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
（ 文 链 接 ：ｔ ／ 原 ｈｔ ／ ｐ：ｗｗｗ．ｃ ｅｓ ａａ ｆａｇ ｖｓｒ ｔ／ｄｈ ａ ｃ ｓｄ ｔ． ．ｏ ／ｃｉ ｓｃ ｒ ／ ｄ ｐ
ｃｄ ｃ／Ｉ ｆ ｏ ｓｃＲＥＳｒｓｃｍ ？ｄ ９ ６ ６） ／ ．ｆ ｉ＝ ４ ０ ｅ
Ｂ ｏｋｙ ａ ， ｒｏ ｌ Ｐｒ ＭＮ ５ ２ 。 同 时 ， 求 将 召 回 证 明 传 真 至 ｎ ｋ ５４ ８ 要 公 司 ， 以表 明 已确 认 召 回 通 知 并 确 定 召 回 数 量 。 如 果 您
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
27
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？
28
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？
8
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？
9
数据完整性管理基本要求
13
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；
14
数据完整性管理基本要求
20
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
•
•
•
Home
© Crown copyright
Phase la Investigation
Obvious found
Document and Correct Invalid Result
Initiate Phase Ib Laboratory Investigation
Safeguarding public health
Out Of Specification Investigations.
© Crown copyright
How to Use The Investigation of Out Of Specification Flowchart
Navigation:
No Further Investigation Required
Slide 6
Home
© Crown copyright
Phase la Investigation Definition:
•
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
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
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）。