美国FDA原料药生产质量管理规范（ 中英文） 

equipment such as micronizers and microfluidizers).

12.73 取样应当包括擦拭法、冲洗法或可供选择的方法（如直接萃取），如果合适的话，同时检测不溶性和可溶性的残留物。所用的取样方法应当能定量地检测出清洗之后留在设备表面的残留物质。当与产品接触的表面，由于设备的设计和/或工艺限制（如，软管的内表面，运输管道，反应釜的开口很小或装卸有毒物质，以及一些小的复杂的设备，如微粉粉碎机，流化床式微粉机），很难触及时，擦拭取样就无法实施。

12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.

12.74 应当采用验证过的、具有检测残留物或污染物的灵敏度的分析方法。每一个分析方法的检测限度必须足够灵敏，来检测到残留物或污染物的规定的可接受水平。应当规定方法的可达到的回收率。残留物的限度切实可行的，可检测的，并由最有害的残留物来确定。可以根据原料药或其最有害的组分的已知最小药理、毒理或生理活性浓度来制定限度。

12.75 Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).

12.75 对于需要降低原料药中的总微生物数或内毒素的工艺，或担心此类污染的其它工艺（如，用于生产无菌产品的非无菌原料药），设备清洗/消毒的研究应当对付微生物和内毒素污染。

12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

12.76 验证后，清洗程序应当在适当的时间间隔进行监测，以确保这些程序用在日常生产中是有效的。设备的清洁程度可以根据可行性通过测试或目测来监测。目测能检测到用取样和/或分析方法测不到的集中在小面积上的严重的污染。

12.8 Validation of Analytical Methods 12.8 分析方法的验证

12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. 12.80 分析方法应当进行验证，除非采用的方法列在相关的药典或其它公认的参照标准中。然而，所有测试方法的适应性应当在实际使用条件下加以证实，并归档备查。

12.81 Methods should be validated to include consideration of characteristics included within the

ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

12.81 方法验证应当包括ICH分析方法验证指南中的特征的考虑。方法验证进行的程度应当反映分析的目的和原料药生产工艺的步骤。

12.82 Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.

12.82 在开始分析方法验证前，应当考虑对分析设备的适当的确认。

12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method. 12.83 已验证过的分析方法的任何修改都应当保存完整的记录。这类记录应当包括修改的理由和合适的数据，以证实该修改所产生的结果和规定的方法同样准确、可靠。

13. CHANGE CONTROL 13.变更的控制

13.10 A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API. 13.10 应当建立正式的变更控制系统，以评估可能影响中间体或原料药生产和控制的所有变更。

13.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.

13.11 对原料、质量标准、分析方法、设施、支持系统、设备（包括计算机硬件）、工艺步骤、标签和包装材料、计算机软件的变更进行认证、提供文件、适当的审核和批准，应当提供书面程序。

13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s). 13.12 与GMP有关的任何变更提案都应当由相应的部门进行拟定、审核和批准，并由质量部门审核和批准。

13.13 The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process. 13.13 应当评估所提议的变更对中间体或原料药质量的潜在影响。一种分类方法可能有助于确定为了说明对一个已验证的工艺作变更所需的测试、验证和文件工作的程度。变更可以根据变更的性质和程度及其可能对工艺产生的影响来分类（如，次要的或主要的）。

应当用科学的判断来决定，为证明对一个已验证工艺的变更可行，什么样的附加测试和验证研究是适当的。

13.14 When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.

13.14 实施已核准的变更时，应当采取措施确保所有变更影响的文件都已修订。

13.15 After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

13.15 变更实施后，应当对变更之后生产或测试的的头几个批次进行评估。

13.16 The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

13.16 关键的变更对规定的复验期和有效期的影响可能性应当进行评估。如有必要，可以将用修改了的工艺生产的中间体或原料药的样品放入一个加速稳定性计划，并/或稳定性监测计划。

13.17 Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.

13.17 应当将可能影响原料药质量的对已确定的生产及工艺控制步骤所作的变更通知目前制剂药制造商。

14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用 14.1 Rejection 14.1 拒收

14.10 Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

14.10 不合格中间体和原料药应当做有标志，并隔离。这些中间体和原料药可以按下述方法进行返工或重新加工。应当记录不合格物料的最终处置情况。

14.2 Reprocessing 14.2 返工

14.20 Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

14.20 将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或其它合适的化学或物理处理步骤（如，蒸馏、过滤、层析、磨粉），这种做法通常是可以接受的。然而，如果这种返工用于大多数的批号，那么该返工就应当作为标准生产工艺的一部分。

14.21 Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

14.21 在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，是正常工艺的一部分，不属于返工。

14.22 Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely affected due to the potential formation of by-products and over-reacted materials. 14.22 将未反应的物料返回某一工序，并重复化学反应，这是进行返工，除非它已被列入规定的工艺中。在进行这种返工前，要仔细评估，以确保不会由于可能形成的副产物和过度反应物而对中间体或原料药的质量产生不良影响。

14.3 Reworking 14.3 重新加工

14.30 Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed. 14.30 在决定对不符合规定的标准或规格的批号进行重新加工前，应当对不符合的原因进行调查。

14.31 Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for reworked procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable. 14.31 重新加工的批号应当接受适当的评估、测试，如有理由还要做稳定性测试，并成文备查，以表明重新加工后的产品与原工艺生产的产品质量相等。同步验证常常是重新加工程序的合适的验证方法。允许用一方案来规定重新加工程序、如何进行和预期结果。如果只有一批产品重新加工，利用写一份报告，一旦认为该批可接受，即可放行。

14.32 Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

14.32 应当有程序对每一重新加工过的批号与用规定的工艺生产的批号进行杂质概况的比较。如果常规分析方法不足以描绘重新加工批号的特征，应当采用另外的方法。

14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收

14.40 Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

14.40 只要有核准的回收方法，并且回收的物料符合其使用标准，反应物、中间体或原料药的回收（例如，从母液或滤液中）是可以接受的。

14.41 Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials. 14.41 溶剂可以回收，并在同一工序或不同工序重新使用，只要回收过程得到了控制和监测，确保在重新使用或与其它核准的物料混合前，这种溶剂符合一定的标准。

14.42 Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

14.42 新鲜的和回收溶剂和试剂可以混合，如果有足够的测试表明它们适用于所参与的生产工序。

14.43 The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

14.43 回收溶剂、母液和其它回收的物料的使用应当有足够的文件作证。

14.5 Returns 14.5 退货

14.50 Returned intermediates or APIs should be identified as such and quarantined. 14.50 退回的原料药和中间体应当作有标志，并隔离。

14.51 If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate. 14.51 如果在中间体或原料药退货之前或退货期间的储存或运输条件，或者其包装容器的状况可能对其质量产生影响，退回的中间体或原料药应当根据情况进行返工、重新加工或销毁。

14.52 Records of returned intermediates or APIs should be maintained. For each return, documentation should be include:

14.52 退回的中间体或原料药应当存有记录。每次退货的记录内容应当包括：

15. COMPLAINTS AND RECALLS 15.投诉与召回

15.10 All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

15.10 所有与质量有关的投诉，无论以口头或书面方式收到，都应当根据书面程序进行记录和调查。

15.12 Records of complaints should be retained to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.15.12 投诉记录应当保存，旨在评估其变化趋势、涉及产品的发生频率及其严重性，以便采取额外的，有时是即时的纠正措施。

15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.

15.13 应当有书面程序规定在何种情况下应当考虑召回中间体或原料药。