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表 1: 本指南在原料药生产中的应用
生产类型 化学品的生产 本指南在用于各类生产的工艺步骤（灰色背景）中的应用 原料药起始物料的生产 动物源原料药 器官、分泌物或组织的收集 从植物源提取的原料药 草药提取物用作原料药 由粉碎的或粉末状草药组成的原料药 生物技术：发酵/细胞培养 “经典” 发酵生产原料药 植物的收集和/或培养和收获 主细胞库和工作细胞库的建立 细胞库的建立 细胞库的维护 细胞引入发酵 分离和纯化 物理加工和包装 工作细胞库的维护 细胞培养和/或发酵 分离和纯化 物理加工和包装 切割/粉碎 物理加工和包装 植物的收集 切割和初步提取 植物的收集 原料药起始物料引入工艺过程 切割、混合和/或初步加工 切割和初步提取 原料药起始物料引入工艺过程 原料药起始物料引入工艺过程 进一步提取 物理加工和包装 分离和纯化 物理加工和包装 分离和纯化 物理加工和包装 中间体的生产 分离和纯化 物理加工和包装
GMP的要求增加
2. QUALITY MANAGEMENT 2．质量管理 2.1 Principles 2.1总则
2.10 Quality should be the responsibilities of all 2.10 参与原料药生产的每一个人都应当对质persons involved in manufacturing. 量负责。
2.11 Each manufacturer should establish, 2.11 每一个生产商都应当建立并执行一套有document, and implement an effective system 管理人员和有关员工积极参与的有效的质量for managing quality that involves the active 管理体系，并使其文件化。 participation of management and appropriate manufacturing personnel.
2.12 The system for managing quality should 2.12 质量管理体系应当包括组织机构、规程、encompass the organizational structure, 工艺和资源，以及确保原料药会符合其预期procedures, process and resources, as well as 的质量与纯度要求所必需的活动。所有涉及activities to ensure confidence that the API will 质量管理的活动都应当明确规定，并使其文meet its intended specifications for quality and 件化。 purity. All quality-related activities should be defined and documented.
2.13 There should be a quality unit(s) that is 2.13 应当设立一个独立于生产部门的质量部independent of production and that fulfills both 门，同时履行质量保证(QA)和质量控制 (QC)quality assurance (QA) and quality control 的职责。依照组织机构的大小，可以是分开(QC) responsibilities. The quality unit can be in 的QA和QC部门，或者只是一个人或小组。
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the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
2.14 The persons authorized to release intermediates and APIs should be specified.
2.15 All quality-related activities should be recorded at the time they are performed.
2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.
2.17 No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in Section 10 or the use of raw materials or intermediates pending completion of evaluation).
2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).
2.2 Responsibilities of the Quality Unit(s) 2.20 The quality unit(s) should be involved in all quality-related matters.
2.21 The quality unit(s) should review and approve all appropriate quality-related documents.
2.22 The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not
2.14 应当指定授权发放中间体和原料药的人员。
2.15 所有有关质量的活动应当在其执行时就记录。
2.16 任何偏离既定规程的情况都应当有文字记录并加以解释。对于关键性偏差应当进行调查，并记录调查经过及其结果。
2.17 在质量部门对物料完成满意的评价之前，任何物料都不应当发放或使用，除非有合适的系统允许此类使用（如10.20条款所述的待检情况下的使用，或是原料或中间体在等待评价结束时的使用）。
2.18 应当有规程能确保公司的责任管理部门能及时得到有关药政检查、严重的GMP缺陷、产品缺陷及其相关活动（如质量投诉，召回，药政活动等）的通知。
2.2质量部门的责任
2.20 质量部门应当参与所有与质量有关的事物。
2.21 所有与质量有关的文件应当由质量部门审核批准。
2.22 独立的质量部门的主要职责不应当委派给他人。这些责任应当以文字形式加以说明，而且应当包括，但不限于：
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necessarily be limited to:
1. Releasing or rejecting all APIs. Releasing
or rejecting intermediates for use outside the control of the manufacturing company 2. Establishing a system to release or reject
raw materials, intermediates, packaging, and labeling materials
3. Reviewing completed batch production and
laboratory control records of critical process steps before release of the API for distribution
4. Making sure that critical deviations are
investigated and resolved
5. Approving all specifications and master
production instructions
6. Approving all procedures affecting the
quality of intermediates or APIs
7. Making sure that internal audits
(self-inspections) are performed
8. Approving intermediate and API contract
manufacturers
9. Approving changes that potentially affect
intermediate or API quality
10. Reviewing and approving validation
protocols and reports
11. Making sure that quality-related complaints
are investigated and resolved
12. Making sure that effective systems are used
for maintaining and calibrating critical equipment
13. Making sure that materials are
appropriately tested and the results are reported
14. Making sure that there is stability data to
support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate
15. Performing product quality reviews (as
defined in Section 2.5)
2.3 Responsibility for Production Activities The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:
1. 所有原料药的放行与否。用于生产商控制
范围以外的中间体的放行与否；
2. 建立一个放行与拒收原材料、中间体、包
装材料和标签的系统；
3. 在供销售的原料药放行前，审核已完成的
关键步骤的批生产记录和实验室检验记录；
4. 确保已对重大偏差进行了调查并已解决；
5. 批准所有的规格标准和主生产指令；
6. 批准所有可能影响原料药和中间体质量
的规程；
7. 确保进行内部审计（自检）；
8. 批准中间体或原料药的委托生产商；
9. 批准可能影响到中间体或原料药质量的
变更；
10. 审核并批准验证方案和报告；
11. 确保调查并解决质量问题的投诉；
12. 确保用有效的体系来维护和校验关键设
备；
13. 确保物料都经过了适当的检验并报告结
果；
14. 确保有稳定性数据支持中间体或原料药
的复验期或有效期和储存条件；
15. 开展产品质量审核（详见2.5节）。
2.3生产作业的职责
生产作业的职责应当以文字形式加以说明，并应当包括，但不限于以下内容：
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1. Preparing, reviewing, approving, and
distributing the instructions for the production of intermediates or APIs according to written procedures
2. Producing APIs and, when appropriate,
intermediates according to pre-approved instructions
3. Reviewing all production batch records and
ensuring that these are completed and signed
4. Making sure that all production deviations
are reported and evaluated and that critical deviations are investigated and the conclusions are recorded
5. Making sure that production facilities are
clean and, when appropriate, disinfected 6. Making sure that the necessary calibrations
are performed and records kept
7. Making sure that the premises and
equipment are maintained and records kept 8. Making sure that validation protocols and
reports are reviewed and approved
9. Evaluating proposed changes in product,
process or equipment
10. Making sure that new and, when
appropriate, modified facilities and equipment are qualified
2.4 Internal Audits (Self Inspection)
2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
2.41 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.
2.5 Product Quality Review
2.50 Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should
1. 按书面程序起草、审核、批准和分发中间
体或原料药的生产指令；
2. 按照已批准的指令生产原料药或者中间
体；
3. 审核所有的批生产记录确保其完整并有
签名；
4. 确保所有的生产偏差都已报告、评价，对
关键的偏差已做了调查，并记录结论；
5. 确保生产设施的清洁，必要时要消毒；
6. 确保进行必要的校验，并有记录；
7. 确保对厂房和设备进行保养，并有记录；
8. 确保验证方案和报告的审核与批准；
9. 对产品、工艺或设备拟作的变更进行评
估；
10. 确保新的或已改进的生产设施和设备经
过了确认。
2.4内部审计（自检）
2.40 为确实符合原料药GMP原则，应当按照批准的计划进行定期的内部审计。
2.41 审计结果及整改措施应当形成文件，并引起公司责任管理人员的重视。获准的整改措施应当及时、有效地完成。
2.5产品质量审核
2.50 原料药的定期质量审核应当以证实工艺的一致性为目的来进行。此种审核通常应当每年进行一次，并记录，内容至少应当包括：
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normally be conducted and documented annually and should include at least:
● A review of critical in-process control
and critical API test results ● A review of all batches that failed to
meet established specification(s) ● A review of all critical deviations or
nonconformances and related investigations ● A review of any changes carried out to
the processes or analytical methods ● A review of results of the stability monitoring program ● A review of all quality-related returns, complaints and recalls ● A review of adequacy of corrective
actions
2.51 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.
3. PERSONNEL
3.1 Personnel Qualifications
3.10 There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.
3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.
3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee’s functions. Records of training
● 关键工艺控制以及原料药关键测试
结果的审核；
● 所有不符合既定质量标准的产品批
号的审核；
● 所有关键的偏差或违规行为及有关
调查的审核；
● 任何工艺或分析方法变动的审核； ● 稳定性监测的审核；
● 所有与质量有关的退货、投诉和召回
的审核；
● 整改措施的适当性的审核。
2.51 应当对质量审核结果进行评估，并做出是否需要整改或做任何再验证的评价。此类整改措施的理由应当文件化。获准的整改措施应当及时、有效地完成。
3. 人员
3.1员工的资质
3.10 应当有足够数量的员工具备从事和监管原料药和中间体生产的教育、培训和/或经历等资格。
3.11 参与原料药和中间体生产的所有人员的职责应当书面规定。
3.12 应当由有资格的人员定期进行培训，内容至少应当包括员工所从事的特定操作和与其职能有关的GMP。培训记录应当保存，并应当定期对培训进行评估。
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