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Annex 2:
Active Substances Used As Starting Materials
《Good
Manufacturing Practice (2010 revision)
》
Annex 2 Technical Reviewed by ISPE
Michael Lee, Zhao Chunhua
Zhao Yunxia, He Guoling, Ji Yiyun
Initial Translation from NNE Pharmaplan
附录2：
Annex 2:
原料药
Active Substances Used As Starting Materials
目录
Table of content
第一章 范围..............................................................................................43
Chapter 1 Scope
.............................................................................................43
第二章 厂房与设施...................................................................................43
Chapter 2 Buildings and
Facilities...................................................................43
第三章 设备..............................................................................................44
Chapter 3 Equipment
......................................................................................44
第四章 物料..............................................................................................46
Chapter 4 Materials
.........................................................................................46
第五章 验证..............................................................................................48
Chapter 5 Validation
........................................................................................48
第六章 文件..............................................................................................52
Chapter 6 Documentation
...............................................................................52
第七章 生产管理.............................................................................................54
Chapter 7 Production Management
................................................................54
第八章 不合格中间产品或原料药的处理.........................................................60
Chapter 8 Rejected Intermediates or
APIs......................................................60
第九章 质量管理.............................................................................................63
Chapter 9 Quality Management
......................................................................63
第十章 采用传统发酵工艺生产原料药的特殊要求...........................................64
Chapter 10 Specific Requirement for APIs Manufactured
43
by Fermentation
..............................................................................................64
第十一章 术语.................................................................................................68
Chapter 11
Glossary........................................................................................68
第一章 范围
Chapter 1 Scope
第一条
本附录适用于非无菌原料药生产及无菌原料药生产中非无菌生产
工序的操作。
Article 1 The annex applies to the manufacture of non-sterile active
substances and the operations of non-sterile process during the sterile
substance production.
第二条
原料药生产的起点及工序应当与注册批准的要求一致。
Article 2: The point at which production of the active substance begins and its
process should be designated in accordance with the registered and authorised
process.
第二章 厂房与设施
Chapter 2 Buildings and Facilities
第三条
非无菌原料药精制、干燥、粉碎、包装等生产操作的暴露环境应
当按照D
级洁净区的要求设置。
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Article 3: The exposed environment where purification, drying, milling, and
packaging of non-sterile active substances are carried out should meet grade D
area described in Annex 1.
第四条
质量标准中有热原或细菌内毒素等检验项目的，厂房的设计应当
特别注意防止微生物污染，根据产品的预定用途、工艺要求采取相应的控制措施。
Article 4: Where pyrogen or endotoxin specification have been established
for the intermediate or API, , The facilities,should be designed with particular
attention to prevent the microbialogical contamination, e.g. relevant
precautions
should be set up according to the intended use of products and process
requirements.
第五条
质量控制实验室通常应当与生产区分开。当生产操作不影响检验
结果的准确性，且检验操作对生产也无不利影响时，中间控制实验室可设在生产
区内。
Article 5: Quality control laboratory areas should normally be separated
from production areas. Laboratory areas used for in-process control can be
located in production areas , provided the manufacturing operations do not
affect
the accuracy of the laboratory measurements, and the laboratory and its
operations do not adversely affect the production process.
第三章 设备
Chapter 3 Equipment
第六条
设备所需的润滑剂、加热或冷却介质等，应当避免与中间产品或
原料药直接接触，以免影响中间产品或原料药的质量。当任何偏离上述要求的情
况发生时，应当进行评估和恰当处理，保证对产品的质量和用途无不良影响。
Article 6: Any substances associated with the operation of equipment, such
as lubricants, heating fluids or coolants, should not contact intermediates or
APIs
so as to alter their quality beyond the official or other established
specifications.
Any deviations from this should be evaluated and handled properly to ensure
that there are no detrimental effects upon the fitness for purpose and quality
of
the products.
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第七条
生产宜使用密闭设备；密闭设备、管道可以安置于室外。使用敞
口设备或打开设备操作时，应当有避免污染的措施。
Article 7: Closed or contained equipment should be used whenever
appropriate. Closed equipment and pipelines can be placed outdoor. Where
open equipment is used, or opened, appropriate precautions should be taken to
avoid the risk of contamination.
第八条
使用同一设备生产多种中间体或原料药品种的，应当说明设备可
以共用的合理性，并有防止交叉污染的措施。
Article 8: Where equipment shared with different intermediates or APIs, the
rational should be provided. Appropriate precautions should be taken to prevent
from the risk of cross-contamination.
第九条
难以清洁的设备或部件应当专用。
Article 9: The equipment or component which is difficult to clean should be
used dedicated.
第十条
设备的清洁应当符合以下要求：
Article 10: Equipment cleaning
（一）同一设备连续生产同一原料药或阶段性生产连续数个批次时，宜间隔适
当的时间对设备进行清洁，防止污染物（如降解产物、微生物）的累积。如有影
响原料药质量的残留物，更换批次时，必须对设备进行彻底的清洁。
1. Where the equipment is assigned to continuous production or campaign
production of successive batches of the same intermediate or API, the
equipment should be cleaned at appropriate intervals to prevent build-up of
contaminants (e.g. degradants or objectionable levels of micro-organisms). The
equipment should be cleaned thoroughly between productions of different
batches to prevent cross-contamination where carry-over with adversely affect
the quality of APIs or intermediates.
（二）非专用设备更换品种生产前，必须对设备（特别是从粗品精制开始的非
专用设备）进行彻底的清洁，防止交叉污染。
2. Non-dedicated equipment (especially the ones for the starting material
purification) should be cleaned between productions of different products to
prevent cross-contamination.
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（三）对残留物的可接受标准、清洁操作规程和清洁剂的选择，应当有明确规
定并说明理由。
3. Acceptance criteria for residues and the choice of cleaning procedures
and cleaning agents should be defined and justified.
第十一条
非无菌原料药精制工艺用水至少应当符合纯化水的质量标准。
Article 11: Process water used in the final purification steps of non-sterile
APIs should, at a minimum, meet the quality standards of purified water.
第四章 物料
Chapter 4 Materials
第十二条
进厂物料应当有正确标识，经取样（或检验合格）后，可与现有
的库存（如储槽中的溶剂或物料）混合，经放行后混合物料方可使用。应当有防
止将物料错放到现有库存中的操作规程。
Article 12: The incoming materials should be labelled correctly. After
sampling (or testing), these material can be mixed with existing stocks (e.g.,
solvents or stocks in silos), then release for production using. Procedures
should
be available to prevent discharging wrong incoming materials into the existing
stock.
第十三条
采用非专用槽车运送的大宗物料，应当采取适当措施避免来自槽
车所致的交叉污染。
Article 13: If bulk deliveries are made in non-dedicated tankers,
precautions should be taken to assure no cross-contamination from the tanker.
第十四条
大的贮存容器及其所附配件、进料管路和出料管路都应当有适当
的标识。
Article 14: Large storage containers, and their attendant manifolds, filling
and discharge lines should be appropriately labeled.
第十五条
应当对每批物料至少做一项鉴别试验。如原料药生产企业有供应
商审计系统时，供应商的检验报告可以用来替代其它项目的测试。
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Article 15: At least one test to verify the identity of each batch of material
should be conducted. A supplier's Certificate of Analysis can be used in place
of
performing other tests, provided that the manufacturer has a system in place to
evaluate suppliers.
第十六条
工艺助剂、有害或有剧毒的原料、其它特殊物料或转移到本企业
另一生产场地的物料可以免检，但必须取得供应商的检验报告，且检验报告显示
这些物料符合规定的质量标准，还应当对其容器、标签和批号进行目检予以确认。
免检应当说明理由并有正式记录。
Article 16: Processing aids, hazardous or highly toxic raw materials, other
special materials, or materials transferred to another production area within
the
company’s
control do not need to be tested if the manufacturer’s
Certificate of
Analysis is obtained, showing that these raw materials conform to established
specifications. Visual examination of containers, labels, and recording of batch
numbers should help in establishing the identity of these materials. The lack of
on-site testing for these materials should be justified and documented.
第十七条
应当对首次采购的最初三批物料全检合格后，方可对后续批次进
行部分项目的检验，但应当定期进行全检，并与供应商的检验报告比较。应当定
期评估供应商检验报告的可靠性、准确性。
Article 17 Full analyses should be conducted on at least the first three
batches before reducing in-house testing. However, a dull analysis should be
performed at appropriate intervals and compared to the Certificates of Analysis
from supplier. The reliability and accuracy of the certificates offered by
supplier
should be evaluated periodically.
第十八条
可在室外存放的物料，应当存放在适当容器中，有清晰的标识，并
在开启和使用前应当进行适当清洁。
Article 18: Certain materials in suitable containers can be stored outdoors,
provided identifying labels remain legible and containers are appropriately
cleaned before opening and use.
第十九条
必要时（如长期存放或贮存在热或潮湿的环境中），应当根据情况
重新评估物料的质量，确定其适用性。
Article 19: Materials should be re-evaluated as appropriate to determine
their suitability for use (e.g., after prolonged storage or exposure to heat or
humidity).
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第五章 验证
Chapter 5 Validation
第二十条
应当在工艺验证前确定产品的关键质量属性、影响产品关键质量
属性的关键工艺参数、常规生产和工艺控制中的关键工艺参数范围，通过验证证
明工艺操作的重现性。
关键质量属性和工艺参数通常在研发阶段或根据历史资料和数据确定。
Article 20: The critical product quality attributes , critical process
parameters that could affect these attributes, the range for each critical
process parameter expected to be used during routine manufacturing and
process control should be defined before process validation. The reproducibility
of the process operations should be ensured by validation activities.
Critical quality attributes and process parameters should normally be identified
during the development stage or from historical data.
第二十一条
验证应当包括对原料药质量（尤其是纯度和杂质等）有重要影
响的关键操作。
Article 21: Validation should cover those operations determined to be
critical to the quality (especially to the purity and impurity)
第二十二条
验证的方式：
Article 22 Approaches to process validation
（一）原料药生产工艺的验证方法一般应为前验证。因原料药不经常生产、批
数不多或生产工艺已有变更等原因，难以从原料药的重复性生产获得现成的数据
时，可进行同步验证。
1. Prospective validation should normally be performed for all API
processes. Concurrent validation can be conducted when API batches are
produced infrequently, only a limited number of API batches have been
produced, or API batches are produced by a modified process, where data
from replicate production runs are unavailable.
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（二）如没有发生因原料、设备、系统、设施或生产工艺改变而对原料药质量
有影响的重大变更时，可例外进行回顾性验证。该验证方法适用于下列情况：
2. An exception can be made for retrospective validation for processes that
have been used without significant changes to API quality due to changes in raw
materials, equipment, systems, facilities, or the production process. This
validation approach may be used where:
1.关键质量属性和关键工艺参数均已确定；
1) Critical quality attributes and critical process parameters have been
identified;
2.已设定合适的中间控制项目和合格标准；
2) Appropriate in-process acceptance criteria and controls have been
established;
3.除操作人员失误或设备故障外，从未出现较大的工艺或产品不合格的问题；
3) There have not been significant process/product failures attributable to
causes other than operator error or equipment failures unrelated to equipment
suitability; and
4.已明确原料药的杂质情况。
4) Impurity profiles have been established for the existing API.
（三）回顾性验证的批次应当是验证阶段中有代表性的生产批次，包括不合格
批次。应当有足够多的批次数，以证明工艺的稳定。必要时，可用留样检验获得
的数据作为回顾性验证的补充。
3. Batches selected for retrospective validation should be representative of
all batches made during the review period, including any batches that failed to
meet specifications, and should be sufficient in number to demonstrate process
consistency. Where necessary, the testing data of retained samples can be used
as supplements of retrospective validation.
第二十三条
验证计划：
Article 23: Process Validation program
（一）应当根据生产工艺的复杂性和工艺变更的类别决定工艺验证的运行次
数。前验证和同步验证通常采用连续的三个合格批次，但在某些情况下，需要更
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多的批次才能保证工艺的一致性（如复杂的原料药生产工艺，或周期很长的原料
药生产工艺）。
1. The number of process runs for validation should depend on the
complexity of the process or the magnitude of the process change being
considered. For prospective and concurrent validation, three consecutive
successful production batches should be used as a guide, but there may be
situations where additional process runs are warranted to prove consistency of
the process (e.g., complex API processes or API processes with prolonged
completion times).
（二）工艺验证期间，应当对关键工艺参数进行监控。与质量无关的参数（如
与节能或设备使用相关控制的参数），无需列入工艺验证中。
2. Critical process parameters should be controlled and monitored during
process validation studies. Process parameters unrelated to quality, such as
control variables to minimize energy consumption or equipment use, need not to
be included in the process validation.
（三）工艺验证应当证明每种原料药中的杂质都在规定的限度内，并与工艺研
发阶段确定的杂质限度或者关键的临床和毒理研究批次的杂质数据相当。
3. Process validation should confirm that the impurity profile for each API
is within the limits specified. The impurity profile should be comparable to the
data of the profile determined during process development or of batches used
for pivotal clinical and toxicological studies.
第二十四条
清洁验证：
Article 24: Cleaning validation
（一）清洁操作规程通常应当进行验证。清洁验证一般应当针对污染物、所用
物料对原料药质量有最大风险的状况及工艺步骤。
1. Cleaning procedures should normally be validated. In general, cleaning
validation should be directed to situations or process steps where contamination
or carryover of materials poses the greatest risk to API quality.
（二）清洁操作规程的验证应当反映设备实际的使用情况。如果多个原料药或
中间产品共用同一设备生产，且采用同一操作规程进行清洁的，则可选择有代表
性的中间产品或原料药作为清洁验证的参照物。应当根据溶解度、难以清洁的程
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度以及残留物的限度来选择清洁参照物，而残留物的限度则需根据活性、毒性和
稳定性确定。
2. Validation of cleaning procedures should reflect actual equipment
usage patterns. If various APIs or intermediates are manufactured in the same
equipment and the equipment is cleaned by the same process, a representative
intermediate or API can be selected for cleaning validation. This selection
should
be based on the solubility and difficulty of cleaning and the calculation of
residue
limits based on activity, toxicity, and stability.
（三）清洁验证方案应当详细描述需清洁的对象、清洁操作规程、选用的清洁
剂、可接受限度、需监控的参数以及检验方法。该方案还应当说明样品类型（化
学或微生物）、取样位置、取样方法和样品标识。专用生产设备且产品质量稳定的，
可采用目检法确定可接受限度。
3. The cleaning validation protocol should describe the equipement to be
cleaned, cleaning procedures, cleaning agents, acceptable criteria, parameters
to be monitored and controlled, and analytical methods. The protocol should
also indicate the type of samples (e.g. chemicals or micro organisms), location
of
sampling, methods of sampling, label of samples to be obtained. Visual
inspection can be adapted as the testing method to dedicated equipment and
with consistent product quality.
（四）取样方法包括擦拭法、淋冼法或其它方法（如直接萃取法），以对不溶
性和可溶性残留物进行检验。
4. Sampling should include swabbing, rinsing, or alternative methods
(e.g., direct extraction), as appropriate, to detect both insoluble and soluble
residues.
（五）应当采用经验证的灵敏度高的分析方法检测残留物或污染物。每种分析
方法的检测限必须足够灵敏，能检测残留物或污染物的限度标准。应当确定分析
方法可达到的回收率。残留物的限度标准应当切实可行，并根据最有害的残留物
来确定，可根据原料药的药理、毒理或生理活性来确定，也可根据原料药生产中
最有害的组分来确定。
5. Validated and high sensitive analytical methods should be used to
detect residues or contaminants. The detection limit for each analytical method
should be sufficiently sensitive to detect the established acceptable level of
the
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residue or contaminant. The method’s
attainable recovery level should be
established. Residue limits should be practical 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.
（六）对需控制热原或细菌内毒素污染水平的生产工艺，应当在设备清洁验证
文件中有详细阐述。
6. Equipment cleaning validation protocol should address pyrogen and
endotoxin contamination for those processes where there is a need to control
endotoxins or pyrogens.
（七）清洁操作规程经验证后应当按验证中设定的检验方法定期进行监测，保
证日常生产中操作规程的有效性。
7. Cleaning procedures should be monitored by analytical methods
established at appropriate intervals after validation to ensure that these
procedures are effective when used during a routine production.
第六章 文件
Chapter 6 Documentation
第二十五条
企业应当根据生产工艺要求、对产品质量的影响程度、物料的
特性以及对供应商的质量评估情况，确定合理的物料质量标准。
Article 25: Incoming material quality specification should be established
according to process requirements, the impact on the product quality, material
nature, as well as the suppliers quality assessment .
第二十六条
中间产品或原料药生产中使用的某些材料，如工艺助剂、垫圈
或其它材料，可能对质量有重要影响时，也应当制定相应材料的质量标准。
Article 26: Quality specification should be established for certain materials,
such as process aids, gaskets, and other materials with critical impact on
quality
during the production of intermediates or APIs.
第二十七条
原料药的生产工艺规程应当包括：
Article 27: Master production instructions should include:
（一）所生产的中间产品或原料药名称。
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1. The name of the intermediate or API being manufactured;
（二）标有名称和代码的原料和中间产品的完整清单。
2. A complete list of raw materials and intermediates designated by
names or codes;
（三）准确陈述每种原料或中间产品的投料量或投料比，包括计量单位。如果
投料量不固定，应当注明每种批量或产率的计算方法。如有正当理由，可制定投
料量合理变动的范围。
3. An accurate statement of the quantity or ratio of each raw material or
intermediate to be used, including the unit of measure. Where the quantity is
not
fixed, the calculation for each batch size or rate of production should be
included.
Variations to quantities should be included where they are justified;
（四）生产地点、主要设备（型号及材质等）。
4. The production location and major production equipment to be used
(model type and materials etc.);
（五）生产操作的详细说明，包括：
5. Detailed production instructions, including:
1.操作顺序；
1) The sequences to be followed;
2.所用工艺参数的范围；
2) Ranges of process parameters to be used;
3.取样方法说明，所用原料、中间产品及成品的质量标准；
3) Sampling instructions and quality specification of raw materials,
intermediates and APIs;
4.完成单个步骤或整个工艺过程的时限（如适用）；
4) Time limits for completion of individual processing steps and/or the total
process, where appropriate;
5.按生产阶段或时限计算的预期收率范围；
5) Expected yield ranges at appropriate phases of processing or according
to time;
6.必要时，需遵循的特殊预防措施、注意事项或有关参照内容；
6) Where appropriate, special notations and precautions to be followed, or
cross references to these; and
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7.可保证中间产品或原料药适用性的贮存要求，包括标签、包装材料和特殊贮
存条件以及期限。
7) The instructions for storage of the intermediate or API to assure its
suitability for use, including the labeling and packaging materials and special
storage conditions with time limits, where appropriate.
第七章 生产管理
Chapter 7 Production Management
第二十八条
生产操作：
Article 28: Production operations
（一）原料应当在适宜的条件下称量，以免影响其适用性。称量的装置应当
具有与使用目的相适应的精度。
Raw materials should be weighed or measured under appropriate
conditions that do not affect their suitability for use. Weighing and measuring
devices should be of suitable accuracy for the intended use.
（二）如将物料分装后用于生产的，应当使用适当的分装容器。分装容器应
当有标识并标明以下内容：
If a material is subdivided for later use in production operations, the
receiving container should be suitable and should be so identified with the
following information:
1.物料的名称或代码；
1) Material name and/or item code;
2.接收批号或流水号；
2) Receiving lot number or serial number;
3.分装容器中物料的重量或数量；
3) Weight or measure of material in the sub-container; and
4.必要时，标明复验或重新评估日期。
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4) Re-evaluation or retest date if appropriate.
（三）关键的称量或分装操作应当有复核或有类似的控制手段。使用前，生产
人员应当核实所用物料正确无误。
3. Critical weighing, measuring, or subdividing operations should be
reviewed or subjected to an equivalent control. Prior to use, production
personnel should verify that the materials is for intended used t.
（四）应当将生产过程中指定步骤的实际收率与预期收率比较。预期收率的
范围应当根据以前的实验室、中试或生产的数据来确定。应当对关键工艺步骤收
率的偏差进行调查，确定偏差对相关批次产品质量的影响或潜在影响。
4. Actual yields should be compared with expected yields at designated
steps in the production process. Expected yields with appropriate ranges should
be established based on previous laboratory, pilot scale, or manufacturing data.
Deviations in yield associated with critical process steps should be
investigated
to determine their impact or potential impact on the resulting quality of
affected
batches.
（五）应当遵循工艺规程中有关时限控制的规定。发生偏差时，应当作记录
并进行评价。反应终点或加工步骤的完成是根据中间控制的取样和检验来确定的，
则不适用时限控制。
5. If time limits are specified in the master production instruction, these
time limits should be met strictly. Deviations should be documented and
evaluated. Time limits may be inappropriate to a target value, where completion
of reactions or processing steps are determined by in-process sampling and
testing.
（六）需进一步加工的中间产品应当在适宜的条件下存放，确保其适用性。
6. Intermediates held for further processing should be stored under
appropriate conditions to ensure their suitability for use.
第二十九条
生产的中间控制和取样：
Article 29: In-process controls and sampling
（一）应当综合考虑所生产原料药的特性、反应类型、工艺步骤对产品质量
影响的大小等因素来确定控制标准、检验类型和范围。前期生产的中间控制严格
程度可较低，越接近最终工序（如分离和纯化）中间控制越严格。
1. The acceptance criteria, type and extent of testing can depend on the
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nature of the intermediate or API being manufactured, the reaction or process
step being conducted, and the degree to which the process introduces variability
in the product’s
quality. Less stringent in-process controls may be appropriate in
early processing steps, whereas tighter controls may be appropriate for later
processing steps (e.g., isolation and purification steps).
（二）有资质的生产部门人员可进行中间控制，并可在质量管理部门事先批
准的范围内对生产操作进行必要的调整。在调整过程中发生的中间控制检验结果
超标通常不需要进行调查。
2. In-process controls can be performed by qualified personnel in
production department and the process adjusted without prior quality unit if the
adjustments are made within pre-established limits approved by the quality
unit(s). Out-of-specification (OOS) investigations are not normally needed for
in-process tests that are performed during the adjusting process.
（三）应当制定操作规程，详细规定中间产品和原料药的取样方法。
3. Written procedures should describe the sampling methods for
in-process materials, intermediates, and APIs.
（四）应当按照操作规程进行取样，取样后样品密封完好，防止所取的中间
产品和原料药样品被污染。
4. In-process sampling should be conducted according to the written
procedures, and samples should be sealed properly to prevent contamination of
the sampled material and other intermediates or APIs.
第三十条
病毒的去除或灭活：
Article 30 Viral removal/inactivation steps
（一）应当按照经验证的操作规程进行病毒去除和灭活。
1. Viral removal and viral inactivation steps should be performed
according to validated procedure.
（二）应当采取必要的措施，防止病毒去除和灭活操作后可能的病毒污染。
敞口操作区应当与其它操作区分开，并设独立的空调净化系统。
2. Appropriate precautions should be taken to prevent potential viral
contamination from pre-viral to post-viral removal/inactivation steps. Open
processing should be performed in areas that are separate from other
processing activities and have separate air handling units.
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（三）同一设备通常不得用于不同产品或同一产品不同阶段的纯化操作。如
果使用同一设备，应当采取适当的清洁和消毒措施，防止病毒通过设备或环境由
前次纯化操作带入后续纯化操作。
3. The same equipment is not normally used for different purification
steps, i.e. different products or different phases of the same product. If the
same
equipment is to be used, the equipment should be appropriately cleaned and
sanitized before reuse. Appropriate precautions should be taken to prevent
potential virus carry-over (e.g. through equipment or environment) from previous
steps.
第三十一条
原料药或中间产品的混合：
Article 31 Blending batches of intermediates or APIs
（一）本条中的混合指将符合同一质量标准的原料药或中间产品合并，以得
到均一产品的工艺过程。将来自同一批次的各部分产品（如同一结晶批号的中间
产品分数次离心）在生产中进行合并，或将几个批次的中间产品合并在一起作进
一步加工，可作为生产工艺的组成部分，不视为混合。
1. For the purpose of this article, blending is defined as the process of
combining APIs within the same specification to produce a homogeneous API.
In-process mixing of fractions from single batches (e.g., collecting several
centrifuge loads from a single crystallisation batch) or combining fractions
from
several batches for further processing is considered to be part of the
production
process and is not considered to be blending.
（二）不得将不合格批次与其它合格批次混合。
2. Out-Of-Specification batches should not be blended with other
batches.
（三）拟混合的每批产品均应当按照规定的工艺生产、单独检验，并符合相
应质量标准。
3. Each batch incorporated into the blend should have been
manufactured using an established process and should have been individually
tested and found to meet appropriate specifications prior to blending.
（四）混合操作可包括：
4. Acceptable Blending operations include but not limited to:
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1.将数个小批次混合以增加批量；
1) Blending of small batches to increase batch size
2.将同一原料药的多批零头产品混合成为一个批次。
2) Blending of tailings from batches of the same API to form a single
batch.
（五）混合过程应当加以控制并有完整记录，混合后的批次应当进行检验，
确认其符合质量标准。
5. Blending processes should be adequately controlled and documented
and the blended batch should be tested for conformance to established
specifications where appropriate.
（六）混合的批记录应当能够追溯到参与混合的每个单独批次。
6. The batch record of the blending process should allow traceability
back to the individual batches that make up the blend.
（七）物理性质至关重要的原料药（如用于口服固体制剂或混悬剂的原料药），
其混合工艺应当进行验证，验证包括证明混合批次的质量均一性及对关键特性（如
粒径分布、松密度和堆密度）的检测。
7. Where physical attributes of the API are critical (e.g., APIs intended
for use in solid oral dosage forms or suspensions), validation should include
testing which can show homogeneity of the combined batch, and testing of
critical attributes (e.g., particle size distribution, bulk density, and tap
density)
that may be affected by the blending process.
（八）混合可能对产品的稳定性产生不利影响的，应当对最终混合的批次进
行稳定性考察。
8. If the blending could adversely affect stability, stability testing of the
final blended batches should be performed.
（九）混合批次的有效期应当根据参与混合的最早批次产品的生产日期确定。
9. The expiry or retest date of the blended batch should be based on the
manufacturing date of the oldest tailings or batch in the blend.
第三十二条
生产批次的划分原则：
Article 32: Principles for distinguishing batches
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（一）连续生产的原料药，在一定时间间隔内生产的在规定限度内的均质产
品为一批。
In case of continuous production , the homogenous product which is
produced in a fixed time intervalshould be considered as a single batch.
（二）间歇生产的原料药，可由一定数量的产品经最后混合所得的在规定限
度内的均质产品为一批。
For batch production, a specific quantity of homogenous product which
is blended by a certain number of products should be considered as a single
batch.
第三十三条
污染的控制：
Article 33: Contamination control
（一）同一中间产品或原料药的残留物带入后续数个批次中的，应当严格控
制。带入的残留物不得引入降解物或微生物污染，也不得对原料药的杂质分布产
生不利影响。
Adequate controls should be implemented where residual materials are
carried over into successive batches of the same intermediate or API. Such
carryover should not result in the carryover of degradants or microbial
contamination that may adversely alter the established API impurity profile.
（二）生产操作应当能够防止中间产品或原料药被其它物料污染。
Production operations should be conducted in a manner that prevent
contamination of intermediates or APIs from other materials.
（三）原料药精制后的操作，应当特别注意防止污染。
Precautions to avoid contamination should be taken when APIs are
handled after purification.
第三十四条
原料药或中间产品的包装：
Article 34: Packaging of APIs and intermediates
（一）容器应当能够保护中间产品和原料药，使其在运输和规定的贮存条件
下不变质、不受污染。容器不得因与产品发生反应、释放物质或吸附作用而影响
中间产品或原料药的质量。
1. Containers should provide an adequate protection against
deterioration or contamination of the intermediate or API that may occur during
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transportation and recommended storage. These containers should not be
reactive, additive, or absorptive so as to alter the quality of the intermediate
or
API beyond the specified limits.
（二）应当对容器进行清洁，如中间产品或原料药的性质有要求时，还应当
进行消毒，确保其适用性。
2. Containers should be clean and, where indicated by the nature of the
intermediate or API, sanitized to ensure that they are suitable for their
intended
use.
（三）应当按照操作规程对可以重复使用的容器进行清洁，并去除或涂毁容
器上原有的标签。
3. If containers are re-used, they should be cleaned in accordance with
operational procedures and all previous labels should be removed or defaced.
（四）应当对需外运的中间产品或原料药的容器采取适当的封装措施，便于
发现封装状态的变化。
4. Intermediate or API containers that are transported outside of the
manufacturer's control should be properly sealed in a manner such that, the
recipient will be alerted when the seals alter.
第八章 不合格中间产品或原料药的处理
Chapter 8 Rejection
第三十五条
不合格的中间产品和原料药可按第三十六条、第三十七条的要
求进行返工或重新加工。不合格物料的最终处理情况应当有记录。
Article 35: Intermediates and APIs failed to meet specifications can be
reprocessed or reworked as described in Articles 36 and 37. The final
disposition
of rejected materials should be recorded.
第三十六条
返工：
Article 36: Reprocessing
（一）不符合质量标准的中间产品或原料药可重复既定生产工艺中的步骤，
进行重结晶等其它物理、化学处理，如蒸馏、过滤、层析、粉碎方法。
1. Introducing an intermediate or API, including one that does not conform
to standards or specifications, back into the process and reprocessing by
repeating a crystallisation step or other appropriate chemical or physical
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manipulation steps, e.g., distillation, filtration, chromatography, milling,
that are
part of the established manufacturing process is generally considered
acceptable.
（二）多数批次都要进行的返工，应当作为一个工艺步骤列入常规的生产工
艺中。
2. If such reprocessing is used for a majority of batches, such
reprocessing should be included as part of the standard manufacturing process.
（三）除已列入常规生产工艺的返工外，应当对将未反应的物料返回至某一
工艺步骤并重复进行化学反应的返工进行评估，确保中间产品或原料药的质量未
受到生成副产物和过度反应物的不利影响。
3. 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
impacted due to the potential formation of by-products and over-reacted
materials.
（四）经中间控制检测表明某一工艺步骤尚未完成，仍可按正常工艺继续操
作，不属于返工。
4. If continuation of a process step after an in-process control test has
shown that the step is incomplete, it still can be processed following the
normal
process. This is not considered to be reprocessing.
第三十七条
重新加工：
Article 37: Reworking
（一）应当对重新加工的批次进行评估、检验及必要的稳定性考察，并有完
整的文件和记录，证明重新加工后的产品与原工艺生产的产品质量相同。可采用
同步验证的方式确定重新加工的操作规程和预期结果。
1. 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 can be used to define the rework procedure, how
it will be carried out, and the expected results.
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（二）应当按照经验证的操作规程进行重新加工，将重新加工的每个批次的
杂质分布与正常工艺生产的批次进行比较。常规检验方法不足以说明重新加工批
次特性的，还应当采用其他的方法。
2. Reworking should be performed according to approved operational
procedure, 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.
第三十八条
物料和溶剂的回收：
Article 38: Recovery of materials and solvents
（一）回收反应物、中间产品或原料药（如从母液或滤液中回收），应当有经
批准的回收操作规程，且回收的物料或产品符合与预定用途相适应的质量标准。
1. 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.
（二）溶剂可以回收。回收的溶剂在同品种相同或不同的工艺步骤中重新使
用的，应当对回收过程进行控制和监测，确保回收的溶剂符合适当的质量标准。
回收的溶剂用于其它品种的，应当证明不会对产品质量有不利影响。
2. Solvents can be recovered and reused in the same process step or in
different process step of the same product, provided that the recovery
procedures are controlled and monitored to ensure that recovered solvents meet
appropriate standards. Provided no adverse impact on product quality , recovery
solvents can be used in different products.
（三）未使用过和回收的溶剂混合时，应当有足够的数据表明其对生产工艺
的适用性。
3. Fresh and recovered solvents and reagents can be combined if an
adequate testing has shown their suitability for all manufacturing processes in
which they may be used.
（四）回收的母液和溶剂以及其它回收物料的回收与使用，应当有完整、可
追溯的记录，并定期检测杂质。
4. The use of recovered solvents, mother liquors, and other recovered
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materials should be adequately documented with traceability, and the impurity
be tested regularly.
第九章 质量管理
Chapter 9 Quality Management
第三十九条
原料药质量标准应当包括对杂质的控制（如有机杂质、无机杂
质、残留溶剂）。原料药有微生物或细菌内毒素控制要求的，还应当制定相应的限
度标准。
Article 39: The specifications should include a control of impurities (e.g.
organic impurities, inorganic impurities, and residual solvents).
Microbiological or
endotoxin specification should be established where applicable.
第四十条
按受控的常规生产工艺生产的每种原料药应当有杂质档案。杂质
档案应当描述产品中存在的已知和未知的杂质情况，注明观察到的每一杂质的鉴
别或定性分析指标（如保留时间）、杂质含量范围，以及已确认杂质的类别（如有
机杂质、无机杂质、溶剂）。杂质分布一般与原料药的生产工艺和所用起始原料有
关，从植物或动物组织制得的原料药、发酵生产的原料药的杂质档案通常不一定
有杂质分布图。
Article 40: 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 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 an origin of the API. Impurity
profiles are normally not necessary for APIs from herbal or animal tissue origin
and manufactured by fermentation process.
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第四十一条
应当定期将产品的杂质分析资料与注册申报资料中的杂质档
案，或与以往的杂质数据相比较，查明原料、设备运行参数和生产工艺的变更所
致原料药质量的变化。
Article 41: The impurity profile should be compared at appropriate
intervals against the impurity profile in the register submission or compared
against historical data in order to detect changes to the API resulting from
modifications in raw materials, equipment operating parameters, or the
production process.
第四十二条
原料药的持续稳定性考察：
Article 42: Stability monitoring of APIs
（一）稳定性考察样品的包装方式和包装材质应当与上市产品相同或相仿。
1) Stability samples should be stored in containers that simulate or are
same with the marketed product container.
（二）正常批量生产的最初三批产品应当列入持续稳定性考察计划，以进一
步确认有效期。
2) Normally the first three commercial production batches should be
placed on the stability monitoring program to confirm the expiry date.
（三）有效期短的原料药，在进行持续稳定性考察时应适当增加检验频次。
3) For APIs with short shelf-lives, testing should be done more frequently
during the stability monitoring.
第十章 采用传统发酵工艺生产原料药的特殊要求
Chapter 10 Specific Requirement for APIs Manufactured
by Classical Fermentation
第四十三条
采用传统发酵工艺生产原料药的应当在生产过程中采取防止物污染
的措施。(?????)
Article 43: Appropriate control should be used to minimize the risk of
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microbial contaminations during manufacture of APIs, which are produced by
classical fermentation process
第四十四条
工艺控制应当重点考虑以下内容：
Article 44: Process controls should take into account:
（一）工作菌种的维护。
1. Maintenance of the working cell bank;
（二）接种和扩增培养的控制。
2. Proper control of inoculation and expansion of the culture;
（三）发酵过程中关键工艺参数的监控。
3. Control of the critical operating parameters during fermentation/cell
culture;
（四）菌体生长、产率的监控。
4. Monitoring of the process for cell growth and productivity
（五）收集和纯化工艺过程需保护中间产品和原料药不受污染。
5. Harvest and purification procedures while protecting the intermediate or
API from contamination
（六）在适当的生产阶段进行微生物污染水平监控，必要时进行细菌内毒素
监测。
6. Monitoring of microbial contamination level and, where needed,
endotoxin levels at appropriate stage of production
第四十五条
必要时，应当验证培养基、宿主蛋白、其它与工艺、产品有关
的杂质和污染物的去除效果。
Article 45: Where appropriate, the removal of media components, host cell
proteins, other process-related and product-related impurities and contaminants
should be demonstrated.
第四十六条
菌种的维护和记录的保存：
Article 46: Cell bank maintenance and record keeping
（一）只有经授权的人员方能进入菌种存放的场所。
1. Access to cell banks should be limited to authorized personnel.
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（二）菌种的贮存条件应当能够保持菌种生长能力达到要求水平，并防止污
染。
2. Cell banks should be maintained under storage conditions designed to
maintain a required viability level and prevent contamination.
（三）菌种的使用和贮存条件应当有记录。
3. Records of the use of the vials from the cell banks and storage
conditions should be maintained.
（四）应当对菌种定期监控，以确定其适用性。
4. Cell banks should be periodically monitored to determine suitability for
use.
（五）必要时应当进行菌种鉴别。
5. When necessary, strain identification should be conducted.
第四十七条
菌种培养或发酵：
Article 47: Cell culture/fermentation
（一）在无菌操作条件下添加细胞基质、培养基、缓冲液和气体，应当采用
密闭或封闭系统。初始容器接种、转种或加料（培养基、缓冲液）使用敞口容器
操作的，应当有控制措施避免污染。
1. Where aseptic addition of cell substrates, media, buffers, and gases is
needed, closed or contained systems should be used. If the inoculations of the
initial vessel, subsequent transfers or additions (media, buffers) are performed
in
open vessels, there should be controls and procedures in place to avoid the risk
of contamination.
（二）当微生物污染对原料药质量有影响时，敞口容器的操作应当在适当的
控制环境下进行。
2. Where the quality of the API can be affected by microbial
contamination, manipulations using open vessels should be performed in the
proper controlled environment.
（三）操作人员应当穿着适宜的工作服，并在处理培养基时采取特殊的防护
措施。
3. Personnel should be appropriately gowned and take special
precautions when handling the cultures.
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（四）应当对关键工艺参数（如温度、pH
值、搅拌速度、通气量、压力）进
行监控，保证与规定的工艺一致。必要时，还应当对菌体生长、产率进行监控。
4. Critical operating parameters (for example temperature, pH, agitation
rates, addition of gases and pressure) should be monitored to ensure
consistency with the established process. Cell growth, productivity should also
be monitored where appropriate.
（五）必要时，发酵设备应当清洁、消毒或灭菌。
5. As appropriate, fermentation equipment should be cleaned, and
sanitized or sterilised.
（六）菌种培养基使用前应当灭菌。
6. Culture media should be sterilised before use.
（七）应当制定监测各工序微生物污染的操作规程，并规定所采取的措施，
包括评估微生物污染对产品质量的影响，确定消除污染使设备恢复到正常的生产
条件。处理被污染的生产物料时，应当对发酵过程中检出的外源微生物进行鉴别，
必要时评估其对产品质量的影响。
7. There should be appropriate procedures in place to detect microbial
contamination occurred during the process operations and determine the course
of action to be taken, including procedures to determine the impact of microbial
contamination on the product and those to decontaminate the equipment and
return it to normal production condition. When dealing with contaminated
materials, foreign micro organisms observed during fermentation processes
should be identified as appropriate and the effect of their presence on product
quality should be assessed, if necessary.
（八）应当保存所有微生物污染和处理的记录。
8. Records of micro contamination events and corresponding handling
should be maintained.
（九）更换品种生产时，应当对清洁后的共用设备进行必要的检测，将交叉
污染的风险降低到最低程度。
9. Shared (multi-product) equipment should be warranted by conducting
necessary tests after cleaning between product campaigns, as appropriate, to
minimize the risk of cross-contamination.
第四十八条
收获、分离和纯化：
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Article 48: Harvesting, isolation and purification
（一）收获步骤中的破碎后除去菌体或菌体碎片、收集菌体组分的操作区和
所用设备的设计，应当能够将污染风险降低到最低程度。
1. Harvesting steps, either to remove cells or cellular components or to
collect cellular components after disruption, should be performed in equipment
and areas designed to minimize the risk of contamination.
（二）包括菌体灭活、菌体碎片或培养基组分去除在内的收获及纯化，应当
制定相应的操作规程，采取措施减少产品的降解和污染，保证所得产品具有持续
稳定的质量。
2. Harvest and purification procedures including inactivating cells,
removing cellular debris and media components should be established and
corresponding procedures should be conducted to minimize degradation and
contamination, so as to ensure that the intermediate or API is recovered with
consistent quality.
（三）分离和纯化采用敞口操作的，其环境应当能够保证产品质量。
3. If open systems are used, isolation and purification and should be
performed under environmental conditions appropriate for the preservation of
product quality.
（四）设备用于多个产品的收获、分离、纯化时，应当增加相应的控制措施，
如使用专用的层析介质或进行额外的检验。
4. Additional controls, such as the use of dedicated chromatography
medium or additional testing, may be appropriate if the equipment is to be used
for harvest, isolation or purification of multiple products.
第十一章 术语
Chapter 11 Glossary
第四十九条
下列术语含义是：
Article 49: The following glossaries mean:
（一）传统发酵
1. Classical fermentation
指利用自然界存在的微生物或用传统方法（如辐照或化学诱变）改良的微生
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物来生产原料药的工艺。用“传统发酵”生产的原料药通常是小分子产品，如抗生素、
氨基酸、维生素和糖类。
The term
“classical fermentation” refers to
processes that use
microorganisms existing in nature and/or modified by conventional methods (e.g.
irradiation or chemical mutagenesis) to produce APIs. APIs produced by
“classical fermentation” are
normally low molecular weight products such as
antibiotics, amino acids, vitamins, and carbohydrates.
（二）非无菌原料药
2. Non-sterile APIs
法定药品标准中未列有无菌检查项目的原料药。
This refers to APIs of which the sterile inspection items are not listed in
statutory standards.
（三）关键质量属性
3. Critical quality attributes
指某种物理、化学、生物学或微生物学的性质，应当有适当限度、范围或分
布，保证预期的产品质量。
This refers to attributes of physical, chemical, biological or
microorganism, should be of certain limits, scope or distribution, so as to meet
expectant product quality.
（四）工艺助剂
4. Process aids
在原料药或中间产品生产中起辅助作用、本身不参与化学或生物学反应的物
料（如助滤剂、活性炭，但不包括溶剂）。
This refers to the materials (e.g. filter aid, activated carbon, etc,
excluding solvents), used as an aid in the production of an intermediate or API
that do not participate in a chemical or biological reaction itself.
（五）母液
5. Mother liquor
结晶或分离后剩下的残留液。
The residual liquid remains after the crystallisation or isolation processes.
Annex 2 reviewed by Zhao Chunhua, Zhao Yunxia
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