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components while protecting the intermediate or API from contamination (particularly of a microbiological nature) and from loss of quality;

● Monitoring of bioburden and, where needed,

endotoxin levels at appropriate stages of production; and

● Viral safety concerns as described in ICH

Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.

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.

18.21 Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

18.22 Records of the use of the vials from the cell banks and storage conditions should be maintained.

18.23 Where appropriate, cell banks should be periodically monitored to determine suitability for use.

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.

18.3 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

● 在适当的生产阶段进行生物负载控制，必要

时做内毒素的控制；

● 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”中描述的生物制品的病毒安全性。

18.17应当根据情况证明培养基、宿主细胞蛋白、其它与工艺有关的杂质、与产品相关的杂质和污染物的去除效果。

18.2细胞库的维护和记录的保存

18.20应当只有授权的人员才能进入细胞库。

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细胞库中小瓶细胞的使用和储存条件应当有记录。

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细胞繁殖/发酵

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。

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controls and procedures in place to minimize the risk of contamination.

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.

18.32 Personnel should be appropriately gowned and take special precautions handling the cultures.

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.

18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.

18.35 Culture media should be sterilized before use when appropriate to protect the quality of the API.

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.

18.37 Records of contamination events should be maintained.

18.38 Shared (multi-product) equipment may

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应当保存染菌记录。

18.38共用(多产品)设备在换产品的清洁后，根

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warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.

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.

18.41 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.

18.42 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.

18.43 If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

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.

18.5 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.

18.51 Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

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

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收取、分离和精制

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 病毒的去除/灭活步骤

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。

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activities and have separate air handling units.

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.

19. APIs for Use in Clinical Trials 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.

19.11 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.

19.2 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.

19.21 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.

19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

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. 用于临床研究的原料药 19.1 总则

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 质量

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。

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