foods.In addition to strategies to increase consump-tion of dietary Ca sources,supplementation should be considered as an acceptable method of increasing Ca intake among women with low bone mineral den-sity(French et al.,2008).In a study in USA,African Americans in all age groups did not meet dairy re-commendations from the2005US Dietary Guidelines and the2004National Medical Association(Fulgoni III et al.,2007).Calcium and Zn intakes in Australian children from core foods were below70%of the recommended dietary intakes for adolescent girls(Rangan et al.,2008).It was concluded that the extra foods are over-consumed at two to four times the recommended limits and con-tribute excessively to the energy,fat and sugar intakes of Australian children,while providing relatively few micronutrients,including Ca(Rangan et al.,2008).Milk,cheese and most other dairy products,beans (Phaseolus vulgaris),broccoli(Brassica olereracea var. italica)kale(Brassica oleracea var.acephala),collards (Brassica oleracea hardiness)and raisins are some of the best sources of Ca(Stipanuk and Caudill,2012).ChlorideDrinking water disinfection has been shown to be an important public health measure since the turn of the century.In USA,it was perhaps the single most important factor in controlling typhoid fever,a water-borne disease that was rampant throughout the world during the last century(Akin et al.,1982).Disinfec-tion was important in limiting diseases,such as cholera, amoebiasis,salmonellosis,and hepatitis A(Akin et al., 1982).Still,despite its beneficial effects and lifesaving reputation,other chlorine effects on health and envi-ronment are dangerous to humans(Conjecture Corpo-ration,2003).Chlorine is essential for bodyfluid regulations in humans(Evans and Solberg,1998)and exists in the safe,inorganic form as the negative chloride ion as NaCl(Belkraft,2005).But when Cl reacts with organic compounds in the water,it produces poisonous che-mical compounds,which cause cancer and other health problems(Belkraft,2005).Following inhalation and skin or eye contact,exposure to HCl acid is toxic by ingestion and skin or eye exposure(Bul,2011).It has been hypothesized that organochlorine pesticides may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men(Safe,1995).Ho-wever,elevation of some organochlorine compounds in breast cancer patients is not consistently observed (Safe,1995).Methyl chloride is very toxic;mice ex-posed to high levels of methyl chloride by inhalation for two years had an elevated incidence of liver and lung tumors(Green,1997).The mouse seems to be unique in its response to methyl chloride and thus it is an inappropriate model to assess human health(Green, 1997).The data from Bangladesh showed that the ma-rine salt deposition is significant up to a distance of about200m from the seashore and from this point onward,the amount of chlorides drops sharply(Hos-sain and Said,2011).Chloride exists in aqueous solu-tions as a monovalent anion and its salts are readily soluble.Consequently,it is not absorbed by organic matter or clay in most soils,and does not readily pre-cipitate out of solution(Hossain and Said,2011).For these reasons,Cl is mobile in the soil and is readily leached where rainfall and/or irrigation exceeds evapo-transpiration.Chloride is one of thefirst elements re-moved from minerals by soil weathering processes.This is why most of the world’s Cl is found in oceans or in salt deposits left by evaporation from old inland seas (International Plant Nutrition Institute,2012).Many soils and crops receive more than an adequate supply of Cl from sea spray carried by rain and snow.This diminishes rapidly with the distance from the ocean (International Plant Nutrition Institute,2012).Results from disinfecting student health centres (SHCs)in Taiwan suggested that the air quality guide-lines prescribed by the Taiwan Environmental Protec-tion Agency for SHCs and other healthcare facilities can best be achieved by applying chlorine dioxide at regular(daily)intervals(Hsu et al.,2012).The results from southern Italy on ground water provided valuable18U.C.GUPTA AND S.C.GUPTAinactivation constants of cultural indicators,e.g.,co-liforms,enterococci,Clostridium spores and viruses in the wastewater that have been injected into the fra-ctured aquifer since1991(Masciopinto et al.,2007). Hypochlorination reduces somatic coliphages and Clo-stridium spores in groundwater but did not achieve complete inactivation in all tests.It was concluded that complete disinfection of groundwater samples was pos-sible only when there was an initial count of Clostrid-ium spores of≤10colony-forming units100mL−1 (Masciopinto et al.,2007).It has been reported that naturally occurring indicator bacteria and bacterio-phages respond differently to chlorination in drin-king water distribution networks in northeastern Spain (Mendez et al.,2004).Though several chlorinated organic compounds are produced by humans,some are also produced by the biotic and abiotic processes in the environment(My-neni,2002).These carcinogenic and toxic compounds are formed at rapid rates from the transformation of in-organic Cl during humification of plant material,thus playing a critical role in Cl cycling,and from the trans-formation of several major and trace elements in the environment and may influence human health(My-neni,2002).Chlorinated drinking water is one of the chief source of Cl.Disinfection with chlorine is one of the safest way of limiting the number of diseases known to be capable of waterborne transmission,e.g.,cholera, amoebiasis,salmonellosis and hepatitis A(Akin et al., 1982).ChromiumChromium is an essential trace mineral that hu-mans require in trace amounts.In1959,Cr wasfirst identified as an element that enables the hormone in-sulin to function properly(Wong,2012).Since then, Cr has been studied for diabetes and has become a po-pular dietary supplement(Wong,2012).Chromium is essential for maintaining health and has many uses and applications in the human body.For instance,there is a great deal of research that suggests that Cr is beneficial to those with impaired glucose tolerance(Stipanuk and Caudill,2012).Impaired glucose tolerance,which is a precursor to type2diabetes for about25%of those who acquire it,is a state in between the glucose levels of dia-betes and normal glucose levels.A meta-analysis on the relationship between Cr and impaired glucose tolerance found that12of the15studies showed a positive effect (Stipanuk and Caudill,2012).The pooled data from the studies using chromium picolinate(CrPic)supple-mentation for type2diabetes mellitus subjects showed substantial reductions in hyperglycemia and hyperin-sulinemia,which equate to a reduced risk for disease complications(Broadhurst and Domenico,2006).Col-lectively,the data support the safety and therapeutic value of CrPic for the management of cholesterolemia and hyperglycemia in subjects with diabetes(Broad-hurst and Domenico,2006).Tissue Cr levels of subjects with diabetes are lower than those of normal control subjects,and a correla-tion exists between low circulating Cr levels and the incidence of type2diabetes(Hummel and Schnell, 2009).However,supplementation with Cr has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type2diabetes (Hummel and Schnell,2009).The effect of Cr treat-ment on glycemic control in a Western population of insulin-dependent patients with type2diabetes using high-dose Cr treatment showed no evidence that it was effective in obese patients with type2diabetes (Kleefstra et al.,2006).There is evidence of hormonal effects of supplemental Cr besides the effect on in-sulin.Chromium supplementation does result in tis-sue retention,especially in the kidneys,although no pathogenic effect has been demonstrated despite con-siderable study(Lamson and Plaza,2002).In two cases,one involving a diabetic patient and the other a non-diabetic patient,Cr administration appeared to decrease insulin requirements.Infusion of chromic chloride appeared to reduce insulin requirements in one diabetic patient and one non-diabetic patient(Phung et al.,2010).Chromium deficiencies result in decreased insulin sensitivity,glucose intolerance and increased risk of diabetes.In a French study,the Cr status decreased with age,suggesting that the elderly may be at a high risk of Cr deficiency(Roussel et al.,2007).Although these subjects had well-balanced diets,their daily Cr intakes did not reach the French recommendations.It is likely that the low Cr intakes were due to the low Cr density of the foods.A negative correlation was found between Cr intakes and insulin,body mass index and leptin(Roussel et al.,2007).Of all the“essential”elements,the role of Cr is un-doubtedly the most controversial.Recently,its status as an essential element,first proposed nearly60year ago,has been challenged;this challenge will probably result in the general consensus on the status changing (Stallings and Vincent,2006).These new researchers were attracted to thefield by the rapidly expanding po-pular attention received by Cr nutritional supplements, which was not being mirrored by scientific advances in understanding how these supplements could work at a。

P HARMACEUTICAL Q UALITYS YSTEM Q10制药质量体系Q10Current Step 4 version dated 4 June 2008 当前版本，2008年6月4日，第4步TABLE OF CONTENTS目录1. PHARMACEUTICAL QUALITY SYSTEM1．制药质量体系1.1 Introduction 1．1绪论1.2 Scope 1．2范围1.3 Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards and ICH Q7. 1．3ICHQ10与地方GMP要求，ISO标准与ICHQ7之间的关系1.4 Relationship of ICH Q10 to Regulatory Approaches 1．4ICHQ10与法规方法间的关系1.5 ICH Q10 Objectives 1．5ICHQ10目的1.5.1 Achieve Product Realization 1．5．1产品实现1.5.2 Establish and Maintain a State of Control 1．5．2控制状态的建立和实现1.5.3 Facilitate Continual Improvement 1．5．3 持续改进1.6 Enablers: Knowledge Management and Quality RiskManagement1．6支持者：知识管理和质量风险管理1.6.1 Knowledge Management 1．6．1知识管理1.6.2 Quality Risk Management 1．6．2质量风险管理1.7 Design and Content Considerations 1．7设计和内容方面的考虑1.8 Quality Manual 1．8质量手册2. MANAGEMENT RESPONSIBILITY2．管理职责2.1 Management Commitment 2．1管理承诺2.2 Quality Policy 2．2质量方针2.3 Quality Planning 2．3质量策划2.4 Resource Management 2．4资源管理2.5 Internal Communication 2．5内部沟通2.6 Management Review 2．6管理评审2.7 Management of Outsourced Activities and PurchasedMaterials2．7外包活动和物料采购的管理2.8 Management of Change in Product Ownership 2．8产品所有权变更管理3. CONTINUAL IMPROVEMENT OF PROCESSPERFORMANCE AND PRODUCT QUALITY3．工艺性能和产品质量的持续改进3.1 Lifecycle Stage Goals 3．1生命周期阶段目标3.1.1 Pharmaceutical Development 3．1．1物料研发3.1.2 Technology Transfer 3．1．2技术转移3.1.3 Commercial Manufacturing 3．1．3商业化生产3.1.4 Product Discontinuation 3．1．4产品终止3.2 Pharmaceutical Quality System Elements 3．2制药质量体系原理3.2.1 Process Performance and Product Quality Monitoring 3．2．1工艺性能和产品质量监控体系System3.2.2 Corrective Action and Preventive Action (CAPA)System3．2．2纠正预防体系3.2.3 Change Management System 3．2．3变更管理体系3.2.4 Management Review of Process Performanceand Product Quality3．2．4工艺性能和产品质量的管理评审4. CONTINUAL IMPROVEMENT OF THEPHARMACEUTICAL QUALITY SYSTEM4．制药质量体系的持续改进4.1 Management Review of the Pharmaceutical QualitySystem4．1制药质量体系的管理评审4.2 Monitoring of Internal and External Factors Impactingthe Pharmaceutical Quality System4．2制药质量体系的内外部影响因素的监控4.3 Outcomes of Management Review and Monitoring 4．3管理评审和监控成果5. GLOSSARY5．术语Annex 1:Potential Opportunities to Enhance Science and Risk Based Regulatory Approaches 附件1：基于法规方法对科学和风险进行改进的潜在机会Annex 2:Diagram of the ICH Q10 Pharmaceutical QualitySystem Model附件2：ICH Q10 制药质量体系模型图P HARMACEUTICAL Q UALITY S YSTEM制药质量体系1. PHARMACEUTICAL QUALITY SYSTEM1．制药质量体系1.1 Introduction 1．1绪论This document establishes a new ICH tripartite guideline describing a model for an effective quality management system for the pharmaceutical industry, referred to as the Pharmaceutical Quality System. Throughout this guideline, the term “pharmaceutical quality system” re fers to the ICH Q10 model.本文确立了新的ICH三方指南，叙述了制药工业有效质量管理体系的一个模型，被称之为制药质量体系。

V ALIDATION DOCUMENT验证文件Validation Master Plan for the First Phase20XX年验证总计划Document No./ 文件编号：VD01001Issue No./版本号： 1Issue Date/颁发日期：20XX年12月28日Written by/起草人:TValidation Manager /验证经理Signed/签名: Date/日期:年月日Authorized by/授权人:RTechnical Director/技术总监Signed/签名: Date/日期:年月日Document check/审核DistributionQA Validation archive (Completed original) QA验证档案（完整的原件）Technical Director (Copy) 技术总监（复印件）Engineering Manager (Copy) 维修经理（复印件）QC Manager (Copy) QC经理（复印件）Production Manager (Copy) 生产经理（复印件）QA Manager (Copy) QA经理（复印件）Packing Manager (Copy) 包装经理（复印件）Validation Manager (Copy) 验证经理（复印件）Commercial Manager (Copy) 商务经理（复印件）Production Director (Copy) 生产总监（复印件）Table of Content/目录1Purpose/目的 (6)2Summary/概述 (6)2.1 Company introduction and summary of fist stage project / 公司及一期工程项目概述 (6)2.2 Scope/验证范围 (6)2.3 Validation Policy /验证方针 (6)3Validation Organizational Chart and Personnel Responsibilities/验证组织结构及人员职责 (7)3.1 Organizational Chart/组织结构图 (7)3.2 Validation Committee/验证委员会 (7)3.3 Validation/Qualification Team/验证小组 (7)3.4 Responsibilities/职责： (7)3.4.1 Responsibilities of Validation Committee/验证委员会职责 (7)3.4.2 Responsibilities of Validation Team/验证小组职责： (8)3.4.3 All Departmental Managers/所有部门经理职责 (9)3.5 Training /验证培训 (9)4The Writing and Approval of Validation Plan, Protocol and Report/验证计划、方案、报告的起草审批程序 (9)5Documentation/文件 (9)5.1 Content/文件范围 (9)5.1.1Validation Plan/验证计划 (9)5.1.2Validation Protocol/验证方案 (10)5.1.3Validation Report/验证报告 (10)5.1.4Validation Certificate/验证证书 (10)5.2 Format/文件格式 (10)5.3 Validation Document numbering/验证文件的编号 (12)5.4 Validation/Qualification Archiving验证/确认归档 (12)6Validation Implementation/验证实施 (12)6.1 Safety and Health/安全与健康 (12)6.2 Validation Classification and Applicable Scope / 本次验证所用到的验证分类与适用范围.. 126.2.1Prospective Validation / 前验证 (12)6.2.2Concurrent Validation/同步验证 (13)6.2.3Revalidation/再验证 (13)6.3 Validation Implementation/验证的实施 (13)6.4 Validation Project Collection/本次验证的项目汇总 (13)6.4.1Analytical Methods Validation/分析方法学 (14)6.4.2Facilities/设施 (14)6.4.3Instruments and equipments/仪器设备 (14)6.4.4Process/工艺 (15)6.4.5Equipment Cleaning/设备清洁 (16)6.4.6Computerized system/计算机化系统 (16)6.5 Schedule/本次验证的时间计划安排 (17)6.5.1First Phase/第一阶段 (17)6.5.2Second phase/第二阶段 (18)6.5.3Third phase/第三阶段 (19)6.5.4Fourth phase第四阶段 (19)7Validation Method and Acceptance Criteria/验证方法和可接受标准 (20)7.1 URS/用户需求标准 (20)7.2 Analytical methods validation/分析方法学验证 (20)7.3 Facilities Validation/厂房设施、仓库设施的验证 (21)7.3.1Design Qualification/设计确认 (21)7.3.2Installation Qualification/安装确认 (21)7.3.3Operational Qualification/运行确认 (22)7.4 Validation of Clean Rooms and Air-conditioning System/洁净车间、空调系统的验证 (22)7.4.1Design Qualification/设计确认 (22)7.4.2Installation Qualification/安装确认 (22)7.4.3Operational Qualification运行确认 (23)7.4.4Performance Qualification/性能确认 (24)7.5 Purified water system validation/纯化水系统验证 (25)7.5.1Design Qualification/设计确认 (25)7.5.2Installation Qualification/安装确认 (25)7.5.3Operational Qualification/运行确认: (25)7.5.4Performance Qualification/性能确认 (26)7.6 Compressed air system validation/压缩空气系统验证 (27)7.6.1Design Qualification/设计确认 (27)7.6.2Installation Qualification/安装确认 (27)7.6.3Operational Qualification/运行确认 (28)7.6.4Performance Qualification/性能确认 (28)7.7 Instruments and equipments validations/仪器设备验证 (28)7.7.1Design Qualification/设计确认 (28)7.7.2Installation Qualification/安装确认 (29)7.7.3Operational Qualification/运行确认 (29)7.7.4Performance Qualification/性能确认 (30)7.8 Equipment cleaning validation/设备清洁验证 (30)7.8.1Establishment of cleaning procedure/建立清洁规程 (31)7.8.3Validation of sampling method/验证取样方法 (31)7.8.4Confirmation of Chemical Residue/确定化学残留量 (31)7.8.5Confirmation of microbes residue/确定微生物残留量 (31)7.8.6Expiry Date of Cleaned Equipment/确定清洁设备的存放有效期 (32)7.9 Process Validation/生产工艺验证 (32)7.9.1Preconditions/验证先决条件 (32)7.9.2Validation Method/验证方法 (32)7.10 Validation of Computerized System/计算机化系统验证 (32)7.10.1Hardware/硬件 (33)7.10.2Operational System/操作系统 (33)7.10.3Firmware/生产或支持设备使用的固件 (33)7.10.4Commercial system/商业化系统 (33)7.10.5Configurable software package/可配置软件包 (33)8Deviations and change control/偏差处理及变更控制 (33)9History of Change /文件变更及历史 (34)10References/参引 (34)11Annex/附录 (34)1Purpose/目的This Validation Master Plan (VMP) describes the V alidation and Qualification activities that will be undertaken at Tripardus Pharmaceuticals Ltd. at first phase before start-up. It summarizes the company’s Validation intentions, philosophy, policy, project, plan, and approach and acceptance criteria.本验证总计划（VMP）描述了瑞博德制药有限公司新建的一期工程在启用前应该进行的验证和确认活动，概括地阐述验证目的、原则、方针、项目、计划、方法和可接受标准等。

转基因食品贴标签英语作文英文回答：As a consumer, I believe that genetically modified (GM) foods should be labeled. It is important for consumers to have the right to know what they are eating and to make informed choices about the food they purchase. Without proper labeling, consumers are unable to make decisions about the products they buy, and this goes against the principles of transparency and consumer rights.Labeling GM foods is not about banning or stigmatizing them, but rather about providing consumers with the information they need to make choices that align with their values and beliefs. For example, some people may have ethical or religious reasons for not consuming GM foods, and labeling would allow them to easily identify and avoid these products.Furthermore, there are also concerns about thepotential health and environmental impacts of GM foods, and labeling would allow consumers to make decisions based on their own risk tolerance. For instance, some individuals may prefer to avoid GM foods due to concerns about thelong-term effects on human health or the environment, and labeling would enable them to do so.中文回答：作为一个消费者，我认为转基因食品应该贴上标签。

是否购买医疗保健品的英语作文Should You Buy Medical Healthcare Products?With the rise of healthcare products targeting various health concerns, it can be overwhelming to decide whether or not to purchase them. From vitamins and supplements to topical creams and devices, the market is flooded with options that claim to improve our well-being. But are these products really worth the investment, or are they just a waste of money?One of the main factors to consider when deciding whether to purchase healthcare products is the scientific evidence behind their claims. Many products on the market make bold promises about their ability to improve our health, but not all of these claims are backed by solid research. Before making a purchase, it is important to do your own research and look for reputable sources that can support t he product’s efficacy.In addition, it is essential to consider the potential risks associated with using healthcare products. While many products are safe when used as directed, some may have side effects or interact with other medications you are taking. Before introducing a new healthcare product into your routine, it isadvisable to consult with a healthcare professional to ensure that it is safe for you to use.Another important factor to consider is the cost of healthcare products. Some products can be quite expensive, and it is important to weigh the potential benefits against the financial cost. It may be worthwhile to invest in products that have been proven to be effective and improve your health, but it is important to consider your budget and prioritize products that will have the most impact on your well-being.Ultimately, the decision of whether or not to purchase healthcare products is a personal one that should be based on your individual health needs and goals. While some products may offer benefits that align with your health concerns, others may not be necessary or provide little value. It is important to be an informed consumer and make decisions that are in your best interest.In conclusion, the decision of whether to purchase healthcare products should be based on careful consideration of the scientific evidence, potential risks, and financial cost. By prioritizing products that have been proven effective, consulting with healthcare professionals, and making informed decisions,you can ensure that the products you choose will have a positive impact on your health and well-being.。

转基因食品贴标签英语作文英文回答：As a consumer, I believe that labeling genetically modified (GM) foods is essential for making informed choices about what we eat. GM foods, also known as genetically modified organisms (GMOs), are plants or animals that have had their genetic makeup altered in order to exhibit specific traits, such as resistance to pests or herbicides. While some people argue that GM foods are safe to eat and have the potential to address food security issues, others are concerned about the potential health and environmental risks associated with consuming these products.One of the main reasons I support labeling GM foods is because it allows consumers to make informed decisions about the products they purchase. For example, if I am shopping for groceries and see that a product contains GM ingredients, I have the right to know and can choosewhether or not to buy it based on my personal beliefs and preferences. Without clear labeling, consumers are left in the dark about what they are consuming, which can be frustrating and even worrying for those who want to avoid GM foods.Furthermore, labeling GM foods can also help to track potential health effects associated with their consumption. If people have the option to choose non-GMO products, it becomes easier to conduct studies and gather data on the long-term effects of GM foods on human health. This information is crucial for understanding the potentialrisks and benefits of GM foods, and it can help to inform future regulations and policies regarding their production and labeling.In addition, labeling GM foods can also benefit farmers who choose not to grow GM crops. By clearly indicating which products contain GM ingredients, farmers who produce non-GMO foods can differentiate their products in the market and potentially attract consumers who prefer non-GMO options. This can create a fairer playing field for allfarmers and promote diversity in agriculture.Overall, I believe that labeling GM foods is a necessary step in providing transparency and choice for consumers. It allows people to make informed decisions about the foods they eat, supports research on the potential health effects of GM foods, and promotes diversity in agriculture.中文回答：作为一个消费者，我认为标注转基因（GM）食品对于我们做出明智的食物选择至关重要。

WARNINGWARNING: DO NOT install or use this equipment without first reading and understanding these instructions. If you are unable to understand the Warnings, Cautions or Instructions, contact a healthcare professional, dealer or technical personnel before attempting to use this equipment - otherwise, injury or damage may occur.WARNING: Maximum Weight Capacity 300 lb - EVENLY DISTRIBUTED.WARNING: GF Health Products, Inc. assumes no responsibility for any damage or injury caused by improper installation, assembly or use of this product.WARNING: ALWAYS inspect the bath stool to ensure that it is properly positioned and stable before using. DO NOT use if bath seat is wobbly or unstable.WARNING: If components are damaged or missing, contact your GF Health Products, Inc. distributor immediately. DO NOT use substitute parts.WARNING: Check leg tips for rips, tears, cracks or wear. If any of these conditions exist, replace leg tips IMMEDIATELY.WARNING: DO NOT use this as a transfer bench or climbing device.WARNING: All four leg tips MUST be in contact with shower/tub floor at all times.WARNING: Ensure that the four chair legs are adjusted to the same height and that the push buttons fully protrude through their respective adjustment holes BEFORE use.WARNING: Only use GF Health Products, Inc. accessories with this product.WARNING: This product should only be used with tub floors wider than 18 ¾ inches.WARNING: Users with limited physical capabilities must be supervised or assisted when using the bath seat.WARNING: Make certain ALL screws and nuts are tight at all times.WARNING: DO NOT submerge product in water, otherwise damage may result.WARNING: Notice for California CustomersCalifornia Proposition 65 WARNING: This product contains a chemical known to the State of California to cause cancer and reproductive or developmental harm.WARNING: To avoid falling or tipping: Have someone help you until you know the balance points of your Bath Seat and how to avoid tipping. Do not put downward weight on one side or corner of the Bath Seat. Do not put downward weight on the backrest. Do notreach or lean if you must shift your weight to do so. Ask for help or use a device to extend your reach. Never try to reach an object if you must move forward in your seat and your buttocks do not stay in full contact with the seat. Never lean backward to reach an object.Maintenance• Use a mild soap and water solution, rinse with clear water, then dry with a soft cloth. Ensure that product is well rinsed before using.• Never use organic solvents, abrasive cleaners, or scouring pads on any part of the product. • Check fit and tightness of all nuts, bolts and knobs weekly to ensure that product is safe to use.• To guarantee the best service from your product, always specifiy Lumex replacement parts, available from your GF Health Products, Inc. authorized distributor.NOTE: Check ALL parts for shipping damage. If shipping damage is noted, DO NOTuse. Contact carrier/dealer for further instruction.Safety Guidelines –Please Read Before UseInstructions for Use –Please Read All Instructions Before Use.Setup1. Remove seat from cartonAdjusting Height1. Press push button and slide leg extension up or down to desired adjustment hole.2. Ensure push button fully protrudes through the leg adjustment holes of the leg extension. NOTE: An audible “click” will be heard when push button securely protrudes through the adjustment hole.3. Repeat STEPS 1 and 2 for the other three legs.NOTE: Ensure all four legs are adjusted to the same height and that all height adjustment buttons protrude fully through the adjustment holes before use.Item 2060ABath StoolGF0500033RevE14© 2014, GF Health Products, Inc.,• Anodized aluminum frame is lightweight, durable and rust-resistant• Seat height is adjustable in 1" increments • Tool-free assembly• Maximum Weight Capacity 300 lb EVENLY DISTRIBUTEDGF Health Products, Inc. (“GF”) warrants to the original retail purchaser or lessee (either is the “Customer”) only, that it will replace or repair components, at GF’s sole discretion, that are defective in material or workmanship under normal use and service. The warranty is for parts only and does not include labor or costs of shipping. All warranties are conditioned upon the proper use of the product strictly in accordance with applicable GF instructions. Product provided to users asrentals must be serviced by the provider and inspected prior to delivery. Each user must be properly trained on the operation and safety of this product prior to use. Within the guidelines set forth in this document, the frame is warranted for five (5) years and the normal wear components such as tips, wheels/casters, and handgrips are warranted for three (3)months. The applicable warranty period shall commence from date of shipment to the Customer, unless there is an expiration date on the component in which case the warranty shall expire on the earlier of the warranty period or the expiration date.EXCLUSIONSThe warranty does not cover and GF shall not be liable for the following: 1) Defects, damage, or other conditions caused by misuse, abuse, negligence, alteration, accident, freight damage, tampering or failure to seek and obtain repair or replacement in a timely manner; 2) Products not installed, used, or properly cleaned and maintained; and 3) Labor or shipping charges. Other exclusions apply.ENTIRE WARRANTY, EXCLUSIVE REMEDY AND CONSEQUENTIAL DAMAGES DISCLAIMERTHIS WARRANTY IS GF’S ONLY WARRANTY AND IS IN LIEU OF ALL OTHER WARRANTIES, EXPRESS OR IMPLIED.Limited WarrantyUser Instructionsand Warranty InformationImportant: Read Before UseSeatLeg。

解释英文文案1. What does this product do?这个产品是做什么用的？2. Who is it for?它是为谁设计的？3. How does it work?它是如何工作的？4. What are the benefits?它有哪些优点？5. What are the features?它有哪些特性？6. What makes it different from other products? 它与其他产品有什么不同之处？7. What is the price?它的价格是多少？8. What type of guarantee or warranty is offered? 提供什么样的保证或保修？9. How do I use this product?我该如何使用这个产品？10. Are there any side effects?有没有任何副作用？11. Is this product safe?这个产品是否安全？12. How long does it take for the results to show? 需要多长时间才能看到效果？13. Can I return the product if I am not satisfied? 如果我不满意，能否退回产品？14. What are the ingredients?它的主要成分是什么？15. Are there any allergens in the product?这个产品中是否有任何过敏原？16. Can I use this product with other medications? 我能和其他药物一起使用这个产品吗？17. What is the recommended dosage?推荐的剂量是多少？18. How do I store the product?我该如何存储这个产品？19. How long is the shelf life?它的保质期有多长？20. What are the instructions for special use cases? 特殊用途的使用说明是什么？。