1、1. PURPOSE 目的Whenever a product, material or system fails to meet the specifications or in the event of a failure to comply with relevant documentation or regulatory requirements, an appropriate investigation must be undertaken, the cause(s) identified and the necessary corrective actions taken当产品、物
2、料或系统不符合质量标准要求或某事件不符合相关文件或法规要求时，必须进行适当的调查，查明原因并采取必要的改正措施。2. SCOPE 范围This SOP covers all failures and unplanned incidents related to Chemical components, Packaging materials, Drug Products, Processes, Systems, Equipments, Utilities and Facilities used to produce and control them.本 SOP 适用于处理所有失误及非计划性故障
3、事件，含概用于产品并控制产品的化学成分、包装材料、药品、工艺、系统、设备、公共设施和厂房等。 3. DEFINITIONS/ABBREVIATIONS 定义/缩写Deviation（also known as anomaly）：Any unplanned change from a written procedure/document, during manufacturing or testing or a non-conformance to approved specifications or any failure on GMP-related systems. Deviations
4、are assessed according to compliance and /or the risk they present to patient health and/or with regulatory requirements. Deviations are to be classified as “critical or major or minor”偏差（通常也称为异常）：在药品生产过程中，任何与既定的程序、文件不符的非计划的变更或与批准的质量标准不符，或与GMP 相关的系统失败。偏差按照对患者造成的风险何国家法规的符合性进行评估。偏差可分为三类“严重偏差、主要偏差、微小偏差
5、”Critical Deviations:严重偏差：Critical deviations require immediate investigation, root cause analysis and corrective-preventive action.严重偏差需要立即进行调查，查找问题的根本原因并制定纠正预防措施。A deficiency in material, drug product, medical device, system or service that can affect significantly the quality, purity, safety or e
6、fficacy of a product/medical device or can lead to health threatening conditions in drug product, or medical device. Alternatively, any deficiency that can lead to a non-compliant drug product/medical device or to a situation that may be cited by regulatory authorities as critical.存在物料、产品、医疗器械或任何系统、
7、维护方面能严重影响产品质量、纯度、安全、功效，能对产品或身体健康产生危害的缺陷；或者会导致产品质量不符合，或可能被法规部门视为严重缺陷项的缺陷；Major Deviation:主要偏差：Major deviations require investigations, root cause analysis and corrective-preventive action.主要偏差需要进行调查，查找问题的根本原因并制定纠正预防措施。A non-critical deviation which potentially affects the quality, purity, safety or e
8、fficacy of a product/medical device or ability to meet GMP requirements.非严重偏差可能潜在影响产品的质量、纯度、安全、功效或GMP法规的依从性。Minor Deviation：微小偏差：Minor deviation require investigation, root cause analysis and corrective-preventive action.微小偏差需要调查，查找问题的根本原因并制定纠正预防措施。A deviation not classified as critical or major, wh
9、ich potentially impacts a GMP system, utility, equipment, material, component, environment or documentation, but does not affect product/medial device quality, purity, safety, or efficacy.潜在影响GMP系统，公用设施，设备、物料、成分、环境或文件，但不影响产品的质量、纯度、安全、功效，不属于严重及主要偏差的缺陷。Deviations will typically, but not exclusively, f
10、all into one of the following categories: Confirmed Out of Specification (OOS) test results Controlled Zone Environmental results outside of limits Failure to comply with instructions in standard documents (Deviation from Standard Operating Procedures, Deviation from Batch processing parameters duri
11、ng Manufacture, Packaging, labelling orTesting) Process or equipment failure which affects product quality Reconciliation or yield outside Specification Failure to comply with established program (calibration, preventive maintenance and stability test, etc) Material damage or contamination in storag
12、e or handling偏差通常，但不绝对，发生在以下几个类别中: 确认的超出标准的测试结果 受控区域环境超标 不符合标准文件规定的操作（不符合标准操作规程的操作，生产、包装、贴标签或测试过程中操作参数的错误等） 影响产品质量的操作失误或设备故障 物料平衡或产率超过限度 物料在储存或处理过程中出现的损坏和污染情况。 活动未能按照计划进行（校准，预防性维护及稳定性试验等）4. SAFETY 安全N.A. 无5. PROCEDURE 程序5.1 RESPONSIBILITIES 责任5.1.1 Manufacturing, Logistic, Engineering,QC,HR Managers
13、 生产、物流、工程部、QC、HR 经理 It is their responsibility to immediately notify to QA of the occurrence of any event that could lead to a potential failure event and to actively participate in investigation process其职责为当那些可能导致潜在失误事件发生时，立即通知 QA，并积极参与调查活动。 Initiate the Quality Deviation Report.起草质量偏差报告 Implementi
14、ng corrective action resulting from deviation reports when approved by the Head of Quality .执行质量部经理批准的偏差改正措施。 Ensuring all personnel in their Department are trained in the content of this SOP and know that all quality deviations are to be reported.确保本部门人员接受本 SOP 的培训并清楚所有需要报告的偏差。5.1.2 Site IQC manage
15、r is responsible for 质量部经理负责 Ensuring that this SOP is maintained and complies with corporate and local GMP standards.确保本 SOP 始终符合集团及中国 GMP 的要求。 Approval of corrective action resulting from deviation reports.批准偏差的改正措施。 Approval the disposition of the batch in case of Batch deviations.当发生批生产偏差时决定批次的处
16、理。 Site IQC Manager is responsible for further communication to the impacted unit and to the respective Operational Industrial Quality and Compliance (IQC) management If the failure or deviation is critical or if other sites/sub-contractors are potentially impacted.如异常事件或偏差程度严重或其他工厂或下级合同商可能受到影响，工厂质量
17、部经理负责与受影响的单位以及相关区域质量运营部进一步沟通。 For critical deviations affecting product on the market, please follow the SOP “Quanlity Alert Management” ,site IQC Management is responsible to involve Industrial Quality and Compliance/Risk Management to ensure the consistent handling of such critical deviations. 对于影
18、响到市场产品的严重偏差，按照“质量警戒的管理”，由质量部经理负责利用风险评估系统向 IQC 通报以确保类似严重偏差处理的一致性。5.1.3 QA is responsible for QA 负责 Assure that the appropriate investigation is conducted into any failure and that an investigative report is issued to document the situation according to the requirements of this SOP 确保每个偏差都进行了适当的调查，并按本
19、 SOP 要求发放偏差报告。 Maintaining a log of all deviation reports.保管登记所有偏差报告的日志。 Filing a copy of all deviation reports.将偏差报告存档 Following up reports ensuring that they are closed out in a timely manner.跟踪偏差报告确保它们及时结束。 Reviewing all deviations of this year at least annually etc.至少每年进行一次当年所有偏差的审阅等。5.1.4 QC ma
20、nager is responsible for QC 经理负责 Ensuring all test result deviations are reported according to SOP S-QC035, Out of Specification Results “OOS”.确保按照 SOP S-QC035 报告实验结果发生的偏差。 Perform all the tests requested by the investigation report to investigate the cause of the deviation and/or the quality of the
21、 product.进行调查所需的测试以配合查明原因或确定产品质量。 Reviewing all OOS of the year at least annually and producing a report showing trends etc.至少每年进行一次当年所有 OOS 的审阅并作趋势分析等。5.1.5 All Department Personnel are responsible for 所有人员负有如下责任 Reporting all quality deviations to their Department Supervisor or Department Head.向部门
22、主管或部门经理报告所有质量偏差。 Ensure communication to Health, Safety and Environment (HSE) if the deviation may have an impact on HSE matters.如果偏差可能影响到 HSE 确保通知健康、安全、环境部门。5.2 Reporting of Quality Deviations 质量偏差的报告5.2.1 Planned Deviations 计划性偏差Planed Deviation must not be done on an ongoing basis but exceptional
23、 use only.计划性的偏差只能作为非常规的特例使用。Planed Deviation must be pre-authorized by QO Manager.计划性的偏差一定要被质量部经理预先授权认可。Documentation of the purpose of the deviation and approval by QO Manager is required.要求书面记录偏差的目的以及经质量部经理批准。5.2.2 Unplanned Deviations 非计划性偏差All instances of quality deviations must be reported im
24、mediately to the relevant area Department Manager or Supervisor.所有质量偏差必须立即向相关的部门主管或经理报告。The area Department is to initiate the Quality Deviation Report using the form shown in the Attachments section of this SOP. 偏差发生部门负责起草质量偏差报告（见本 SOP 附件）5.2.3 Principles and methods 偏差处理的原则及方法5.2.3.1 Deviation ini
25、tial 偏差发起The following guidelines are given to assist completion of the report.以下方针用以协助报告的完成1. The Manager/Supervisor or the operator of the Department where the deviation occurred is to complete the following details in the sections 1, 2,3：发生偏差的部门的经理/主管或发现偏差的操作人员应填写第 1、2、3、部分：In the section 1: 第 1
26、部分- Department name 部门名称- Date raised 发现日期- Raised by (name) 发现者（姓名）In the section 2:第 2 部分- Product name and batch number if it is a Product failure, Equipment name if one equipment failure or Utility name if the failure affected one utility. 若是产品偏差，记录发生的产品名称和批号；如果是设备误差，记录设备名称；如果是影响到公共设施的偏差，记录受影响的公
27、共设施的名称。In the section 3: 第 3 部分- Detailed explanation of the incident and the other products/batches can be affected in their quality. 误差事故的详细描述及可能影响到质量的其他产品/批次。- Report every immediate action which is approved by department manager or supervisor after deviation found. 报告偏差发现后采取的每一个部门经理或主管批准的紧急措施。5.
28、2.3.2 Deviation Evaluation 偏差的评估After completion of these steps the Quality Deviation Form has to be given to QA to:在这些质量偏差报告步骤完成后交给 QA 以进行：- QA should make a decision whether it is necessary to quarantine product or materials if the deviation is product or material related. The decision shall be fi
29、lled in section 3 as an immediate action. 如果偏差与产品或物料有关，发生后 QA 应立即决定是否需要立即将产品或物料“待检”起来。决定应被记录在第 3 部分作为一项紧急措施。- Fill the section 4 and record in the Deviations logbook.填写第 4 部分并在日志中登记。- Call and organize a meeting with the involved Department Manager / Supervisor and all other functions that can help
30、in discussing and set the investigation to find the cause(s) of the failure/deviation召集所有相关部门的经理/主管以及其他对于讨论并找出偏差的原因有帮助的职能部门人员开会。- During the investigation the extent of the problem, for example, implications for previous or subsequent batches of the same/other product(s) should be taken into conside
31、ration, as well as, depending on the nature of the deviation, it may be necessary to execute additional stability studies and so on. Report the investigation observation in the section 5 of the form Quality Deviation Report. Attach to the form all the memos, e-mails and so on related to the problem.
32、在调查过程中，要考虑问题的扩展程度，比如是否牵涉相同/不同产品的前几批或后几批；还有，依据偏差的性质，可能需要进行额外的稳定性试验等。在质量偏差报告的第 5 部分报告调查的发现。将所有与调查有关的备忘、电子邮件等等附在报告上。The deviation evaluation is based on the comparison to the safty risk evaluation and capability to detect the defect偏差评估应基于对质量安全风险的评估及缺陷被发现的可能性的综合评价。The severity of the impact is defined
33、as per below descriptions:严重性等级分类描述如下：Rating等级Classification分类Description描述1 Minor微小Compliance with dossier/cGMP but increase risk for complaints符合注册文件及现行 GMP 的要求，但增加投诉的风险Or/and defect leading to products that do not cause any adverse health reaction. They may pose a constraint for the user or may i
34、mpair the market imagine of the products.和/或缺陷导致产品不会对健康产生任何不良影响，但可能致产品使用受到限制或影响产品形象。2 Moderate一般Non compliance with dossier /cGMP ; no or minor influence on product quality(safety , efficiency)；不符合注册文件或现行 GMP 要求，对产品质量无影响或微小影响；Or and defects ,which may not pose a significant hazard to health but wher
35、e a recall could be initiated (perhaps not required by the competent authority) for other reasons, but are not class 1 or 2;和/或缺陷，不会对健康产生严重影响但可能会因其他原因发起召回（可能不会被法规部门要求） ，但不属于 1、2类缺陷；A situation in which use of or exposure to a compromised product is not likely to cause adverse health consequences；使用或
36、让步使用的情形不会对公众健康产生不良影响；4 Major关键Non compliance with dossier /cGMP ; major influence on product quality(safety , efficiency)；不符合注册文件或现行 GMP 要求，对产品质量（安全、功效）产生重大影响；Or and defects ,which could cause illness or mistreatment, but are not class 1;和/或缺陷，可能导致疾病或错误治疗，但不属于一类缺陷；A situation in which use of or expo
37、sure to a compromised product may cause temporary or medically reversible adverse health consequences is remote；使用或让步使用的情形对患者健康产生临时或可逆的治疗不利影响的可能极小；5 Severe严重Non compliance with dossier /cGMP ; critical influence on product quality(safety , efficiency)；不符合注册文件或现行 GMP 要求，对产品质量（安全、功效）产生严重影响；Or/ and def
38、ects ,which are potentially life threading or could cause serious risk to health;和/或缺陷，对生命存在潜在威胁或可能导致对健康产生严重风险；A situation in which there is a reasonable probability that the use of or exposure to a compromised product will cause serious adverse health consequences or death.有依据可证明使用或让步使用的情形对健康产生严重不良
39、影响或致死；The occurrence definitions are proposed: 可能性分类如下：Rating等级Occurrence可能性Description描述1Extremely rare/very unlikely极少/几乎不可能Very unlikely 几乎不可能First time that the event is observed第一次发现此事件2 Remote/rare微乎其微/很少Rare很少Isolated in the concerned batch在相关的批次中独立3 Occasional偶尔Possible, do not expect reoccu
40、rrence可能，不希望再次发生Event observed 0 to 1 time a month/a campaign or/and isolated cluster in the concerned batch在一个月内或一个批组内内发生 0-1 次的事件，或在不连续的批次内发生。4 Likely可能Probable, possible reoccurrence很可能，可能再次发生Event observed 2 to 3 times a month/a campaign or/and Unpredictable number of units impacted in the conce
41、rned batch在一个月内或一个批组内内发生 2-3 次的事件，或在相关的批次内不可预知发生的次数。5Almost certain or unknown 几乎肯定会发生/不能确定Frequent to permanent, or unknown occurrence频繁固定的发生，或不可知发生性Event observed 4 to 5 times a month/a campaign or/and previous and/or following batches also impacted.在一个月内或一个批组内内发生 4-5 次的事件，或在后续的批次也深受影响的。The safety
42、 risk level is given by multiplying the severity of impact and the likelihood of occurrence. The result is compared to the following chart:质量风险严重等级来自于缺陷的严重性及发生的可能性的乘积，结论见下表：Severity of impactMinor 1 Moderate 2 Major 4 Sever 5Likelihood of OccurrenceAlmost certain or even 5 10 20 25unknown 5Likely 4
43、4 8 16 20Occasional 3 3 6 12 15Remote 2 2 4 8 10Extremely rare 1 1 2 4 5Based on the results given in the above chart, the safety risk level is evaluated:Low if the number is 4（green area）Moderate if the number is 3 and 10 (orange area)High if the number is 8 (red area)根据上表，质量风险严重等级为：如果乘积小于 4（绿色区域）为
44、低；如果乘积大于 3 而小于 10（黄色区域）为中；如果乘积大于 8（红色区域）为高；The Detection definitions are proposed: 可发现性分类如下： Rating等级Detection可发现性Description描述1 High 高100% control with a performance close to 100%;100%控制性能指标，检查接近 100%High probability to detect and reject the defect 发现并剔除缺陷产品的可能性很高；2 moderate100%c control with a per
45、formance significantly different to 100% or partial control (e.g. IPC, statistical);100%控制性能指标，大量检查但不能 100%检查或采用部分检查（如：IPC, 数理统计等） ；Would most probably be detected during distribution or by the handler (health care professional ) or by the patient (odour, color, appearance)在销售或处理（医务人员）或患者（品种，颜色，外观）等
46、极有可能被发现的；3 lowLow probability to detect, most likely by random chance.发现的可能性很低，可能会被很偶然的机会发现Would most probably not be detected before the use在使用前几乎不可能被发现Severity risk level质量风险的严重等级Low 1 Moderate 2 High 3 Low 1 3 6 9Moderate 2 2 4 6Probability of detection可发现性High 3 1 2 3Based on the results given i
47、n the above chart, the deviation is evaluated:Minor if the number is 3（green area ）Major if the number is 2and 6 (orange area)Critical if the number is 4 (red area)根据上表的结果，偏差等级评估为：如果两者乘积小于 3（绿色区域）为微小偏差；如果两者乘积大于 2，小于 6（黄色区域）为主要偏差；如果两者乘积大于 4（红色区域）为严重偏差；When investigation has been finished, department
48、manager shall fill evaluation of investigation and immediate actions, and QA make batch determination, if the deviation is product related, in section 5. 当调查结束后部门经理应在第 5 部分填写对调查和紧急措施的评价，如果偏差与产品有关，QA同时做出批次处理决定。According to the classification of deviation and the evaluation, QA tick the type of the de
49、viation in section 5 as “critical /major and minor”.根据偏差的分类及对本偏差的评价结果，由 QA 在偏差报告表的第五部分偏差类型“严重/主要/微小”打勾做好标记。5.2.3.3 Corrective action and preventive action 纠正预防措施After the investigation has been completed, the department manager/supervisor has to report in the section 6 of the form the recommended corrective actions identified, clarify who is responsible for each action and the due date. The corrective action must be approved and signed by Quality manager. 在调查结束后，部门经理/主管必须在第 6 部分中记录建议的改正措施，明确各项活动的负责人和预
