内容发布更新时间 : 2024/11/9 2:49:28星期一 下面是文章的全部内容请认真阅读。
Q7a
11. LABORATORY CONTROLS 11.1 General Controls
11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.
11.11 There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.
11.12 All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).
11.13 Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.
11.14 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.
11.15 Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any
11.实验室控制 11.1 控制通则
11.10 独立的质量部门应当有受其支配的、足够的实验室设施。
11.11 应当备有阐述物料取样、测试、物料批准或拒收，和实验室的记录及保存的书面程序。实验室记录应当按照6.6节中所述要求保存。
11.12 所有的质量标准，取样方案和测试程序都应当科学合理并适当，以确保原料、中间体、原料药，标签和包装材料能达到规定的质量和/或纯度标准。质量标准和测试方法应当与注册/申报中的一致。可以有注册/申报以外的附加的质量标准。质量标准、取样方案和测试程序，包括相应的变更，应当由相关的组织机构起草，并由质量部门审核、批准。
11.13 应当根据已接受的标准和与生产工艺的一致性来制订合适的原料药质量标准。质量标准应当包括对杂质的控制（如有机杂质、无机杂质，和残留溶剂）。如果原料药有微生物纯度的质量规格，应当制订并达到合适的总菌落数和致病菌的处置限度。如果原料药有内毒素的质量规格，应当制订并达到合适的内毒素的处置限度。
11.14 应当遵守实验室控制，并边操作边记录。对上述程序的任何偏离都应当有记录并作解释。
11.15 得到的任何不符合质量标准的结果都应当按照程序进行调查，并备案。该程序应当要求对数据进行分析，评价是否有值得注意的问题存在，分配整改措施的任务和结论。发现不符合质量标准的结果后，任何重新取样和/或重新测试都应当按照成文的程序进行。
37
Q7a
resampling and/or retesting after OOS results should be performed according to a documented procedure.
11.16 Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.
11.17 Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.
11.18 Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.
11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.
11.2 Testing of Intermediates and APIs
11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.
11.21 An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the
11.16 应当按照书面程序来配制试剂和标准溶液以及贴标签。分析试剂或标准溶液应当酌情采用“用至”日期。
11.17 原料药生产时应当酌情获得合适的基本参考标准品。每一个基本参考标准品的来源要备案。应根据标准品供应商的要求进行标准品的储存和使用，并进行相应记录同时保存记录。对于从官方认可的渠道获得的基本参考标准品，在按照供应商的建议的保存条件进行保存的情况下，通常无需检验就可以使用。
11.18 从官方认可的货源处无法得到基本参考标准品时，应该制备一个“内部基本标准品”。应当做合适的测试来全面制订该基本参考标准品的鉴别和纯度。该测试的相关证明文件应当保留。
11.19 二级参考标准品应当用合适的方法来制备，鉴别，测试，批准和储存。每一批二级参考标准品在第一次使用前，应当与基本参考标准品进行比较，来确定其适用性。每一批二级参考标准品应当根据书面方案，定期进行重新确认。
11.2 中间体和原料药的测试
11.20 每一批中间体和原料药都应当进行适当的实验室测试，以确定是否符合质量标准。
11.21 每一种原料药都应当有杂质概况，描述用一特别控制的生产工艺生产出的典型批号中存在的已确定和未确定的杂质。杂质概况应当包括观测到的每一个杂质的鉴别或某个定量分析的标志（如保留时间）、范围，以及已确定杂质的
38
Q7a
identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.
11.22 The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.
11.23 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.
11.3 Validation of Analytical Procedures See Section 12.
11.4 Certificates of Analysis
11.40 Authentic certificates of analysis should be issued for each batch of intermediate or API on request.
11.41 Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
11.42 The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).
11.43 Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the
类别（如有机的、无机的、溶剂）。杂质概况一般与原料药的生产工艺和起源有关。从植物或动物组织中得到的原料药通常不一定要有杂质概况。ICH指南Q6B讲述了对生物技术的考虑。
11.22 每隔一端时间应当将杂质概况与药政申报中的杂质概况，或与以往的数据比较，以查明原材料、设备操作参数和生产工艺的修改所造成的原料药的变化。
11.23 在规定微生物质量时，应当对每一批中间体和原料药作适当的微生物测试。
11.3 分析方法的验证 见第12章
11.4 分析报告单
11.40 有要求时应当为每一批中间体或原料药出具可信的分析报告单。
11.41 分析报告单应当提供中间体或原料药的名称，必要时包括其等级、批号和放行日期。有有效期的中间体或原料药，应当在标签和分析报告单上提供失效期。有复验期的中间体或原料药，应当在标签和/或分析报告单上提供复验期。
11.42 报告单应当列明按药典或客户要求所做的各项测试，包括可接受的限度，和得到的数值结果（如果测试结果是数值）。
11.43 报告单应当由指定的质量部门人员写明日期并签名，而且应当注明原生产商的名称、地址和电话。如果测试是由重新包装者或重新加工者做的，则分析报告单应当注明重新包装者/重
39
Q7a
analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.
11.44 If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address, and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.
11.5 Stability Monitoring of APIs
11.50 A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.
11.51 The test procedures used in stability testing should be validated and be stability indicating.
11.52 Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.
11.53 Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.
11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.
11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs
新加工者的名称、地址和电话，并附注原生产商的名称。
11.44 如果由重新包装者/重新加工者、代理人，中间人或由其代表出具新的报告单，这些报告单上应当注明做分析的实验室的名称、地址和电话。还应当附注原生产商的名称和地址，并附上原始检验报告单复印件。
11.5 原料药的稳定性监测
11.50 应当建立一个文件化的、持续监测的规程，以监测原料药的稳定性特征，而其结果应当用于确定适当的贮存条件和复验日期或有效期。
11.51 用于稳定性测试的测试规程应当经过验证，并能显示稳定性。
11.52 稳定性样品应当存放在与销售容器相仿的容器中。例如，如果原料药是装在纤维桶内的袋子里销售的，稳定性样品可以包装在同样材料的袋中，放入相似或相同与销售容器的材料的材料较小的桶中。
11.53 通常头三个销售批号应当放入稳定性监测计划，以证实复验期或有效期。然而，如果以前的研究数据表明原料药至少在两年内可望保持稳定，则所用的批号可少于三批。
11.54 以后每年至少应当加一批生产的原料药到稳定性监测计划（除非当年不生产），并且至少每年测试，以证实其稳定性。
11.55 对于储存期较短的原料药，应当更频繁的测试。例如，储存期不超过一年的生物工程/生物制品或其它原料药，应当有稳定性样品，头三
40