MHRA指南(中英文)
英国MHRA发布英维康(Invacare)公司的警戒通告
２ １０ １８ ０ ０ ８ ９７等 的 产 品 。具 体 详 见 原 文 。
召 回级别 ： Ｉ级
召 回 原 因 ： 美 敦 力 公 司 已 收 到 关 于 Ｏｃ ｐ ｓＮｕｏ 组 织 固 ｔ ｕ ｖ ｏ 定 器 的 报 告 ， 告 中 说 明 ， 使 用 过 程 中 夹 头 （ 一 器 械 报 在 一个 组 成 元 件 ， 于 固 定 连 接 头 ） 裂 ， 而 导 致 连 接 头 立 即 用 断 从 与 器 械 杆 脱 离 。 造 成 的 潜 在 危 害 是 夹 头 碎 片 可 能 落 入 患 者胸 腔并 使心脏 受 到损 害 。 召 回 措施 ： ｄｏｉ 司 在 ２ １ Ｍｅ ￣ ｎｃ公 ０ ０年 ９ 月 １ 日 向 每 个 受 ４ 影 响 客 户 的 风 险 经 理 发 送 了 一 份 紧 急 医 疗 器 械 召 回 通 知 。 信 中 描 述 了 问题 ， 定 了 受 影 响 批 号 ， 求 立 即 停 止 确 要 使 用 该器 械 ，隔 离 所有 未 使 用 的 器械 并将 其 返 回 公 司 。
需 要 更 多 信 息 ，请 联 系 美 敦 力 心 血 管 生 命 线 技 术 服 务
部 ， 系 电 话 是 ８７５６７ ９ ， 联 系 当 地 的 美 敦 力 销 售 联 ７ —２ ．８ ０ 或
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MHRA_OOS调查译文
Out Of Specification Investigations.OOS调查MHRA：英国药品和健康产品管理局怎么使用OOS调查流程图？导航：这个文件使用幻灯片浏览。
点击流程图幻灯片里这些带有粗边的工艺步骤框，会带你到一个新的幻灯片有更详细的有关步骤。
每走一步都有链接返回到浏览幻灯片。
这将向上滑动。
这将下滑到下一张幻灯片实验室分析实验室分析OOS/OOT典型结果调查必须在以下情况中：---批次放行检验和原材料的检验。
---过程控制测试：如果数据用于批量计算/决定，以及档案和分析证书。
---对成品和或原料药销售批次的稳定性研究，正在进行/跟进的稳定（无压力测试）---先前放行的在OOS调查中作为参考样品的批次，显示出有OOS或可疑结果。
---临床试验批次。
所有溶液和试剂必须被保留，直到所有数据都被第二个人确定为是在已定义的验收标准范围内。
药典对特定的测试的附加分析有具体的标准（即S1，S2和S3测试的溶解级规范；20个附加试验的剂量均匀度单位规范；无菌检测）。
然而，如果样品测试标准通常是第一级的测试，以及一个样品必须在新的水平测试，这应该是它没有按照正常的发展趋势进行调查。
当努力达到生产过程的终点即生产过程的调整（如PH值，粘度）时，OOS过程不适用于过程测试。
并进行可变参数的研究，检查变化（工艺验证中的可变参数）的影响。
OOS/ OOT结果OOS结果-------测试的结果不符合预先规定的验收标准（例如，提出申请，药物主文件，经核准的营销提交，或官方药典或内部验收标准）。
----测试结果超出了药典或公司文件规定的验收标准（即，原料规格，过程中/最终产品测试等）。
超趋势（OOT）结果------通常是一个稳定的结果，不遵循预期的趋势，无论是与其他批次的稳定性或相对于先前稳定性研究收集的结果相比较。
然而起始原料和过程样品的趋势也可能产生趋势外的数据。
其结果不一定是OOS，但看起来并不像一个典型的数据点。
13-数据完整性与数据管理规范
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1、有关数据完整性的故事
（2）未能给每个可以使用化验室系统的化验员设立单独的授 权密码 1、这个在执行上是否有点难？ 2、如何设立才有效果？ 3、权限密码改如何设立，如何发放，谁来发放？ 4、权限的重要性？
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1、有关数据完整性的故事
（3）在你们化验室使用了不受控的记录表来记录原始分析数 据 1、实验室记录为什么有不受控的呢？ 2、如何避免？ 3、严重吗？ （4）在一个抽屉里发现有许多不受控的色谱图、记录表，以 及不知来源的便条 1、这个问题没法解释； 2、为什么我们存在这种情况，而且非常普遍； 3、数据完整性仅仅是针对电子数据吗？
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数据完整性管理基本要求
数据必须符合 ALCOA 原则： A -- 可追踪至生产数据的人； 1、数据是否有手工签名或电子签名？ 2、有些数据的产生是不需要人的，例如，自动记录数据，怎
么办？ 3、如果数据的来源没有明确的人员怎么办，例如，昨晚半夜 温湿度报警，早上才被发现？
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数据完整性管理基本要求
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数据必须符合 ALCOA 原则
• A -- 可追踪至生产数据的人； • L -- 清晰、在数据的整个生命周期内均可以获得，必要时能 永久保存 (如长达30年）； • C -- 同步； • O -- 原始（或真实复制）: 可根据原始数据对数据生产的整 个活动进行重现； • A --准确性；
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数据完整性管理基本要求
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数据完整性-源于设计管理要求
8、员工数据复核检查时进入原始数据的权限； 9、使用专人记录来代替另一个操作人记录实施活动只有在例 外下考虑： 9.1、记录行为会使产品或活动产生风险，如一些无菌操作； 9.2、陪同人员的语音/文字受限，由其他管理人员进行证明和 记录
MHRA OOS指南
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Phase la Investigation
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Out Of Specification Investigations.
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How to Use The Investigation of Out Of Specification Flowchart
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Phase la Investigation Definition:
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Phase la investigation is to determine whether there has been a clear obvious errors due to external circumstances such as power failure or those that the analyst has detected prior to generating data such as spilling sample that will negate the requirement of a Phase Ib and Phase ll investigation. It is expected that these issues are trended even if a laboratory investigation Phase lb or Phase ll was not raised.
GCP Lab Guidance Issue 1-MHRA
GOOD CLINICAL PRACTICE Guidance on the maintenance of regulatory compliance in laboratories that perform the analysis or evaluation of clinical trial samples.Issue 1. July 2009CONTENTS PAGE1.Foreword (3)2.Introduction (3)3.Glossary of terms (4)4.Guidance for Good Clinical Practice (GCP) Laboratories (8)anisation (8)4.2.Personnel (8)4.3.Serious Breaches (9)4.4.Contracts and Agreements (9)4.5.Study conduct (10)4.6.Requests for additional work (11)4.7.Sub-contracting laboratory analysis (11)4.8.Patient safety (12)rmed consent (12)4.10.Sample receipt and chain of custody (13)4.11.Method validation (14)4.12.Repeat analysis (14)4.13.Data recording (14)4.14.Reporting (14)4.15.Facilities (15)4.16.Equipment maintenance (15)puterised systems (15)4.18.Quality Assurance (QA) processes (17)4.19.Quality Control (QC) (18)4.20.Standard Operating Procedures (SOPs) and facility policies (19)4.21.Blinding/unblinding (19)4.22.Retention of data (20)4.23.Preparation and distribution of clinical kits (21)5.References (21)1. ForewordThe Medicines for Human Use (Clinical Trials) Regulations 2004 (the Regulations) regulate the conduct of clinical trials in the United Kingdom. The regulations relate to persons or organisations that participate in any aspect of a human clinical trial including organisations that analyse or evaluate samples collected as part of a clinical trial. The purpose of this guidance document is to provide such facilities with information that will help them develop and maintain quality systems which will comply with the Regulations. It will also provide information on the expectations of the MHRA’s inspectors who may be assigned to inspect facilities that perform work in support of human clinical trials.2. IntroductionThe transposition of the EU Clinical Trials Directive 2001/20/EC into UK law (The Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No.1031. as amended) provides provision for the inspection of laboratories that perform the analysis or evaluation of samples collected as part of a clinical trial. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has responsibility for monitoring such laboratories for compliance with these Regulations. Compliance is assessed by inspections which will be performed approximately every two years. However, it is important to note that the frequency of inspections may increase or decrease in line with the MHRA’s risk assessment process depending on the level of compliance maintained by the laboratory.The analysis of samples collected from healthy volunteers and patients participating in clinical trials forms a key part of the clinical trials process. Sample analysis or evaluation provides important data on a range of endpoints which is used, for example, to assess the pharmacokinetic profile of investigational medicinal products and to monitor their safety and efficacy. Consequently, it is essential that sample analysis or evaluation is performed to an acceptable standard which will ensure patient safety is not compromised and that data is reliable and accurately reported.3. Glossary of terms“Amendment to the clinical trial authorisation” means an amendment to:(i) the terms of the request for authorisation to conduct that trial or the application foran ethics committee opinion in relation to that trial,(ii) the protocol for that trial, or(iii) the other particulars or documents accompanying that request for authorisation or application for ethics committee approval“Substantial amendment to the clinical trial authorisation” means an amendment to the clinical trial authorisation which is likely to affect to a significant degree:(i) the safety or physical or mental integrity of the subjects of the trial,(ii) the scientific value of the trial,(iii) the conduct or management of the trial, or(iv) the quality of safety of any investigational medicinal product used in the trial. “Archivist” means the person responsible for the management of the archive.“Chief Investigator” means(a) in relation to a clinical trial conducted at a single trial site, the investigator for that site, or(b) in relation to a clinical trial conducted at more than one trial site, the authorised health professional, whether or not he is an investigator at any particular site, who takes primary responsibility for the conduct of the trial.“Clinical Kit” means the necessary components required to collect clinical trial samples prior to their analysis of evaluation in a laboratory.“Clinical Protocol” is a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial.“Clinical Trial” means any investigation in human subjects, other than a non-interventional trial, intended(a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products,(b) to identify any adverse reactions to one or more such products, or(c) to study absorption, distribution, metabolism and excretion of one or more such products, with the object of ascertaining the safety or efficacy of those products.“Computerised System” is a system (consisting of one or more hardware components and associated software) that is involved with the direct or indirect capture of data, processing or manipulation of data, reporting and storage of data, and may be an integral part of automated equipment. Examples include: a programmable analytical instrument or a personal computer linked to a laboratory information management system.“Clinical Trials Regulations” - means Statutory Instrument 2004:1031 (as amended). Part 1 Regulation 2 contains interpretations and definitions of key phrases used within the Regulations, it is recommended these terms are referred to when reading the regulations anddeveloping systems and procedures to assure the quality of clinical laboratory procedures and data.“Schedule 1” of the Clinical Trials Regulations SI 2004:1031, as amended, contains information relating to the conditions and principles of good clinical practice applicable to all trials, and the protection of clinical trial subjects.“Subject” means, in relation to a clinical trial, an individual, whether a patient or not, who participates in a clinical trial –(i) as a recipient of an investigational medicinal product or of some other treatment orproduct, or(ii) without receiving any treatment or product, as a control.“Clinical trial samples” means any sample collected from a participant of a clinical trial as required by the clinical protocol. Samples may include but are not limited to: plasma, serum, urine, faeces, tissues and cells.“Declaration of Helsinki” means the Declaration of Helsinki adopted by the World Medical Assembly in June 1964, and subsequent amendments as referenced in Directive 2005/28/EC, Chapter 2, Article 3.“EU Directive” means Directive 2001/20/EC of the European Parliament and the Council of 4th April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use and Commission Directive 2005/28/EC laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing and importation of such products.Part 1, Regulation 2 of the Clinical Trials Regulations: "conducting a clinical trial" includes –Carrying out any test or analysis –(i) to discover or verify the clinical, pharmacological or other pharmacodynamiceffects of the investigational medicinal products administered in the course of the trial, (ii) to identify any adverse reactions to those products, or(iii) to study absorption, distribution, metabolism and excretion of those products,but does not include any activity undertaken prior to the commencement of the trial which consists of making such preparations for the trial as are necessary or expedient;“Good Clinical Practice” (GCP) means a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and data reporting of clinical trials that provides assurance that the data and the reported results are credible and accurate, and that the rights, integrity, and confidentiality of the trial subjects are protected.“Investigational Medicinal Product” means a pharmaceutical from an active substance or placebo being tested, or to be tested, or used, or to be used, as a reference in a clinical trial, and includes a medicinal product which has marketing authorisation, but is for the purposes of the trial:(i) used or assembled (formulated or packaged) in a way different from the form of theproduct authorised under the authorisation;(ii) used for an indication, not included in the summary of product characteristics under the authorisation for that product, or(iii) used to gain further information about the form of that product as authorised under the authorisation.“Laboratory” means a facility that conducts manipulation, analysis or evaluation of samples collected as part of a clinical trial; such analysis or evaluation may include the generation of pharmacokinetic data,safety data, primary efficacy data, histopathology data or data used to support any other stated end point.“Laboratory management” is the individual(s) having control and formal responsibility for the organisation and functioning of a laboratory in which work that forms part of a clinical trial is conducted.“Master service level agreement”is an overarching contract of general terms & conditions between two parties such as a laboratory and a sponsoring organisation which may be used to underpin work for a number of clinical trials. Study-specific terms, conditions, details, roles and responsibilities are then further defined in other documented agreements.“Principal Investigator” means, in relation to a clinical trial, the authorised health professional responsible for the conduct of that trial at a trial site, and if the trial is conducted by a team of health professionals at a trial site, the principal investigator is the leader responsible for that team.“Quality Assurance personnel” (QA) means, the individual(s) who are responsible for maintaining the laboratories quality assurance processes. (see “Quality Assurance processes”).“Quality Control” (QC) means a formal process for the systematic checking of processes and data to ensure accuracy.“Quality assurance processes” are defined as the activities employed by an organisation to ensure that regulatory requirements are met and internal standards maintained. These activities are documented, established and managed in a systematic and visible manner, with a clear focus on prevention. Quality Assurance activities should be performed by staff who are not directly involved with the analysis of clinical samples.“Source Data” All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).“Source Documents” Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).“Serious Breach” is a breach which is likely to affect to a significant degree:(i) the safety of physical or mental integrity of the subjects of the trial; or(ii) the scientific value of the trial.Regulation 29A of The Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended) states that the sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of:(i) the conditions and principles of good clinical practice in connection with that trial;or(ii) the protocol relating to that trial, as amended from time to time in accordance with regulations 22 to 25,within 7 days of becoming aware of that breach.“Sponsor” in relation to a clinical trial means, the individual(s) who takes responsibility for the initiation, management, and financing (or arranging the financing) of that trial.“Validation of a computerised system” is a documented process that demonstrates that a computerised system is suitable for its intended purpose.“Work instruction”is a written plan which will include, but is not limited to, the purpose of the analysis and the methodology that will be used to perform the analysis. This may also be referred to as an “analytical protocol” or an “analytical plan”.4. Guidance for Good Clinical Practice (GCP) Laboratories4.1. OrganisationRoles and responsibilities within a laboratory should be established and documented prior to the initiation of analytical work. These will include but not be limited to identifying personnel that are responsible for laboratory management, quality assurance and scientific analysis.It is the responsibility of laboratory management to ensure that laboratory personnel are appropriately trained to perform the roles and responsibilities assigned to them.Laboratory management should ensure that each individual involved in the analysis of clinical trial samples is provided with a current job description detailing the individual’s role and responsibilities within the laboratory.Care should be taken not to confuse terminology. For example, a principal investigator has a specific meaning in the context of a clinical trial (see glossary of terms) or a GLP study. Consequently, this title should be avoided when describing the position held by a scientist responsible for conducting laboratory analysis.The analysis or evaluation of clinical trial samples should be overseen by a named individual(s) who assumes responsibility for the conduct and reporting of the work. This individual(s) should ensure that all laboratory work is performed in compliance with the Clinical Trials Regulations, the clinical protocol and any associated work instruction.The named individual(s) is responsible for reporting the results of the analysis or evaluation and any deviations from the work instruction or clinical protocol to the sponsor or their representative.If any serious breaches of GCP are identified they must be reported to the sponsor or their representative immediately. In some circumstances it may be necessary for laboratory personnel to report serious breaches directly to the MHRA. The laboratory should maintain a documented procedure to describe the actions that would be taken in the event of a serious breach.Prior to the initiation of any analysis, the persons designated as “laboratory management” should make provision to ensure that sufficient resources are available to conduct the analysis in accordance with the clinical protocol, work instructions and associated methods. Prior to the initiation of analytical work, lines of communication should be established and documented between the sponsor or their representative and the individual who is responsible for coordinating the laboratory analysis.4.2. PersonnelProcedures and systems should be implemented to ensure that individuals involved in the organisation and conduct of the analysis or evaluation of samples collected as part of a clinical trial are appropriately educated, experienced and trained. Laboratory personnel should be fully aware of their roles and responsibilities with respect to the analysis or evaluation they are performing.The Clinical Trials Regulations state that “No person shall conduct a clinical trial other than in accordance with the conditions and principles of good clinical practice” (SI2004:1031 as amended, Part 4 Regulation 28). It therefore follows, that all staff involved in the analysis or evaluation of clinical trial samples should receive GCP training commensurate with their roles and responsibilities.It is appropriate for laboratory staff to receive periodic GCP refresher training. Such training is especially important following changes to statutory regulations and associated guidance documents.Laboratory personnel must receive an appropriate level of technical training prior to their participation in the analysis or evaluation of clinical trial samples. Specifically, laboratory management should ensure that staff are competent to perform the techniques required by the clinical protocol, work instructions or associated methods.A record of training should be maintained for each individual involved in the analysis or evaluation of clinical trial samples. Laboratory management should ensure a copy of this information is retained when staff leave the organisation.If an individual has relevant experience that has been gained through previous employment, they should maintain a record of this experience in addition to a record of training provided by their current employer.It is recommended that training records are periodically reviewed, signed and dated to ensure the information they contain is up to date and remains relevant.4.3. Serious BreachesIt is the responsibility of the sponsor of a clinical trial to notify the licensing authority in writing of any serious breach of the conditions and principles of GCP or of the clinical protocol. If the laboratory becomes aware of circumstances that may potentially constitute a breach, the relevant information must be communicated to the sponsor or, if appropriate, directly to the MHRA. For example, in cases were fraudulent activity is suspected.An effective mechanism should be established to ensure the reporting of incidents that may constitute a “serious breach” is performed in a timely manner.4.4. Contracts and AgreementsThe analysis or evaluation of clinical trial samples may be organised in a number of different ways depending on the requirements of the sponsor, the type of data that is being generated, the volume of samples that are received and the time lines within which data is required. In all circumstances the analysis should be organised and conducted in such a way that the findings are transparent and stand up to retrospective verification.Contractual agreements between relevant parties should be in place prior to the initiation of any work. This will usually take the form of a legally binding contract which is signed by the sponsor (or their delegated representative) and laboratory management.Contracts and agreements between the laboratory and the sponsoring organisation should not conflict with the requirements outlined in the clinical protocol or work instruction. It is advisable to review the contract, the relevant sections of the clinical protocol and (where applicable) the work instruction prior to the initiation of laboratory analysis or evaluation in order to ensure that the documents are not contradictory and that their requirements are not incompatible. It is also appropriate to ensure these agreements comply with local legal regulatory and ethical requirements, and again that there are no conflicting terms.If a laboratory performs analysis or evaluation of samples associated with more than one clinical trial for the same sponsor, it may be appropriate to conduct the work under a “master service level agreement”. In such circumstances it is important to ensure that the terms and conditions stipulated in the master service level agreement are applicable to all the work conducted for the sponsor in question. Care must be taken to ensure that any study-specificschedules or appendices are not over-ridden by the terms of the master service level agreement.The laboratory’s quality system should include a documented procedure for the drafting, agreement, review and revision of contracts. All contracts and agreements, including master service level agreements, should be subject to periodic review to ensure that they remain up to date and relevant. In cases were the contract is provided by the sponsor, the laboratory’s quality system should include procedures for agreement and review of contracts.There is an expectation that a contract or agreement will be implemented between the laboratory and a company or individual that provides a service linked to the analysis or evaluation of clinical trial samples. These agreements will stipulate the nature of the service(s) provided. Examples may include: companies that provide maintenance services for analytical equipment through to scientific experts who are contracted to read pathology slides.4.5. Study conductClinical analyses performed in the UK must be conducted in accordance with the current Clinical Trials Regulations, EU Directives, applicable Commission guidance and the Declaration of Helsinki.Under most circumstances the laboratory will be provided with a copy of the full clinical protocol (and amendments). As a minimum the laboratory should be provided with the sections of the clinical protocol which are relevant to the work that they have been contracted to perform.The laboratory should be able to verify with the sponsor that the clinical protocol (or part there of) provided is current and has not been subject to amendments.A mechanism should be agreed with the sponsor or their representative to ensure that any relevant amendments to the clinical protocol are supplied to the analytical laboratory.Prior to the initiation of sample analysis or evaluation, it is often necessary to prepare a work instruction detailing the methods and procedures which will be used to conduct the analysis or evaluation. Exceptions will include situations were all the relevant information is detailed in the clinical protocol or the contract.The exact nature of a work instruction is not stipulated in the Clinical Trials Regulations and consequently these documents may take a number of different forms. However, care should be taken to ensure that the work instruction contains sufficient detail for the analyst to perform their duties and to allow the reconstruction of techniques used to perform the analysis or evaluation. Checks should be made to ensure that the work instruction does not contradict other documents associated with the laboratory analysis or evaluation, such as the contract and the clinical protocol.It is critical that the work instruction only includes work that is covered by the informed consent given by the trial subjects.If a work instruction is produced by the contract laboratory it must be agreed with the sponsor or their representative prior to the initiation of the work. Verification of this agreement should be documented. Once a work instruction has been agreed it should not be amended without the agreement of the sponsor or their representative.This process will enable the sponsor or their representative to determine if changes to the work instruction constitute a substantial or non substantial amendment to the clinical protocol.All analysis or evaluation of clinical trial samples must be performed in accordance with the clinical protocol. Consequently, a check should be made to ensure that the work instructions do not conflict with or exceed the requirements detailed in the clinical protocol. If a full clinical protocol has not be provided by the sponsor, it would be appropriate for the sponsor toconfirm that they have reviewed the work instruction and it does not exceed or contradict the requirements set out in the full clinical protocol.Appropriate procedures should be implemented to ensure effective and timely communication with the sponsor or their representative, regarding any serious deviations from the work instruction, clinical protocol or contract/agreement. Timely reporting will ensure that the sponsor or their representative are able to determine the significance and impact of the deviation on the safety and well being of the trial subjects and on the integrity and reliability of the trial data. Additionally, it will also allow them to determine if the deviation constitutes a serious breach as described in the Clinical Trials Regulations.The impact of any deviations from the laboratory’s standard operating procedures or documented policies should be assessed and documented. Where there is potential for a deviation to impact on the integrity or reliability of the trial data, patient confidentiality, patient consent or patient safety, appropriate procedures should be implemented to ensure the issue is reported to the study sponsor or their representative immediately.Regardless of the way in which clinical analysis is organised and performed, activities should be driven by documented policies or procedures. In all cases sufficient documentation must be available to confirm that the conduct of the analysis is performed in a manner which assures its quality.4.6. Requests for additional workLaboratories should not perform any work that is not detailed in the original work instructions, contract/agreement or clinical protocol (whichever is applicable). If additional work is requested by the sponsor or their representative all relevant documentation must be amended prior to the initiation of the additional analysis or evaluation. The laboratory should seek a documented assurance from the sponsor that the additional work does not conflict with the requirements of the clinical protocol or compromise the informed consent given by the trial subjects.It should be noted that patient safety is of primary importance. Consequently, if unscheduled analysis or evaluation is required for urgent clinical reasons, for example, as a result of adverse events, then it should not be delayed because it is not stipulated in the work instruction or the contract. The sponsor should notify the MHRA and relevant ethics committee of urgent safety measures within 3 days from the date the measures are taken. Laboratories should maintain a documented policy detailing how they would address this type of situation.4.7. Sub-contracting laboratory analysisIf analysis or evaluation of clinical trial samples is sub-contracted to another laboratory, the ability of the sub-contractor to perform the work must be assessed prior its initiation. Particular attention should be paid to staff training.Before placing work with a sub-contractor the study sponsor, or their representative, must be informed and, if necessary, the contract with the sponsor amended.A contract or service level agreement must be implemented between the two laboratories prior to the initiation of any work. Any such contract or service level agreement should clearly state roles and responsibilities and the scope and nature of the work that will be undertaken by the sub-contractor. Care should be taken to ensure that contracts do not conflict with the requirements of the clinical protocol, work instruction or the contract between the analytical laboratory and the study sponsor.4.8. Patient safetyThe safety of trial subjects takes precedence over any other aspect of the trial. Consequently, prior to the initiation of laboratory work, lines of communication should be established with the study sponsor, or their representative, to ensure that any issues that may impact on patient safety are reported without delay. These may include, but are not limited to, the reporting of unexpected or out or range results and significant deviations from the clinical protocol or work instructions.The need to expedite the reporting of results should always be considered and discussed with the study sponsor or their representative prior to the initiation of any laboratory work.Under most circumstances normal ranges should be established for safety tests prior to the start of analysis. If these ranges are exceeded a mechanism must be established to communicate this information to the study sponsor or their representative as quickly as possible.It is always appropriate to consider the need to expedite the reporting of results regardless of the nature of analysis or evaluation that is being conducted. For example, anomalous results or unexpected values associated with pharmacokinetic analysis may indicate incorrect dosing or marked differences in a subject’s ability to metabolise an investigational medicinal product which may potentially have safety implications.In all cases, results and observations should be reviewed by an appropriately qualified person to identify any anomalous or out of specification data. This review should be performed in a timely manner.In situations where the clinical laboratory and the sponsor, or their representative, are operating in different time zones or in countries with different (public) holiday allocations, consideration should be given to how the laboratory would expedite the reporting of issues that may impact on patient safety or well being. In such situations the laboratory should consider the implementation of an agreed and tested out of hours’ communication policy.4.9. Informed consentPrior to the initiation of a clinical study, informed consent must be obtained from all trial subjects or their legal representatives. The principal investigator is responsible for ensuring that the subjects enrolled on a study (and/or their legal representatives) have been provided with an appropriate level of information concerning the nature of the trial and that consent has been obtained. However, all laboratory personnel that perform work in support of clinical trials must exercise due diligence to ensure that the work they have been contracted to conduct is covered by the consent given by the trial subjects. Mechanisms implemented to address this concern may include a review of the approved clinical protocol, or a documented dialogue with the sponsor to confirm that the consent process covers the work that will be undertaken by the laboratory. It may also be appropriate to include a clause in the contractual agreement between the sponsor and the laboratory which stipulates the need for informed consent to cover any laboratory analysis or evaluation.There should be a mechanism to ensure that the laboratory is informed in a timely manner if consent is withdrawn to ensure that no further data is generated or collected. While the responsibility for providing this information primarily resides with the sponsor, the clinical laboratory must exercise due diligence. It is therefore recommended that these factors be considered and documented in the contractual agreement or other relevant documentation prior to the initiation of any analytical work.。
数据完整性法规概述
数据完整性，是一个老生常谈的话题，就像我们说一个人需要诚信、一个企业要诚信一样，虽然最近两年欧盟和美国的监管机构在检查中发现较多的数据完整性方面的问题，但实际上这并非新话题。
药品生产研发的一个特性是信息不对称，即监管部门和药品的研制生产者在药品技术信息方面是不对称的，药品的研发和生产机构最清楚药品本身的质量、特性和属性以及风险。
而对于监管部门来说，他们对药品的评价都是基于申请者提交的资料。
监管部门做出的批准与否、上市前许可的检查、上市后的监测，实际上都是基于申请者提交的这些技术资料。
如果申请者提交的资料或者数据不完整、不准确，这对于监管部门包括用药者和患者都存在很大风险和不确定性。
数据完整性是什么指的是在药品整个生命周期中，包括药品研发、生产以及上市后的监测，相关的数据和记录要符合数据完整性要求。
1、计算机化系统验证≠数据完整性;计算机化系统验证≠数据完整性与数据管理，但如果要完成计算机化系统的验证，就必须有数据完整性的概念。
而建立数据完整性的“习惯和文化”，也不是一蹴而就的，需要一个庞大而广泛的前提条件的支持。
数据完整性与企业文化息息相关，包含计算机化系统的验证，企业管理者要认同数据完整性这一概念，并提供资源和支持。
2、数据完整性原则：ALCOAA：attributable to the person generating the data 可追溯至数据由谁生成L：legible and permanent 清晰并持久C：contemporaneous 同步O：original (or true copy) 初始(或正确的副本)A：accurate 准确3、中华人民共和国药品管理法第十条除中药饮片的炮制外，药品必须按照国家药品标准和国务院药品监督管理部门批准的生产工艺进行生产，生产记录必须完整准确。
药品生产企业改变影响药品质量的生产工艺的，必须报原批准部门审核批准。
第十一条生产药品所需的原料、辅料，必须符合药用要求。
欧盟 GMP中英文对照
The GMPs tell us what to do, they do not tell us how to do it. 药品生产管理规范告诉我们做什么，而不告诉我们怎样 做。
How comes from: 怎样来源于： – industry standard practice and guidelines 工业标准规范和指南
5
GMP Variations GMP的差异
• The overall principles of Good Manufacturing Practice are similar whether we follow the WHO Guidelines, the EU Guidelines or the FDA guidelines 不管是世界卫生组织指南、欧洲指南，还是美国食品药物管理局指 南，药品生产管理规范的总体原则是相似的 • There are numerous variations in the application of these principles 这些原则在应用上有些差异 • The enforcement of the guidelines varies between different regulatory authorities 不同法规组织在指南的实施上存在差异 • The approach taken by individual inspectors varies 不同检查人员所采用的方法存在差异 • The approach taken by different regulatory authorities varies 不同法规组织所采用的方法存在差异
12
EU Guidelines to GMP 欧洲GMP指南
• Annex 1 Manufacture of Sterile Medicinal Products 附录一 无菌药品的生产 • Annex 2 Manufacture of Biological Medicinal Products for Human Use 附录二 人用生物药品的生产 • Annex 3 Manufacture of Radiopharmaceuticals 附录三 放射药品的生产 • Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products 附录四 非免疫动物药品的生产 • Annex 5 Manufacture of Immunological Veterinary Medicinal Products 附录五 免疫动物药品的生产
英国药监局MHRA介绍及英国药典发展思路
• British Pharmacopoeia (BP), British Pharmacopoeia (Veterinary) and British Approved Names (BAN)
and research.
Executive agency • Government trading fund and an executive agency of the Department of Health and
Social Care (DHSC)
Size • Around 1350 staff
20
The BP in Europe
• More specifically, the standards of the Ph. Eur will continue to be adopted in the BP and the UK, and we will continue to reproduce the Ph. Eur in the BP for the convenience of our users.
Trends of Drug Regulation in the UK and Standards Revisions of BP
James Pound
Group Manager, British Pharmacopoeia & Laboratory Services Inspection, Enforcement & Standards Division
美沙酮在难治性癌痛中的应用
美沙酮在难治性癌痛中的应用龚黎燕;周琴飞【期刊名称】《浙江临床医学》【年(卷),期】2017(019)011【总页数】3页(P2152-2154)【作者】龚黎燕;周琴飞【作者单位】310022 浙江省肿瘤医院;310022 浙江省肿瘤医院【正文语种】中文美沙酮（methadone）是40多年前人工合成的强阿片类药物。
1947美国开始将美沙酮应用于癌痛治疗，1993世界卫生组织（WHO）推荐为癌痛三阶梯止痛治疗中第三阶梯的强效镇痛药［1］。
对一些用其他阿片类无效的癌痛患者，换用美沙酮后疼痛得到良好的控制，且镇痛的临床效果稳定。
20年来，美沙酮作为一个合成的阿片类药物，在难治性癌痛中的治疗地位逐步被认同。
本文对美沙酮药理学特点及在难治性癌痛中的应用作一综述。
临床上用的美沙酮几乎全部是左旋和右旋异构体混合的消旋体，其镇痛作用基本来自于左旋体。
美沙酮属于强阿片类药物［2］，能激活中枢μ和δ阿片受体，及非竞争性拮抗NMDA 受体，有较明显的瞳孔和平滑肌收缩作用，镇静作用较弱，对呼吸有抑制，在引起欣快、耐药、成瘾和戒断症状方面较吗啡轻。
口服吸收完全，生物利用度高是其特点，可达到约80%（41%～91%），相当于吗啡的3倍。
美沙酮药物脂溶性较大［3］，血浆蛋白结合率高，主要与α酸性糖蛋白结合，在人体内分布广泛，分布半衰期2～3h，消除半衰期15～60h，有的甚至长达120h，血药浓度达稳态时间平均为22～35h。
在儿童及未成年人中［4］，美沙酮在血浆浓度和清除动力学方面显示出更大的变异性，消除半衰期为3.8～62h。
由于血浆半衰期较长且个体差异大，用药时应注意防止药物蓄积和延迟性毒性反应。
美沙酮在肝脏经脱甲基代谢，代谢产物未发现有活性，主要经粪便排泄，少量经尿排泄，酸化尿液时排泄加速，较之吗啡，对肾功能要求更低，是第一个可用于肾功能不全患者的强阿片药［5］。
当然，肾功能不全患者可能对副反应更敏感，滴定的起始剂量应减低，滴定时间可适当延长［1］。
MHRA_OOS_OOT_Oct17+中英
化验室分析
如果OOS/OOT/异常结果发生在以下情形，则必须进行调查： • 批放行检测和起始物料检测 • 中控检测：数据用于进行批产品质量的计算/决策，数据将包括在申报资料中，数据
将包括在COA上 • 制剂或原料药上市批次的稳定性试验、持续稳定性试验、稳定性追踪（没有强降解
试验时） • 之前放行的批次用于OOS调查中作为对照样品时发现其结果为OOS或可疑结果 • 临床试验批产品
example, filed applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria). • Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation (i.e., Raw Material Specifications, InProcess/Final Product Testing, etc.).
所有溶液和试剂必须保持原状，直到所有数据由第二人进行核查并认可其在既定的可接 受标准内
药典对有些测试项目有附加分析标准（即，溶出度在S1、S2和S3检测标准的水平，剂量 均匀性标准中有加测20个制剂单位的描述，无菌测试） 但是如果样品测试标准在正常情况下是测试的第一个阶段，一个样品必须进行测试到下 一个阶段，则应进行调查，因为它通常不会满足正常趋势
Out of Specification & Out of Trend Investigations 超标&偏离趋势调查
MHRA_GxP_data_integrity_guide_March_中英文
Medicines & Healthcareproducts Regulatory Agency(MHRA)‘GXP’ Data Integrity Guidance a ndDefinitionsGXP 数据完整性指南和定义March 2018目录1. Background 背景 (3)2. Introduction 概述 (3)3. The principles of data integrity 数据完整性原则 (4)4. Establishing data criticality and inherent integrity risk 建立数据关键性和内在完整性风险 (5)5. Designing systems and processes to assure data integrity; creating the ‘right environment’.设计系统和流程确保数据完整性，创建“正确环境” (7)6. Definition of terms and interpretation of requirements 术语定义和要求诠释 (8)6.1. Data 数据 (8)6.2. Raw data (synonymous with ‘source data’ which is defined in ICH GCP) 原始数据（与ICH GCP 中定义的“源数据”为同义词） (9)6.3. Metadata 元数据 (10)6.4. Data Integrity 数据完整性 (10)6.5. Data Governance 数据管理 (10)6.6. Data Lifecycle 数据生命周期 (11)6.7. Recording and collection of data 数据记录和采集 (11)6.8. Data transfer / migration 数据转移/迁移 (12)6.9. Data Processing 数据处理 (12)6.10. Excluding Data (not applicable to GPvP): 除外数据（不适用于GPvP） (13)6.11. Original record and true copy 原始记录和真实副本 (13)6. 11.1. Original record 原始记录 (13)6.11.2. True copy 真实副本 (14)6.12. Computerised system transactions: 计算机化系统处理 (15)6.13. Audit Trail 审计追踪 (15)6.14. Electronic signatures 电子签名 (17)6.15. Data review and approval 数据审核和批准 (18)6.16. Computerised system user access/system administrator roles 计算机化系统用户权限/系统管理员角色 (19)6.17. Data retention 数据保存 (20)6.17.1. Archive 归档 (20)6.17.2. Backup 备份 (21)6.18. File structure 文件结构 (21)6.19. Validation – for intended purpose (GMP; See also Annex 11, 15) 根据既定用途进行验证（参见附录15 和GAMP5） (22)6.20. IT Suppliers and Service Providers (including Cloud providers and virtualservice/platforms (also referred to as software as a service SaaS/platform as a service(PaaS) / infrastructure as a service (IaaS)). IT 供应商和服务提供商（包括云服务提供商和虚拟服务/平台（也请参见SAAS/PAAS/IAAS）） (22)7. Glossary 术语 (24)8. References 参考文献 (25)1. Background 背景The way regulatory data is generated has continued to evolve in line with the ongoing development of supporting technologies such as the increasing use of electronic data capture, automation of systems and use of remote technologies; and the increased complexity of supply chains and ways of working, for example, via third party service providers. Systems to support these ways of working can range from manual processes with paper records to the use of fully computerised systems. The main purpose of the regulatory requirements remains the same, i.e. having confidence in the quality and the integrity of the data generated (to ensure patient safety and quality of products) and being able to reconstruct activities.随着支持性技术的持续发展，法规数据的生成方式也在继续进化，例如越来越多地使用电子签名捕获、系统自动化和使用远程技术；以及供应链复杂性和工作方式复杂性的增加，例如，通过第三方服务商提供服务。
英国药典2012版序言翻译
序言《英国药典（2012）》代替《英国药典（2011）》。
在顾问团、专家组及工作小组的共同合作与支持下，由英国药典委员会制定。
内容涵盖将近3375篇专论，关于药品实践中使用到的物质、制剂以及论文。
其中有些是国家专论，而其他则转载自《欧洲药典（第七版）》。
该版连同其姐妹篇《英国药典（兽医）2012》，包含了《欧洲药典（第七版）》的所有专论，由附录7.1及7.2进行了修订。
使用英国药典可以在该综合性的索引纲要中找到所有的英国现行的人用药药典标准。
2012英国药典共有6卷组成，如下：第一/二卷药用物质第三卷处方制剂：一般专论处方制剂: 特定专论第四卷草药，草药制剂，草药产品，用于生产顺势疗法制剂的物料，血液制品，免疫学制品，放射性药品制剂和外科药物第五卷红外参考光谱，附录，补充章节，索引第六卷英国药典（兽用药）2012生效日期此版英国药典专论于2012年1月1日起生效。
根据1968年《药品法》中第65(4)部分规定，此版本或者更早版本的英国药典中删除的专论仍然有效。
有关欧洲药典的出版执行日期见补充章节IV B：执行日期。
欧洲药典专论的标题旁边有一连串星星符号。
凡例英国药典凡例（第二部分）的修改内容如下：修改凡例中的度量衡制，使用‘L’作为‘公升’的缩写贯穿新版药典，并按照欧洲指令的80/181/EEC允许继续使用‘l’。
（见以下的编辑修改。
）修改了英国药典凡例（第三部分），以适应《欧洲药典（第七版）》的变更要求。
工作小组已召集新成立的英国药典委员会吸入性药物工作小组，对现行英国药典吸入性药物的专论、相关的一般专论以及补充章节进行审核。
工作小组将会提出建议，以确保英国药典能够适当地对现行销售的吸入性药物质量加以控制。
新增内容在本序言的结尾，给出了首次包括在英国药典2012中的专论清单，包括35个新的国家专论以及31个转载自由附录7.1及7.2进行了修订的欧洲药典（第七版）的新专论。
传统草药；顺势疗法制剂关于传统草药所用物料及加工物料专论的发展完善工作一直在持续进行。
医学英语翻译练习
医疗器械1 医疗器械是一种用于病人诊断，治疗或外科手术等医疗用途的药用器具。
等医疗用途的药用器具。
而药品（也称药剂）是通过药理学，新陈代谢核免疫学等手段来达到其用药主要目的的。
医疗器械则通过其他途径，诸如物理，器械，物理化学或化学等方式。
医疗器械属于医疗科技，比方说压舌板，体温计，血糖测量仪，全人工心脏，血纤蛋白支架，支撑管支架和X射线仪。
2006年，医疗器械在全球市场的交易额大约为2090亿美元并预计到2010年年增长率将达到6%~9%。
定义欧盟的法律框架和定义2 20世纪90年代，基于“新方法”欧盟对医疗器械的安全性及性能等规则进行了协调。
1985年5月欧洲理事会决议确定了“新方法”。
它是技术协调创新之路的一座丰碑。
其旨在瓦解贸易壁垒和消除频繁的不确定因素，以确保营运商在欧盟内商品的自由流通。
其法案的核心包括三个指令：指令90/385/EFC关于有源植入医疗器械指令93/42/EFC关于医疗器械指令98/79/EC关于体外诊断医疗器械这些指令意在高水准的保障人类安全健康和单一市场的良好运作。
若干修改和执行指令一直对这3个重要的指令进行补充，其中包括由指令2007/47EC引出的最后技术性修订指令。
3 指令2007/47EC将医疗器械定义为：任何仪器，仪表，家电，软件，材料或其他物品，包括由软件制造商设计专门用于诊断或治疗用途的设备，无论是单独使用还是组合使用，均需申请方能用于人类。
这些器械主要用于： 诊断，预防，监测，治疗或缓解疾病带来的痛苦诊断，监测，治疗，减轻对残疾者的损伤或对其进行赔偿调查，更换或修改解剖学或生理过程概念控制系统以上器械并不能通过药理学，免疫学或代谢手段在人体上达到其主要设计目的，但能对其运作有辅助作用。
4 在英国药物及保健品规管局（MHRA）是核证机关，而在意大利则是卫生部。
医疗器械不能被误用为药品。
在欧盟，所有的医疗器械都必须有CE标志。
医疗器械列表高风险设备5 高风险设备是指支持生命，临界测量，能量发射和其他设备。
MHRA关于OOS的指南常见问题的QA
MHRA关于OOS的指南常见问题的QAOut of specification (OOS).超标（OOS）常见问答.1. Has the MHRA produced any guidance?Out of specificationinvestigations (194Kb).1. MHRA有相关指南吗？答：见Out of specification investigations(194Kb)2. Why is there a need to conduct an investigation of an OOS test resultif the decision has been taken to reject the batch?Aphase 1 investigation should always be conducted in order to try and establishan assignable cause and determine whether any other batches may be affected. Indetermining the assignable and root cause of the problem appropriate correctiveand preventative actions can be undertaken.2. 如果已决定拒绝该批了为什么还需要进行OOS调查？答：为了尝试和确定一个明确的原因并决定是否有其他批次受到影响，阶段1调查总应进行。
在确定了问题明确的和根本的原因后应进行纠错和预防措施。
)3. Who should investigate OOS?Boththe manufacturers and the laboratories should be involved in the investigation.3. 谁应调查OOS？答：制造商和实验室应参与调查。
sci投稿指南
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英文论文文体指南
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在科学论文出版中，规范表达历来备受重视。学会、协会专门 编著自己的体例指南，以规定其优先选择的文体。 不同领域的代表性体例指南几乎必不可少的内容大致有：缩写、 数字表达、参考文献著录、单词拼写、标点符号、图表的准备、 校样的检查等。另外，还对稿件的准备与投寄、语法、电子版 本、版权等做专门的规定。
英文论文文体指南
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人文科学文体指南 [MLA]Gibaldi J. MLA Style Manual and Guide to Scholarly Publishing. 2nd ed. New York:The Modern Language Association of America, 1998 ISBN: 0-87352-699-6 MLA文体手册和学术出版指南（第二版）美国现代语 言学会编辑、出版。全书包括8章和4个附录，其中对 版权问题、文献注释和学位论文的准备介绍得比较详 细。该体例的中译本已经出版。 MLA文体手册和学术 出版指南（第二版），北京大学出版社，2002年 相关的指南还有伦敦现代人类学研究协会（MHRA）编 辑的MHRA 文体指南，Modern Humanities Research Association. MHRA Style Book:Notes for Authors, Editors and Writers of Theses.5th ed. Leeds:W.S. Maney & Son Ltd,1996
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英文论文文体指南
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生物学 [CBE] CBE (Council of Biology Editors) Style Manual Committee. Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers. 6th ed. Cambridge University Press,1994 科技文体与格式：作者、编辑和出版者 手册（第6版），全书33章和3个附录， 不仅对通用的文体作介绍，还分章节对 化学、药学、植物学、地球科学等专业 领域的文体进行系统的介绍。
ISPE指南目录
ISPE指南目录ISPE指南目录1.引言1.1 本指南的目的1.2 适用范围1.3 定义和缩写词2.质量管理体系2.1 质量方针和目标2.2 组织结构2.3 质量文件和记录2.4 内部审核2.5 管理评审3.设计3.1 设计计划3.2 设计输出3.3 设计验证3.4 设计修改和变更控制3.5 设计审查4.建造和安装4.1 工程执行计划4.2 供应商评估和选择 4.3 工程监督和管理4.4 施工质量控制4.5 现场文件和记录5.验证和验证5.1 验证计划5.2 验证测试5.3 验证文档5.4 验证报告5.5 质量文件和记录6.运营和维护6.1 运营计划和程序6.2 运营培训6.3 运营文件和记录6.4 设备维护计划和程序6.5 设备维护文件和记录7.变更管理7.1 变更控制过程7.2 变更评估和批准7.3 变更实施和验证7.4 变更文件和记录8.验证和验证计划8.1 验证计划编制指南 8.2 验证计划范例8.3 验证计划评审要点8.4 验证计划签发和发布9.附件9.1 样板文件和记录9.2 样板评审指南9.3 样板签发和发布流程本文档涉及附件：附件1：质量文件范例附件2：设计输出范例附件4：验证计划范例本文所涉及的法律名词及注释：1.GMP：良好生产规范（Good Manufacturing Practices），指药品生产中保证质量的一系列规定和标准。
2.FDA：美国食品药品监督管理局（Food and Drug Administration），负责监督和管理美国的药品和食品安全以及相关法规的制定。
3.MHRA：英国药品和医疗保健产品管理局（Medicines and Healthcare products Regulatory Agency），负责监督和管理英国的药品和医疗保健产品安全。
4.SOP：标准操作程序（Standard Operating Procedure），是指对操作过程进行规范化和标准化的文件，以确保操作的一致性和质量。
Lateral Flow Device (LFD) 快速检测设备用户指南 说明书
A guide for healthcare staff self-testing for coronavirus using a Lateral Flow Device (LFD)CTSI D :This guide will help you remain well at work and keep your patients safeThis test is suitable for healthcare workersAbout this test kitThis test is part of the government’s response to the pandemic and its commitment to controlling infection and supporting our patient-facing NHS Scotland staff in hospitals, Scottish Ambulance Service (SAS) and COVID-19 Assessment Centres.Please follow the instructions in this booklet as this sets out how the test can be self-administered. This has been agreed with clinical and subject-matter experts. Other than taking a swab yourself from just inside both nostrils, the process is the same as set out in the manufacturer’s instructions. If you still feel unsure about using this device after receiving training, please contact your local NHS health board.If you have tested positive for COVID-19 via PCR you should notrecommence regular COVID-19 testing until 90 days after your positive test was taken. You will need to liaise with your NHS Board to trackthe date at which the re-testing should start. However, if you developCOVID-19 symptoms during that 90 day period, you should self-isolate in line with government guidance and arrange a PCR test.The content of this resource has been developed from the ScottishGovernment standard operating procedure Novel coronavirus (COVID-19) standard operating procedure: Rollout of lateral flow devices forasymptomatic testing of patient-facing staff in NHS Scotland hospitals, COVID-19 Assessment Centres and the Scottish Ambulance Servicefor SARS CoV-2 and Frequently Asked Questions Guide to TestingHealthcare Workers.The manufacturer’s instructions for use (IFU) are included in the box andare detailed and very technical. These do not need to be followed as NHSstaff will use the test in a slightly different way, which has been agreed with experts, discussed with the Medicines and Healthcare Regulatory Authority(MHRA) and the manufacturer has been informed.This is particularly in relation to use of the test for asymptomatic people,self-administration of the test, and the use of nasal swab inside thelower part of both nostrils. The rest of the process (i.e. the way the test isperformed, and the results are interpreted) is the same as set out in themanufacturer’s instructions.Remember, store the test kit at room temperature – not in direct sunlight and not in a fridge or freezer. Keep the test kit away from children and animalsOverviewYou should only perform this test if you have no symptoms of COVID-19.Here is a quick checklist for how to use the COVID-19 LFD tests. It is really important that you follow these steps in the correct order.You should test yourself twice a week, every 3 to 4 days, to fit your shift pattern – for example, every Monday and Thursday or Wednesday and Sunday.Prepare your test area and unpack your equipment onto a clean and dry surface Take your swab sample (nasal swab only) Process your sample and wait 30 minutes Read your result Report your resultSafely dispose of test equipmentYou must record the result of your test regardless of the results on the COVID-19 Testing Results Portal: www.covidtestingportal.scotBefore you startRead the instructions carefully. Taking the test may feel a littleuncomfortable and unusual for most people.You can see a demonstration of how to take the test by watchingthis video: (https://learn.nes.nhs.scot/40766/coronavirus-covid-19/protecting-yourself-and-your-workplace-environment/covid-19-self-testing-for-healthcare-staff-using-a-lateral-flow-device)Wash your hands thoroughly for 20 seconds, using liquidsoap and warm water. This is so that you do not contaminatethe test kit. Now dry your hands thoroughly.Clean and dry a flat surface, where you will take the test.Unpack the sealed test equipment for one test and place ontothe clean flat surface.Check the test kit contentsEnsure that the test device (called ‘antigen test cartridge’), swab and extraction solution are not damaged, broken or out of date. Use the test kit checklist to make sure you have everything. Use a clean, one-inch deep lid or other small container(e.g. clean egg cup) to keep the extraction tube upright and prevent spillage.Extractionbuffer bottleRapid teststripSwab, insidesealed wrapper Nozzle capExtractiontubePrepare your test Gently blow your nose into a tissue to get rid of excess mucus.Wash and dry your hands again (or use alcohol-based hand rub (ABHR) if this is available).Place the extraction tube in a small cup to keep itupright.Unscrew the extraction buffer bottle.Place 6 drops only of the extraction buffer into the extraction tube. Try to avoid touching the tube with the bottle. Reseal the extraction buffer for future use.Check the swab in the sealed wrapper in front of you. Identify the soft, fabric tip of the swab.6DropsTake your swab sampleReading your resultsLeave your test for the full development time to get an accurate result. Do not read your results before 30 minutes. If the test device is left to develop longer than 30 minutes you may receive a false positive result and you will need to repeat the test.How to record your resultsYou must record your results on the COVID-19 Testing Results Portalwww.covidtestingportal.scot . It does not matter what the result is, it must be recorded on the portal.Positive resultTwo lines – even faint lines – indicate the test is positive.Invalid resultA single line at the T position indicates the test has failed and should be retaken.Negative resultA single line at the C position s indicates the test is negative.CT CTCT Reporting your resultsIf your test result is negative: Record the information on the portal and on the report sheet at the end of this document or one provided by your organisation. If you have coronavirus (COVID-19) symptoms please refer to NHS guidance online Coronavirus (COVID-19) in Scotland | NHS inform as this test may miss some positive cases.Screen 1If your test result is negative you should not regard yourself as free from infection – the test could be a false negative – you may also go on to acquire the virus in the period before the next test. You should remain vigilant to the development of symptoms that could be due to COVID-19.If your test result is invalid: Record the information on the report sheet at the end of this document or one provided by your organisation and on the COVID-19 Testing Results Portal.Repeat the test with a new test kit.Accessing the COVID-19 Testing Results PortalYou can access the testing results portal using a smartphone, tablet device, laptop or computer.You will need to enter www.covidtestingportal.scot into the address bar of your web browser and you will be taken to the homepage.You will be asked to confirm that you are not a robot and on completion this will lead to the screen below.You will now be asked to complete your personal information so that your test results can be linked to you (see Screen 2 on the following page).You must include the Lot and Serial numbers for the testing device. If you have difficulty in reading the Serial number on the device you can use the QR reader on your mobile device, you will not be redirected to anywhere and nor will theinformation be stored, this is only to increase the size of the batch number for ease of reading.It is important to note that you have to format the Lot and Batch numbers correctly or they will not be accepted. The Serial number is one letter followed by eightnumbers. Lot number is one letter followed by seven numbers. Letter in both Serial and Lot MUST be upper case (capital).Once all the required information has been completed press submit.If your LFD test result is positive you will see the below screen.Thank you for submitting your lateral flow test (LFT) results.Your result submitted was:Please now book a follow-up PCR test and return to your address to self-isolate.If your organisation has advice on booking PCR tests, please follow this. If not then please follow the below link to the UK Government Covid 19 test booking site:https:///get-coronavirus-testAdvice for self-isolation can be found at the below links:You have entered a positive lateral flow test result.PositivePlease note: Several of the fields are mandatory and you will require to enter this information every time that you access the portal unless your browser retains your information.Screen 3Thank you for submitting your lateral flow test (LFT) results.Your result submitted was:NegativeIf your LFD test result is negative you will see the screen below.And if your test result is invalid you will see the screen below.Your result submitted was:You will be required to take a new lateral flow test and enter those details in this system once completed. Click on the button below when you have taken the test to enter the result of the new test.You have entered an inconclusive lateral flow test result.InconclusiveThank you for submitting your lateral flow test (LFT) results.Screen 4Screen 5Need more help?If you need more help using the LFD test kit contact the health board that provided you with the test kit.If you can’t perform the test you should contact your employing health board.Disposing of your testIf the test is negative dispose of the testing equipment in the domestic waste and continue your normal activity.Finally, if your test is positive you should double bag the test equipment including the testing solution and store it safely for 72 hours before you dispose of it in the household waste and wash your hands.Disposal advice may be subject to change based upon future waste disposal guidance.Statutory reporting Record of testing sheetName:Job Role:NHS number (if known): Sex: Date of Birth:Department/Ward: Ethinicity:Home address and postcode:It is important that you record your sex and ethnicity as this information helps us understand the risks.。
Medical Device医疗器械相关文本译文
Medical DeviceA medical device is a product which is used for medical purposes in patients ,in diagnosis ,therapy or surgery .Whereas medical products(also called pharmaceuticals)achieve their principal action by pharmacological ,metabolic or immunological means .Medical devices are include in the category :Medical technology .Examples included tongue dangerous medical thermometers ,blood sugar meters ,total artificial hearts ,fibrin scaffolds ,stents and X-ray machines .The global market of medical devices reached roughly 209 billion US Dollar in 2006 and is expected to grow with an average annual rate of 6-9% through 2010.医疗器械医疗器械是一个用于医疗目的的患者，在诊断，治疗或手术，而医疗产品（也称为药品），药理，代谢或免疫手段实现其主要的行动医疗器械包括类别产品。
医疗技术。
包括舌头的危险医疗温度计，血糖米，总的人工心脏，纤维蛋白支架，支架和X光机。
全球医疗器械市场在2006年达到大约209亿美元，预计平均增长到2010年的6-9%的年增长率。
DefinitionsEuropean Union legal framework and definitionBased on the “New Approach ”,rules relating to the safety and performance of medical devices were harmonized in the EU in the 1990s.The “New Approach”,defined in a European Council Resolution of May 1985,represents an innovative way of technical harmonization .it aims to remove technical barriers to trade and dispel the consequent uncertainty for economic operators allowing for the free movement of goods inside the EU .The core legal framework consists of 3 directives:Directive 90/385/EEC ,regarding active implantable medical devices;Directive 93/42/EEC regarding medical devices;Directive 98/79/EC regarding in vitro diagnostic medical devicesThey aim at ensuring a high level of protection or human health and safety and the good functioning of the Single ,Market .These 3 main directives have been supplemented over time by several modifying and implementing directives, including the last technical revision brought about by Directive 2007/47/EC.定义欧洲联盟的法律框架和定义基于“新方法”，医疗器械的安全性和性能有关的规则1990s.这个“新方法”的定义在欧洲议会的决议一九八五年五月在欧盟统一的，统一的技术创新方式它旨在消除技术性贸易壁垒，并允许在欧盟内部货物的自由流动的经济运营商消除由此产生的不确定性。
脱欧-英国MHRA注册与UKCA认证
EU DOC
使用CE Mark
在MHRA注册** （不同分类产品有不同的过渡期）
UKCA合格评定：2023 年6月30日强制执行 符合英国UKCA相关立法规定 （UK MDR 2002）
UKCA DOC
使用UKCA Mark
在MHRA注册***
合法进入GB市场 （非英国境内制造商，需要UK Responsible Person)
• 测试报告 • 技术文档 • 相应合格评定**
程序要求的资料
02
指定英国责任人
英国境外制造商需要指 定英国责任人**（UKRP） 完成MHRA注册
03
递交MHRA注册
UKRP上传注册资料到 MHRA系统，提交注册
04
审核通过，注册完成
MHRA收到申请后，会 完成审核。审核无误， 完成MHRA注册申请
何时需要注 册
2021年1月1日之后，进入英国市场的医疗产品： • 所有产品均需MHRA注册 • 但是根据产品类别不同，具有不同的过渡期（4个月、8个月、12个月）
4个月过渡期
2021年5月1日前完成注册 （4月30日截止）
有源植入式医疗设备 III类医疗产品
IIb类可植入医疗器械 IVD清单A
8个月过渡期
UKRP
英国责任人的选择与指定
Part 01 MHRA注册
（** 以 英 国 境 外 制 造 商 为 例 ）
2021年1月1日，MHRA注册正式开 启
如何注 册
什么时候开始注册
How
When
谁需要注 册
Who
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数据完整性要求等同适用于手工（纸质）和电子数据。生产商和分析化验室应明白将自动化的/ 计算机化的系统转换为人工/纸质的系统并不能消除数据完整性控制的需求。这可能也会是违反 法条2001/83/EC第23款的，该条款要求许可证持有者要考虑科学技术进步，使得药品采用普遍 被接受的科学方法进行生产和检查。 Throughout this guidance, associated definitions are shown as hyperlinks. 在本指南全篇中相关定义均采用了超链接显示。 Establishing data criticality and inherent integrity risk: 建立数据关键性和内在完整性风险 In addition to an overarching data governance system, which should include relevant policies and staff training in the importance of data integrity, consideration should be given to the
MHRA GMP Data Integrity Definitions and Guidance for Industry January 2015 MHRA的GMP数据完整性定义和行业指南/2015年1月 Introduction: 背景介绍 Data integrity is fundamental in a pharmaceutical quality system which ensures that medicines are of the required quality. This document provides MHRA guidance on GMP data integrity expectations for the pharmaceutical industry. This guidance is intended to complement existing EU GMP, and should be read in conjunction with national medicines legislation and the GMP standards published in Eudralex volume 4.
数据管理系统应与EU GMP第1章中描述的药品质量体系相结合。给数据管理提供的努力和资源 应与产品质量的风险相称，还应与其它质量保证资源需求相平衡。因此，并不期待生产商和分 析实验室实施一种司法鉴定的方法来对数据进行检查，而只需要设计和实施一种系统，提供一 种基于数据完整性风险的可接受控制状态，并对支持性理由进行完整记录。 Data integrity requirements apply equally to manual (paper) and electronic data. Manufacturers and analytical laboratories should be aware that reverting from automated / computerised to manual / paper-based systems will not in itself remove the need for data integrity controls. This may also constitute a failure to comply with Article 23 of Directive 2001/83/EC, which requires an authorisation holder to take account of scientific and technical progress and enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.
1
organisational (e.g. procedures) and technical (e.g. computer system access) controls applied to different areas of the quality system. The degree of effort and resource applied to the organisational and technical control of data lifecycle elements should be commensurate with its criticality in terms of impact to product quality attributes. 除了包括相关方针和员工关于数据完整重要性培训的总体数据管理系统外，还要考虑将组织性 （例如，程序）和技术性（例如，计算机系统进入权限）控制应用于质量体系的不同领域。应 用于组织性和技术性控制数据生命周期要素的努力程度和资源配置情况应与其对产品质量属性 的影响关键性相适应。 Data may be generated by (i) a paper-based record of a manual observation, or (ii) in terms of equipment, a spectrum of simple machines through to complex highly configurable computerised systems. The inherent risks to data integrity may differ depending upon the degree to which data (or the system generating or using the data) can be configured, and therefore potentially manipulated (see figure 1).
LC-MS
2
pH 计
过滤器完整性测试仪 UV 光谱仪 FT-IR HPLC 系统 CAPA 系统 LIMS 系统 ERP 系统
无软件
简单软件
Байду номын сангаас
复杂软件
打印 可以代表原始数据
打印不具有代表性
（图示知识格林山 QA LLC）
With reference to figure 1 above, simple systems (such as pH meters and balances) may only require calibration, whereas complex systems require ‘validation for intended purpose’. Validation effort increases from left to right in the diagram above. However, it is common for companies to overlook systems of apparent lower complexity. Within these systems it may be possible to manipulate data or repeat testing to achieve a desired outcome with limited opportunity of detection (e.g. stand-alone systems with a user configurable output such as FT-IR, UV spectrophotometers).
参考上述图1，简单系统（例如pH计和天平）可能只要求进行校正，而复杂系统则需要进行“对 其既定用途进行验证”。验证工作在上图中从左到右逐步增加。但是，公司一般需要会忽略较 低复杂程度的系统。在这些系统中，可能会可以捏造数据或重复测试以达到所想要的结果，而 被发现的机会较低（例如，独立系统具有用户可设置参数的输出，例如，FT-IR，UV分光光度 计）。 Designing systems to assure data quality and integrity 设计系统来保证数据质量和完整性 Systems should be designed in a way that encourages compliance with the principles of data integrity. Examples include: 系统设计方式应鼓励符合数据完整性性原则： Access to clocks for recording timed events 记录事件时间的时钟进入权限 Accessibility of batch records at locations where activities take place so that ad hoc data recording and later transcription to official records is not necessary 在活动进行的当地处理批记录，这样就不需要临时数据记录然后转抄至正式记录 Control over blank paper templates for data recording 控制数据记录所用的空白纸模板 User access rights which prevent (or audit trail) data amendments 用户权限能防止（或审计追踪）数据修改 Automated data capture or printers attached to equipment such as balances
数据可以由以下方式产生（1）人工观察纸质记录（2）仪器，一连串简单仪器直到复杂的高度 可配置的计算机系统。数据完整性的内在风险根据数据可设置参数水平不同而不同，因此是可 以捏造的（参见图 1）。