加载中…美国FDA原料药生产质量管理规范(下部分 中英文）
(2014-08-27 15:28:11)
标签：
原料药生产 |
分类： 杂类合同附件执行计划策划 |
10. STORAGE AND DISTRIBUTION 10.储存和分发
10.1 Warehousing Procedures
10.10 Facilities should be available for the storage of
all materials under appropriate conditions (e.g., controlled
temperature and humidity when necessary). Records should be
maintained of these conditions if they are critical for the
maintenance of material characteristics.
10.10 应当提供在适当条件下（需要时控制温度和湿度）贮存所有物料的设施。应当记录对保持物料特性至关重要的贮存条件。
10.11 Unless there is an alternative system to prevent the
unintentional or unauthorized use of quarantined, rejected,
returned, or recalled materials, separate storage areas should be
assigned for their temporary storage until the decision as to their
future use has been made.
10.11 除非另有其它系统可以防止待验的、不合格的退回或召回的物料的误用或未经许可擅自使用，应当为其临时存放指定单独的存放区域，直至其今后用途确定为止。
10.2 Distribution Procedures 10.2 分发程序
10.20 APIs and intermediates should only be released for
distribution to third parties after they have been released by the
quality unit(s). APIs and intermediates can be transferred under
quarantine to another unit under the company’s control when
authorized by the quality unit(s) and if appropriate controls and
documentation are in place.
10.20 原料药和中间体经质量部门放行后才能分发给第三方。经质量部门授权，而且如果有合适的控制并有文件证明，可允许待验的原料药和中间体在公司的控制范围下，转移到另一部门。
10.21 APIs and intermediates should be transported in a
manner that does not adversely affect their quality.
10.21 原料药和中间体应当以对其质量不产生负面影响的方式运输。
10.22 Special transport or storage conditions for an API
or intermediate should be stated on the label.
10.22 原料药或中间体的特殊运输或贮存条件应当在标签上注明。
10.23 The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.
10.23 生产商应当确保运输原料药或中间体的合同接受方（订约人）了解并遵从相关的运输和贮存条件。
10.24 A system should be in place by which the
distribution of each batch of intermediate and/or API can be
readily determined to permit its recall.
10.24 应当建立一个系统，可用它来对每批中间体和/或原料药的分发随时决定召回。
11. LABORATORY CONTROLS
11.1 General Controls
11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.
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 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.
11.11 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 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).
11.12 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 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.
11.13 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 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.
11.14 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 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 resampling and/or retesting after OOS results should be performed according to a documented procedure.
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。
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.
11.16 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 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.
11.17 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 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.
11.18 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 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.
11.19 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 Testing of Intermediates and APIs 11.2 中间体和原料药的测试
11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.
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 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 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.
11.21 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 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.
11.22 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 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.
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 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.
11.40 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 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.
11.41 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 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).
11.42 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 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 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.
11.43 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/重新加工者的名称、地址和电话，并附注原生产商的名称。
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.
11.44 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 Stability Monitoring of APIs 11.5 原料药的稳定性监测
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.
11.50 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 The test procedures used in stability testing should be validated and be stability indicating.
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 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.
11.52 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 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.
11.53 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 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.
11.54 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 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.
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，头三个月内应当每月测试，随后每三个月测试一次。如果有数据表明原料药的稳定性不会受影响，可以考取消特定的测试间隔（如9个月的测试）。
11.56 Where appropriate, the stability storage conditions
should be consistent with the ICH guidances on
stability.
11.56 根据情况，稳定性储存条件应当与ICH的稳定性指南一致。
11.6 Expiry and Retest Dating
11.60 When an intermediate is intended to be transferred
outside the control of the manufacturer’s material management
system and an expiry or retest date is assigned, supporting
stability information should be available (e.g., published data,
test results).
11.60 当一个中间体要运送到生产商物料管理系统控制范围以外，并已制定了有效期或复验期时，那就应当有支持的稳定性信息（如发表的数据、测试结果）。
11.61 An API expiry or retest date should be based on an
evaluation of data derived from stability studies. Common practice
is to use a retest date, not an expiration date.
11.61 一种原料药的有效期或复验期应当基于稳定性研究所得数据的评估。通常会用复验期，而不用有效期。
11.62 Preliminary API expiry or retest dates can be based
on pilot scale batches if (1) the pilot batches employ a method of
manufacture and procedure that simulates the final process to be
used on a commercial manufacturing scale and (2) the quality of the
API represents the material to be made on a commercial
scale.
11.62 如果（1）中试批号采用的生产方法和规程是模拟用于商业生产规模的最终工艺，而且（2）原料药的质量代表了商业生产规模的物料，则原料药的初步有效期或复验期可基于中试规模的批号。
11.63 A representative sample should be taken for the
purpose of performing a retest.
11.63 应当取一个具有代表性的样品进行复验。
11.7 Reserve/Retention Samples
11.70 The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.
11.70 留样的包装和储存是为了今后可能会对原料药批号的质量进行评价，而不是以将来的稳定性测试为目的的。
11.71 Appropriately identified reserve samples of each API
batch should be retained for 1 year after the expiry date of the
batch assigned by the manufacturer, or for 3 years after
distribution of the batch, whichever is longer. For APIs with
retest dates, similar reserve samples should be retained for 3
years after the batch is completely distributed by the
manufacturer.
11.71 适当标识的每一批原料药的留样应当保留到由生产商规定的该批号的有效期满后一年，或该批产品销售后三年，以较长时间为准。对于有复验期的原料药，相似的留样应当保留到生产商全部销售完该批号后三年。
11.72 The reserve sample should be stored in the same
packaging system in which the API is stored or in one that is
equivalent to or more protective than the marketed packaging
system. Sufficient quantities should be retained to conduct at
least two full compendial analyses or, when there is no
pharmacopoeial monograph, two full specification
analyses.
11.72 留样应当储存在原料药储存的同样的包装系统中，或者与销售包装相同，或更具保护性。应当留足够的量来至少做两次法定的全检，或者没有药典专论时，两次质量标准的全检。
12. VALIDATION
12.1 Validation Policy
12.10 The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.
12.10 公司的总体验证原则、目的和方法，包括生产工艺、清洁规程、分析方法、过程控制测试规程以及计算机系统的验证和负责设计、审核、批准和为各个验证阶段提供证明文件的人员都应当明文规定。
12.11 The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:
12.11 关键的工艺参数/属性通常应当在开发阶段或从以往的数据中加以确定，并应当规定工艺可重复性操作所必需的范围。包括：
定义原料药生产的关键产品属性；
12.12 Validation should extend to those operations
determined to be critical to the quality and purity of the
API.
12.12 验证还应当涉及到那些对原料药质量和纯度至关重要的操作。
12.2 Validation Documentation
12.20 A written validation protocol should be established
that specifies how validation of a particular process will be
conducted. The protocol should be reviewed and approved by the
quality unit(s) and other designated units.
12.20 应当有书面的验证方案，阐明如何进行某个工艺的验证。验证方案应当由质量部门和其他指定的部门审核并批准。
12.21 The validation protocol should specify critical
process steps and acceptance criteria as well as the type of
validation to be conducted (e.g., retrospective, prospective,
concurrent) and the number of process runs.
12.21 验证方案应当明确规定验证的关键工序和认可标准，所要进行的验证类型（回顾性验证、预验证、同步验证）和工序运转的次数。
12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.
12.22 应当拟定一份能交叉引用验证方案的验证报告，概括得到的结果，说明发现的任何偏差，并作出必要的结论，包括为整改而必须做的变更。
12.23 Any variations from the validation protocol should be documented with appropriate justification.
12.23 任何对验证方案的偏离都应当归档备案，并作适当说明。
12.3 Qualification
12.30 Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:
12.4 Approaches to Process Validation
12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
12.41 There are three approaches to validation.
Prospective validation is the preferred approach, but there are
situations where the other approaches can be used. These approaches
and their applicability are discussed here.
12.41 验证方法有三种，预验证是首选的方法，但在其它方法可采用的情况下也有例外。这些方法及其适用性见下文。
12.42 Prospective validation should normally be performed
for all API processes as defined in 12.1. Prospective validation
for an API process should be completed before the commercial
distribution of the final drug product manufactured from that
API.
12.42 12.1中所述的所有原料药生产工艺一般来说都应当进行预验证。对原料药工艺所作的预验证的结果，必须在用该原料药制成的制剂产品销售前完成。
12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. 12.43 有时由于原料药生产批号有限，原料药批号不是经常生产，或原料药是用验证过的，但已变更的工艺生产的，无法从连续生产中得到数据，可进行同步验证。同步验证完成之前，只要对原料药批号进行了充分的监控和测试，这些批号可以放行并用于最终制剂药的商业销售。
12.44 An exception can be made for retrospective validation well-established 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.
2.
3.
4.
12.44 某些工艺已确立了很久，而且原料、设备、系统、设施或生产工艺的变化对原料药的质量没有明显的影响，此时就可以例外地进行回顾性验证。这一验证方法适合于下列情况：
1.
2.
3.
4.
12.45 Batches selected for retrospective validation should
be representative of all batches produced during the review period,
including any batches that failed to meet specifications, and
should be sufficient in number to demonstrate process consistency.
Retained samples can be tested to obtain data to retrospectively
validate the process.
12.45 回顾性验证选用的批号应当能够代表审核时段中的所有批号，包括任何不合格的批号，而且应当有足够的批数来证明工艺的稳定。可用测试留样来获取回顾性工艺验证数据。
12.5 Process Validation Program
12.50 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). For retrospective validation, generally data
from 10 to 30 consecutive batches should be examined to assess
process consistency, but fewer batches can be examined if
justified.
12.50 验证时生产工艺的运行次数，应当由工艺的复杂性或要考虑的工艺变更的大小来决定。作为一个指南，预验证和同步验证应当采用三个连续的、成功的批号，但可能在某些情况下需要更多的批号来保证工艺的一致性（例如，复杂的原料药生产工艺，或原料药工艺耗时很长）。回顾性验证一般应当审查从10到30个连续批号得到的数据来评估工艺的一致性，但是，如果有理由，审查的批数可以少些。
12.51 Critical process parameters should be controlled and
monitored during process validation studies. Process parameters
unrelated to quality, such as variables controlled to minimize
energy consumption or equipment use, need not be included in the
process validation.
12.51 在工艺验证研究时应当控制并监测关键的工艺参数。与质量无关的参数，例如为了将能量消耗或所用设备减到最低而控制的变量，无需包括在工艺验证中。
12.52 Process validation should confirm that the impurity
profile for each API is within the limits specified. The impurity
profile should be comparable to, or better than, historical data
and, where applicable, the profile determined during process
development or for batches used for pivotal clinical and
toxicological studies.
12.52 工艺验证应当确认每一个原料药的杂质概况都在规定的限度内。杂质概况应当与以往的数据相似或更好，如果可能，应当与工艺开发阶段确定的杂质概况，或用于关键的临床和毒理研究的批号的数据相似或更好。
12.6 Periodic Review of Validated Systems
12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
12.60 应当对系统和工艺进行周期性的评价，以确认它们仍然能有效地运作。如果系统或工艺并没有大的变动，而质量回顾证实系统和工艺在稳定地生产着符合其质量标准的物料，通常就不必验证了。
12.7 Cleaning Validation
12.70 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. For example, in early production
it may be unnecessary to validate equipment cleaning procedures
where residues are removed by subsequent purification
steps.
12.71 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 potency, toxicity, and
stability.
12.71 清洗程序的验证应当反映实际的设备使用情况。如果多个原料药或中间体都在同一设备内生产，而该设备用同一个程序清洗，那么就要选择代表性的中间体或原料药来作清洗验证。应当根据溶解性，清洗难度，以及依据效价、毒性和稳定性计算出来的残留物的限量来作选择。
12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.
12.72 清洗验证方案应当描述要清洗的设备、程序、物料、可接受的清洗程度、要监测和控制的参数、以及分析方法。方案还应当指出要得到的样品的种类，和如何取样及标记。
12.73 Sampling should include swabbing, rinsing, or
alternative methods (e.g., direct extraction), as appropriate, to
detect both insoluble and soluble residues. The sampling methods
used should be capable of quantitatively measuring levels of
residues remaining on the equipment surfaces after cleaning. Swab
sampling may be impractical when product contact surfaces are not
easily accessible due to equipment design and/or process
limitations (e.g., inner surfaces of hoses, transfer pipes, reactor
tanks with small ports or handling toxic materials, and small
intricate 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
12.80 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.
12.81 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.
13. CHANGE CONTROL
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).
13.13 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.
13.14 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
14.1 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
14.20 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
14.30 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.
14.32 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
14.40 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
14.50 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:
15. COMPLAINTS AND RECALLS
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。
15.14 The recall procedure should designate who should be
involved in evaluating the information, how a recall should be
initiated, who should be informed about the recall, and how the
recalled material should be treated.
15.14 召回程序应当规定参与评估情况的人员、启动召回的方法、召回应当通知到的对象、以及召回后物料的处理方法。
15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.
15.15 如果情况严重或可能威胁生命，则应当通知地方、国家或国际当局，并征求其建议。
16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
16.协议生产商（包括实验室）
16.10 All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.
16.10 所有协议生产商（包括实验室）应当遵循本指南所规定的GMP。特别应当注意防止交叉污染，并保持可追溯性。
16.11 Companies should evaluate any contractors (including
laboratories) to ensure GMP compliance of the specific operations
occurring at the contractor sites.
16.11 合同委托方应当对协议生产商（包括实验室）进行评估，以确保在合同地点发生的特定操作符合GMP。
16.12 There should be a written and approved contract or
formal agreement between a company and its contractors that defines
in detail the GMP responsibilities, including the quality measures,
of each party.
16.12 合同委托方与合同接受方之间应当有经过认定的书面合同或正式协议书，详细规定各方的GMP责任，包括质量措施。
16.13 A contract should permit a company to audit its
contractor’s
facilities for compliance with GMP.
16.13 合同应当允许合同委托方对合同接受方的设施进行GMP审计。
16.14 When subcontracting is allowed, a contractor should not pass to a third party any of the work entrusted to it under the contract without the company’s prior evaluation and approval of the arrangements.
16.14 在允许分包的情况下，未经合同委托方事先的评估和核准，合同接受方不应当将合同中委托给他的工作转交给第三方。
16.15 Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.
16.16 Changes in the process, equipment, test methods,
specifications, or other contractual requirements should not be
made unless the contract giver is informed and approves the
changes.
17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND
RELABELLERS
17.1 Applicability
17.10 This section applied to any party other than the
original manufacturer who may trade and/or take possession, repack,
relabel, manipulate, distribute, or store an API or
intermediate.
17.10 本章内容适用于除原生产商以外，参与贸易和/或持有、处理、重新包装、重新贴签、运作和储存原料药或中间体的任何一方。
17.11 All agents, brokers, traders, distributors,
repackers, and relabelers should comply with GMP as defined in this
guidance.
17.11 所有的代理、经纪人、贸易商、经销商、重新包装者和重新贴签者都必须遵循本指南的GMP。
17.2 Traceability of Distributed APIs and
Intermediates
17.2已分发的原料药和中间体的可追溯性
17.20 Agents, brokers, traders, distributors, repackers, and relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:
17.3 Quality Management
17.30 Agents, brokers, traders, distributors, repackers,
or relabelers should establish, document and implement an effective
system of managing quality, as specified in Section 2.
17.30 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当按第2节的规定建立并执行一个有效的质量管理系统。
17.4 Repackaging, Relabeling, and Holding of APIs and
Intermediates
17.4原料药和中间体的重新包装、重新贴签和待检
17.40 Repackaging, Relabeling, and holding APIs and
intermediates should be performed under appropriate GMP controls,
as stipulated in this guidance, to avoid mix-ups and loss of API or
intermediate identity or purity.
17.40 原料药和中间体的重新包装、重新贴签和待检应当在本指南中所制定的适当的GMP控制下进行，以防原料药或中间体的特性或纯度的混淆和损失。
17.41 Repackaging should be conducted under appropriate
environmental conditions to avoid contamination and
cross-contamination.
17.41 重新包装应当在合适的，能防止污染和交叉污染的环境条件下进行。
17.5 Stability
17.50 Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.
17.50 如果原料药或中间体的重新包装所使用的容器与原料药或中间体的生产商所使用的不同，就应当进行稳定性研究，以确认规定的失效期或复验期。
17.6 Transfer of Information 17.6 信息的传达
17.60 Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.
17.60 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当将从原料药或中间体生产商和客户之间传递所有质量或药政的信息。
17.61 The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.
17.61 将原料药或中间体提供给客户的代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当提供所供原料药或中间体的原生产商的名称和原批号。
17.62 The agent should also provide the identity of the
original API or intermediate manufacturer to regulatory authorities
upon request. The original manufacturer can respond to the
regulatory authority directly or through its authorized agents,
depending on the legal relationship between the authorized agents
and the original API or intermediate manufacturer. (In this context
authorized refers to authorized by the manufacturer.)
17.62 需要时，代理还应当向药政当局提供原生产商的身份。按照原料药或中间体的原生产商和授权代理人之间的法律关系，原生产商可直接地或通过其授权代理向药政当局作回复。（此处“授权”是指由原生产商所给的授权）
17.63 The specific guidance for certificate of analysis
included in Section 11.4 should be met.
17.7 Handling of Complaints and Recalls
17.70 Agents, brokers, traders, distributors, repackers,
or relabelers should maintain records of complaints and recalls, as
specified in Section 15, for all complaints and recalls that come
to their attention.
17.70 参照第15章的要求，代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留他们收到的所有投诉和召回的记录。
17.71 If the situation warrants, the agents, brokers,
traders, distributors, repackers, or relabelers should review the
complaint with the original API or intermediate manufacturer to
determine whether any further action, either with other customers
who may have received this API or intermediate or with the
regulatory authority, or both, should be initiated. The
investigation into the cause for the complaint or recall should be
conducted and documented by the appropriate party.
17.72 Where a complaint is referred to the original API or
intermediate manufacturer, the record maintained by the agents,
brokers, traders, distributors, repackers, or relabelers should
include any response received from the original API or intermediate
manufacturer (including date and information provided).
17.72 如果投诉是针对原料药或中间体的原生产商，由代理、经纪人、贸易商、经销商、重新包装者或重新贴签者保存的记录应当包括从原料药或中间体原生产商处得到的任何反馈信息（包括提供的日期和内容）。
17.8 Handling of Returns
17.80 Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates.
17.80 退货应当按照14.5章进行处理。代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留原料药或中间体退货的文档。
18. Specific Guidance for APIs Manufactured by Cell
Culture/Fermentation
18.1 General
18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for “classical” processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.
18.10第18节旨在描述对通过细胞繁殖或用天然或重组组织发酵生产的原料药或中间体的一些在前面的章节中没有充分阐明的特殊控制。它不是一个独立的章节。通常，本文件中其他章节的GMP 原则也适用。值得注意的是尽管生产小分子的“经典”工艺的发酵原理和用重组或非重组组织生产蛋白质和/或多肽类的发酵原理是一样的，但是，它们的控制程度不同。本章节将在适当的地方阐述这些不同点。总的来说，用于生产蛋白质和多肽的生物技术工艺的控制要严于经典的发酵工艺。
18.11 The term “biotechnological process” (biotech) refers
to the use of cells or organisms that have been generated or
modified by recombinant DNA, hybridoma or other technology to
produce APIs. The APIs produced by biotechnological processes
normally consist of high molecular weight substances, such as
proteins and polypeptides, for which specific guidance is given in
this Section. Certain APIs of low molecular weight, such as
antibiotics, amino acids, vitamins, and carbohydrates, can also be
produced by recombinant DNA technology. The level of control for
these types of APIs is similar to that employed for classical
fermentation.
18.11 “生物技术”是指用重组DNA、杂交瘤或其它技术产生或修饰的细胞或组织来生产原料药。用生物技术生产的原料药通常由蛋白质和多肽这类高分子量的物质组成，本节介绍其特殊指南。有些低分子量的原料药，如抗生素、氨基酸、维生素和糖类也可以用重组DNA来生产。这几类原料药的控制程度与经典发酵的相似。
18.12 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.
18.12 “经典发酵”是指用天然的和/或以传统方法(如，辐照或化学诱变)修改的微生物来生产原料药的工艺。用“经典发酵”生产的原料药通常是低分子量的产品，如，抗生素、氨基酸、维生素和糖类。
18.13 Production of APIs or intermediates from cell
culture or fermentation involves biological processes such as
cultivation of cells or extraction and purification of material
from living organisms. Note that there may be additional process
steps, such as physicochemical modification, that are part of the
manufacturing process. The raw materials used (media, buffer
components) may provide the potential for growth of microbiological
contaminants. Depending on the source, method of preparation, and
the intended use of the API or intermediate, control of bioburden,
viral contamination, and/or endotoxins during manufacturing and
monitoring of the process at appropriate stages may be
necessary.
18.13用细胞培养或发酵来生产原料药或中间体涉及到诸如细胞培养，或从活体组织提取和纯化物料等生物过程。值得注意的是，还有一些附加的隶属于生产工艺一部分的物理化学修饰。使用的原材料(培养基、缓冲成分)可能为微生物污染提供了可能性。根据物料来源、制备方法和原料药或中间体的预期用途，可能有必要在制造和工艺监测的适当阶段控制微生物、病毒污染和/或内毒素。
18.14 Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.
18.14制造过程的所有阶段都应当建立必要的控制，以保证中间体和/或原料药的质量。尽管本指南从细胞培养/发酵步骤开始，但是前期步骤(如细胞库) 应当在必要的控制下进行。本指南含盖了从细胞库取得用于生产的细胞开始的细胞培养/发酵过程。
18.15 Appropriate equipment and environmental controls
should be used to minimize the risk of contamination. The
acceptance criteria for quality of the environment and the
frequency of monitoring should depend on the step in production and
the production conditions (open, closed, or contained
systems).
18.15应当采取适当的设备和环境控制来将污染的风险降低到最低程度。环境质量的认可标准和监控的频率应当根据生产步骤和生产条件(开口，闭口，或封闭系统)而定。
18.17 Where appropriate, the removal of media components,
host cell proteins, other process-related impurities,
product-related impurities and contaminants should be
demonstrated.
18.2 Cell Bank Maintenance and Record Keeping
18.20 Access to cell banks should be limited to authorized personnel.
18.20应当只有授权的人员才能进入细胞库。
18.21 Cell banks should be maintained under storage
conditions designed to maintain viability and prevent
contamination.
18.21细胞库应当维持在保持细胞活力、防止污染的储存条件下。
18.22 Records of the use of the vials from the cell banks
and storage conditions should be maintained.
18.22细胞库中小瓶细胞的使用和储存条件应当有记录。
18.23 Where appropriate, cell banks should be periodically
monitored to determine suitability for use.
18.23细胞库应当根据情况进行周期性的监测，以确定其适用性。
18.24 See ICH Guideline Q5D Quality of Biotechnological
Products: Derivation and Characterization of Cell Substrates Used
for Production of Biotechnological/Biological Products for a more
complete discussion of cell banking.
18.24有关细胞库的详细论述请参见ICH 指南Q5D“生物制品的质量：用于生物技术/生物制品生产的细胞质的诱导和特性描述”。
18.3 Cell Culture/Fermentation
18.30 Where aseptic addition of cell substrates, media,
buffers, and gases is needed, closed or contained systems should be
used where possible. If the inoculation of the initial vessel or
subsequent transfers or additions (media, buffers) are performed in
open vessels, there should be controls and procedures in place to
minimize the risk of contamination.
18.30在需要进行来进行细胞质、培养基、缓冲液和气体的无菌添加的场合，如果可能的话，应当采用闭口或密闭系统。如果接种或转种或加料(培养基，缓冲液)是在敞口容器中操作的，就应当有控制措施和程序将污染的风险减少到最低限度。
18.31 Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.
18.31在原料药的质量会受微生物污染的影响的情况下，使用敞口容器的操作应当在生物安全橱中，或相似的控制环境下进行。
18.32 Personnel should be appropriately gowned and take
special precautions handling the cultures.
18.32操作人员应当着装适宜，并采取特殊的处理培养物的措施。
18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.
18.33应当监测关键的操作参数(如温度，pH，搅拌速度，通气，压力)，确保与工艺规定一致。对细胞生长，活性(大多数生物技术工艺)， 必要时对生产能力也应当进行监测。不同工艺的关键操作参数是不同的，对经典发酵的某些参数可以不必监测。
18.34 Cell culture equipment should be cleaned and
sterilized after use. As appropriate, fermentation equipment should
be cleaned, and sanitized or sterilized.
18.34细胞培养物的设备，使用后应当清洗和灭菌。发酵设备必要时应当清洗和消毒或灭菌。
18.35 Culture media should be sterilized before use when
appropriate to protect the quality of the API.
18.35为了保证原料药的质量，细胞培养基必要时在使用前应当灭菌。
18.36 There should be appropriate procedures in place to
detect contamination and determine the course of action to be
taken. This should include procedures to determine the impact of
the contamination on the product and those to decontaminate the
equipment and return it to a condition to be used in subsequent
batches. Foreign organisms observed during fermentation processes
should be identified as appropriate and the effect of their
presence on product quality should be assessed, if necessary. The
results of such assessments should be taken into consideration in
the disposition of the material produced.
18.36应当有合适的程序来检测是否染菌，并决定所采取的措施。该程序应当包括确定染菌对产品质量的影响，设备去污染，和恢复到用于以后批号的程序。适当情况下，发酵工艺中发现的外来有机物应当根据需要进行鉴别，必要时应当就其存在对产品质量的影响进行评估。在处理生产出来的物料时应当考虑该评估的结果。
18.37 Records of contamination events should be
maintained.
18.38 Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.
18.38共用(多产品)设备在换产品的清洁后，根据情况可以进行额外测试，以便将交叉污染的风险减少到最低限度。
18.4 Harvesting, Isolation and Purification
18.40 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.
18.40收取步骤，不管去除细胞或细胞组分，还是收集破坏后的细胞组分，都应当在按尽可能减少污染的要求而设计的设备和区域内进行。
18.41 Harvest and purification procedures that remove or
inactivate the producing organism, cellular debris and media
components (while minimizing degradation, contamination, and loss
of quality) should be adequate to ensure that the intermediate or
API is recovered with consistent quality.
18.41将生产有机物、细胞碎片或培养基组分去除或灭活(同时减少降解、污染、质量损失)的收取和精制工艺，应当充分保证回收到的中间体或原料药是均质的。
18.42 All equipment should be properly cleaned and, as
appropriate, sanitized after use. Multiple successive batching
without cleaning can be used if intermediate or API quality is not
compromised.
18.42所有的设备使用后应当适当地清洗，根据情况还应当消毒。如果对中间体和原料药的质量没有危害，可以连续生产几批后清洗。
18.43 If open systems are used, purification should be
performed under environmental conditions appropriate for the
preservation of product quality.
18.43如果使用开口系统，应当在适合于保持产品质量的环境下进行精制。
18.44 Additional controls, such as the use of dedicated
chromatography resins or additional testing, may be appropriate if
equipment is to be used for multiple products.
18.44如果设备用于多个产品，可能有必要作诸如使用专用的层析树脂的额外精制控制，或额外的测试。
18.5 Viral Removal/Inactivation steps
18.50 See the ICH Guideline Q5A Quality of
Biotechnological Products: Viral Safety Evaluation of Biotechnology
Products Derived from Cell Lines of Human or Animal Origin for more
specific information.
18.50更具体的资料参见ICH 指南Q5A“生物制品的质量：从人体或动物组织细胞族得到的生物制品的病毒安全性评估”。
18.51 Viral removal and viral inactivation steps are
critical processing steps for some processes and should be
performed within their validated parameters.
18.51对于某些工艺来说，病毒的去除和灭活是关键的工艺步骤，并按其验证过的参数进行。
18.52 Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.
18.52应当采取合适的预防措施来防止病毒去除/灭活前的步骤对病毒去除/灭活后的步骤的潜在病毒污染。因此，开口工艺应当在与其它操作活动分开的，有独立的空气处理装置的区域内进行。
18.53 The same equipment is not normally used for different purification steps. However, 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.
18.53不同的精制步骤通常不使用同一台设备。如果使用同一台设备，在再使用之前应当进行适当的清洁和消毒。应当采取合适的预防措施来防止病毒从前面的步骤带入(例如，通过设备或环境)。
19. APIs for Use in Clinical Trials 19. 用于临床研究的原料药
19.1 General
19.10 Not all the controls in the previous sections of
this Guide are appropriate for the manufacture of a new API for
investigational use during its development. Section 19 provides
specific guidance unique to these circumstances.
19.10不是本指南前面章节中所有的控制都适合于开发阶段用于研究的新原料药的制造。第19章提供了针对此种情况的特殊指南。
19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.
19.11用于生产临床试验用原料药的生产控制应当与含有该原料药的药品的开发阶段一致。工艺和检验程序应当随着工艺知识的积累，从前期临床阶段到临床阶段的药品临床测试的发展，提供变更的可能性。一旦药物的开发到了为用于临床试验的药品生产原料药的阶段，生产者应当确原料药是在适当的设施中，采用保证原料药质量的适当生产和控制程序生产的。
19.2 Quality
19.20 Appropriate GMP concepts should be applied in the
production of APIs for use in clinical trials with a suitable
mechanism of approval of each batch.
19.20在对每批有合适的批准机制的临床试验用原料药的生产中应当采用适当的GMP观念。
19.21 A quality unit(s) independent from production should
be established for the approval or rejection of each batch of API
for use in clinical trials.
19.21应当建立独立于生产部的质量部门，来确定每批用于临床试验的原料药合格或不合格。
19.22 Some of the testing functions commonly performed by
the quality unit(s) can be performed within other organizational
units.
19.22某些通常由质量部门执行的测试功能可以在其它部门进行。
19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.
19.23质量措施应当包括一个测试原料、包装材料、中间体和原料药的系统。
19.24 Process and quality problems should be
evaluated.
19.24对工艺和质量问题应当进行评估。
19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.
19.3 Equipment and Facilities
19.30 During all phases of clinical development, including
the use of small-scale facilities or laboratories to manufacture
batches of APIs for use in clinical trials, procedures should be in
place to ensure that equipment is calibrated, clean and suitable
for its intended use.
19.30在临床开发的所有阶段，包括使用小型设备或实验室进行临床试验用原料药的生产，应当提供确保设备经过校验、清洁并适于其预定用途的程序。
19.31 Procedures for the use of facilities should ensure
that materials are handled in a manner that minimizes the risk of
contamination and cross-contamination.
19.31设施的使用程序应当确保原料以将污染和交叉污染减少到最低限度的方式操作。
19.4 Control of Raw Materials
19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.
19.40用于临床试验用原料药生产的原料应当通过测试来评估，或者凭供应商的分析报告单接收，并进行鉴别测试。如果原材料有毒性，一份供应商的分析报告单应当够了。
19.41 In some instances, the suitability of a raw material
can be determined before use based on acceptability in small-scale
reactions (i.e., use testing) rather than on analytical testing
alone.
19.5 Production
19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.
19.50临床试验用原料药的生产应当在实验室记录本、批记录中，或以其它适合的方式成文备查。这些文件应当包括所用的生产原料、设备、工艺，和科学观察。
19.51 Expected yields can be more variable and less
defined than the expected yields used in commercial processes.
Investigations into yield variations are not expected.
19.51预期产量同正式生产的预期产量相比可能更具变异性、更不确定。无需对产量变化进行调查。
19.6 Validation
19.60 Process validation for the production of APIs for
use in clinical trials is normally inappropriate, where a single
API batch is produced or where process changes during API
development make batch replication difficult or inexact. The
combination of controls, calibration, and, where appropriate,
equipment qualification assures API quality during this development
phase.
19.60在临床试验用原料药只生产一批，或者有由于原料药开发中工艺的变更使批次的重现困难或不精确的场合，不适合作原料药的工艺验证。控制、校验和必要的设备确认的结合会保证开发阶段的原料药质量。
19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.19.61在生产商业用批号，甚至是中试或小规模生产批号时，应当按照第12章进行工艺验证。
19.7 Changes
19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded
19.70随着知识的积累和生产规模的扩大，在开发阶段会有变更。生产、规格或检验方法的每一个变更都应当适当地记录。
19.8 Laboratory Controls
19.80 While analytical methods performed to evaluate a
batch of API for clinical trials may not yet be validated, they
should be scientifically sound.
19.80虽然评估一批临床试验用原料药的分析方法可能还没有验证，但是，它们应当是科学，合理的。
19.81 A system for retaining reserve samples of all
batches should be in place. This system should ensure that a
sufficient quantity of each reserve sample is retained for an
appropriate length of time after approval, termination, or
discontinuation of an application.
19.81应当有一套保存所有批号留样的系统。该系统应当确保在申请批准、终止或中断后能将足够量的每一个留样保存一段适当的时间。
19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.
19.82按第11.6节规定的设定有效期或复验期适用于现有的临床试验用原料药。对新的原料药，第11.6节通常不适于临床试验的前期阶段。
19.9 Documentation
19.90 A system should be in place to ensure that
information gained during the development and the manufacture of
APIs for use in clinical trials is documented and
available.
19.90应当有一个系统确保在临床试验用原料药的开发和生产过程中得到的信息均成文备查，并可获得。
19.91 The development and implementation of the analytical
methods used to support the release of a batch of API for use in
clinical trials should be appropriately documented.
19.91支持放行一批临床试验用原料药的分析方法的开发和实施应当适当地成文备查。
19.92 A system for retaining production and control
records and documents should be used. This system should ensure
that records and documents are retained for an appropriate length
of time after the approval, termination, or discontinuation of an
application.
19.92应当采用一套保存生产和控制的记录和文件的系统。该系统应当保证记录和文件在申请批准、终止或中断后能记录和文件保存一段适当的时间。
20. Glossary
Acceptance Criteria认可标准
Numerical limits, ranges, or other suitable measures for
acceptance of test results.
接收测试结果的数字限度、范围或其它合适的量度标准。
Active Pharmaceutical Ingredient (API) (or Drug Substance)
Any substance or mixture of substances intended to be used
in the manufacture of a drug (medicinal) product and that, when
used in the production of a drug, becomes an active ingredient of
the drug product. Such substances are intended to furnish
pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease or to affect
the structure and function of the body.
活性药用成分(原料药)旨在用于药品制造中的任何一种物质或物质的混合物，而且在用于制药时，成为药品的一种活性成分。此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或其它直接作用，或者能影响机体的功能和结构。
API Starting Material原料药的起始物料
A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials are normally of defined chemical properties and structure.
用在原料药生产中的，以主要结构单元被并入该原料药的原料、中间体或原料药。原料药的起始物料可能是在市场上有售，能够根据合同或商业协议从一个或多个供应商处购得，或者自己生产。原料药的起始物料通常有特定的化学特性和结构。
Batch (or Lot)
A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.
由一个或一系列工艺过程生产的一定数量的物料，因此在规定的限度内是均一的。在连续生产中，一批可能对应于与生产的某一特定部分。其批量可规定为一个固定数量，或在固定时间间隔内生产的数量。
Batch Number (or Lot Number)
A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.
用于标识一批的一个数字、字母和/或符号的唯一组合，从中可确定生产和销售的历史。
Bioburden生物负载
The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.
可能存在于原料、原料药的起始物料、中间体或原料药中的微生物的水平和种类(例如，致病的或不致病的)。生物负载不应当当作污染，除非含量超标，或者测得致病生物。
Calibration校验
The demonstration that a particular instrument or device
produces results within specified limits by comparison with those
produced by a reference or traceable standard over an appropriate
range of measurements.
Computer System计算机系统
A group of hardware components and associated software,
designed and assembled to perform a specific function or group of
functions.
设计安装用于执行某一项或一组功能的一组硬件元件和关联的软件。
Computerized System计算机化系统
A process or operation integrated with a computer
system.
与计算机系统整合的一个工艺或操作。
Contamination污染
The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.
在生产、取样、包装或重新包装、贮存或运输过程中，具化学或微生物性质的杂质或外来物质进入或沾染原料、中间体或原料药。
Contract Manufacturer协议制造商
A manufacturer performing some aspect of manufacturing on
behalf of the original manufacturer.
Critical关键的
Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.用来描述为了确保原料药符合规格标准，必须控制在预定范围内的工艺步骤、工艺条件、测试要求或其它有关参数或项目。
Cross-Contamination交叉污染
Contamination of a material or product with another
material or product.
一种物料或产品对另一种物料或产品的污染。
Deviation偏差
Departure from an approved instruction or established standard.
对批准的指令或规定的标准的偏离。
Drug (Medicinal) Product药品
The dosage form in the final immediate packaging intended
for marketing. (Reference Q1A)
Drug Substance原料药
See Active Pharmaceutical Ingredient
Expiry Date (or Expiration Date) 有效期
The date placed on the container/labels of an API
designating the time during which the API is expected to remain
within established shelf life specifications if stored under
defined conditions, and after which it should not be
used.
原料药容器/标签上注明的日期，在此规定时间内，该原料药在规定条件下贮存时，仍符合规格标准，超过这一期限则不应当使用。
In-Process Control (or Process Control) 过程控制
Checks performed during production in order to monitor
and, if appropriate, to adjust the process and/or to ensure that
the intermediate or API conforms to its specifications.
生产过程中为监测，在必要时调节工艺和/或保证中间体或原料药符合其规格而进行的检查。
Intermediate中间体
A material produced during steps of the processing of an
API that undergoes further molecular change or purification before
it becomes an API. Intermediates may or may not be isolated. (Note:
this Guide only addresses those intermediates produced after the
point that the company has defined as the point at which the
production of the API begins.)
原料药工艺步骤中产生的、必须经过进一步分子变化或精制才能成为原料药的一种物料。中间体可以分离或不分离。(注：本指南只涉及该公司定义为原料药生产起始点以后生产的中间体。)
Qualification确认
Action of proving and documenting that equipment or
ancillary systems are properly installed, work correctly, and
actually lead to the expected results. Qualification is part of
validation, but the individual qualification steps alone do not
constitute process validation.
证明设备或辅助系统，安装正确、工作正常、确实产生预期的结果，并以文件佐证的行为。确认是验证的一部分，但单独的确认步骤不构成工艺验证。
Quality Assurance (QA) 质量保证
The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.
以确保所有原料药达到其应用所要求的质量，并维持质量体系为目的的全部组织安排的总和。
Quality Unit(s) 质量部门
An organizational unit independent of production which
fulfills both Quality Assurance and Quality Control
responsibilities. This can be in the form of separate QA and QC
units or a single individual or group, depending upon the size and
structure of the organization.
Quarantine待验
The status of materials isolated physically or by other
effective means pending a decision on their subsequent approval or
rejection.
在实物上或以其它有效方式将物料隔离，等待对其随后的批准或拒收做出决定的状态。
Raw Material原料
A general term used to denote starting materials,
reagents, and solvents intended for use in the production of
intermediates or APIs.
用来表示中间体或原料药的生产中要用的起始物料、试剂和溶剂的通用专业名词。
Reference Standard, Primary基准参考标准品
A substance that has been shown by an extensive set of
analytical tests to be authentic material that should be of high
purity. This standard can be: (1) obtained from an officially
recognised source, or (2) prepared by independent synthesis, or (3)
obtained from existing production material of high purity, or (4)
prepared by further purification of existing production
material.
Reference Standard, Secondary二级参考标准品
A substance of established quality and purity, as shown by
comparison to a primary reference standard, used as a reference
standard for routine laboratory analysis.
与基准参考标准品比较显示具有规定的质量和纯度，并用作日常实验室分析的参考标准品。
Reprocessing返工
Introducing an intermediate or API, including one that
does not conform to standards or specifications, back into the
process and 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. 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, and not
reprocessing.
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。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，而不是返工。
Reworking重新加工
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).
Specification质量标准
A list of tests, references to analytical procedures, and
appropriate acceptance criteria that are numerical limits, ranges,
or other criteria for the test described. It establishes the set of
criteria to which a material should conform to be considered
acceptable for its intended use.
“Conformance to specification”
means that the material, when tested according to the listed
analytical procedures, will meet the listed acceptance
criteria.
一系列的测试项目、有关的分析程序和适当的认可标准，此标准可以是数值限度、范围或所述测试项目的其它标准。它规定一套标准，物料应当符合该标准，才被认为可以用作其预期的用途。“符合规格”表示物料按所列的分析程序测试时，会符合所列的接受标准。
Validation验证
A documented program that provides a high degree of
assurance that a specific process, method, or system will
consistently produce a result meeting pre-determined acceptance
criteria.
为某一特定的工艺、方法或系统能够持续地产生符合既定接受标准的结果提供充分保证的文件程序。
Validation Protocol验证方案
A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.
说明如何进行验证和规定接受标准的书面计划。例如，生产工艺验证方案确定工艺设备、关键性工艺参数/操作范围、产品特性、取样、收集的测试数据、验证的次数，以及可接受的测试结果。
Yield, Expected预期产量
The quantity of material or the percentage of theoretical
yield anticipated at any appropriate phase of production based on
previous laboratory, pilot scale, or manufacturing
data.
在以前实验室、中试规模或生产数据的基础上，预计任何适当的生产阶段的物料的量或理论产量的百分比。
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