| 法规 | | | | |
| | | | | 第十二条 质量控制的基本要求：（二）应当有批准的操作规程，用于原辅料、包装材料、中间产品、待包装产品和成品的取样、检查、检验以及产品的稳定性考察，必要时进行环境监测，以确保符合本规范的要求 |
| 第一百零二条 药品生产所用的原辅料、与药品直接接触的包装材料应当符合相应的质量标准。药品上直接印字所用油墨应当符合食用标准要求。 进口原辅料应当符合国家相关的进口管理规定。 |
| 第一百一十条 应当制定相应的操作规程，采取核对或检验等适当措施，确认每一包装内的原辅料正确无误。 |
| 第一百二十条 与药品直接接触的包装材料和印刷包装材料的管理和控制要求与原辅料相同。 |
| 第九十六条 制药用水应当适合其用途，并符合《中华人民共和国药典》的质量标准及相关要求。制药用水至少应当采用饮用水。 第九十七条 水处理设备及其输送系统的设计、安装、运行和维护应当确保制药用水达到设定的质量标准。水处理设备的运行不得超出其设计能力。 第九十八条 纯化水、注射用水储罐和输送管道所用材料应当无毒、耐腐蚀；储罐的通气口应当安装不脱落纤维的疏水性除菌滤器；管道的设计和安装应当避免死角、盲管。 第九十九条 纯化水、注射用水的制备、贮存和分配应当能够防止微生物的滋生。纯化水可采用循环，注射用水可采用70℃以上保温循环。 第一百条 应当对制药用水及原水的水质进行定期监测，并有相应的记录。 第一百零一条 应当按照操作规程对纯化水、注射用水管道进行清洗消毒，并有相关记录。发现制药用水微生物污染达到警戒限度、纠偏限度时应当按照操作规程处理。 |
| | 第五条 生物制品生产企业在生产质量管理过程中，应当按照国家有关生物安全管理法律法规、生物制品生产检定用菌毒种管理规程等建立完善生物安全管理制度体系，应当对包括生物原材料、辅料、生产制造过程及检定等整个生物制品生产活动的生物安全进行评估，并采取有效的控制措施。 |
第三十四条 当原辅料的检验周期较长时，允许检验完成前投入使用，但只有全部检验结果符合标准时，成品才能放行。 |
第五十五条 应当按照《中华人民共和国药典》、国家药品监督管理部门核准的质量标准、相关质控要求对生物制品原辅料、中间产品、原液及成品进行检验。 |
| | 第四十九条 无菌原材料药精制、无菌药品配制、直接接触药品的包装材料和器具等最终清洗、A/B级洁净区内消毒剂和清洁剂配制的用水应当符合注射用水的质量标准。 第五十条 必要时，应当定期监测制药用水的细菌内毒素，保存监测结果及所采取纠偏措施的相关记录。 |
| 第四十二条 进入无菌生产区的生产用气体（如压缩空气、氮气，但不包括可燃性气体）均应经过除菌过滤，应当定期检查除菌过滤器和呼吸过滤器的完整性。 |
| | | | | 十四、原材料及辅料 制剂中使用的辅料和生产中所用的原材料，其质量控制应符合“生物制品生产用原材料及辅料质量控制”及本版药典的相关规定。本版药典未收载者，必须制定符合产品生产和质量控制要求的标准并需经国家药品监督管理部门批准。辅料的生产和使用应符合国家药品监督管理部门的有关规定。 生产用培养基不得含有可能引起人体不良反应的物质。 生产过程使用的过滤介质，应为无石棉的介质。 |
生物制品通则<生物制品生产用原材料及辅料质量控制> | | 对于不同风险级别原材料的质量控制，应充分考虑来源千动物（或人）的生物原材料可能带来的外源因子污染的安全性风险。生产过程中应避免使用毒性较大的化学原材料，有机溶剂的使用应符合本版药典通则”残留溶剂测定法”的相关要求。 |
| 生物制品生产企业用于生物制品注射剂生产的药用辅料，其全检的质量标准中除理化、含量/活性等项目外，应包括常规的安全性检查，如微生物限度或无菌检查、热原和（或）细菌内毒素检查、异常毒性检查等。 |
| 勘误为“表1第1行第3列：“供应商通过药品GMP符合性检查*”表底*：也可提供药品生产GMP证书（证书尚在有效期内）。”（2020-9-27发布） |
| | 勘误为“表2第1行第3列：“供应商通过药品GMP符合性检查*”表底*：也可提供药品生产GMP证书（证书尚在有效期内）。”（2020-9-27发布） |
| 具有毒副作用或特定功能的辅料以及其他需要在生物制品中控制含最的辅料，应在成品检定或适宜的中间产物阶段设定辅料含釐检查项并规定限度要求。 |
| | | 3.3包装及密闭容器系统 应对原液和成品与容器的相容性、容器吸附、制品和包装材料之间的浸出进行检测和确认,以避免蛋白质和制剂辅料和（或）容器包装系统发生相互作用，导致对制品的安全性和有效性带来潜在风险。此外，应采用适宜方法对容器完整性进行检测，防止容器泄漏导致产品无菌状态的破坏。 |
| | | 四、在制定药用辅料标准时既要考虑辅料自身的安全性，也要考虑影响制剂生产、质量、安全性和有效性的性质。药用辅料的标准主要包括两部分：与生产工艺及安全性有关的项目，如性状、鉴别、检查、含量测定等项目；影响制剂性能的功能性相关指标，如黏度、粒度等。药用辅料应满足所用制剂的要求，用于不同制剂时，需根据制剂要求进行相应的质量控制。 药用辅料的残留溶剂应符合要求；药用辅料的微生物限度应符合要求；用于无除菌工艺的无菌制剂的药用辅料应符合无菌要求（通则1101);用于静脉用注射剂、冲洗剂等的药用辅料照细菌内毒素检查法（通则1143)或热原检查法（通则1142)检查，应符合规定。 |
五、本版药典收载的药用辅料标准是对其质量控制的基本标准，对于声称符合《中国药典》的药用辅料必须执行《中国药典》的相应标准。 |
在充分评估的基础上，《中国药典》收载的药用辅料标准应根据已上市药品中使用的药用辅料的质量特点，适时进行修订。 |
| | 预混与共处理药用辅料系将两种或两种以上药用辅料按特定的配比和工艺制成具有一定功能的混合物，作为一个辅料整体在制剂中使用……应根据配方组成、生产工艺、预期功能以及配方组分中各单一组分的特性等，建立反映产品安全性、功能性与质量均一性的检测项目…… |
| | 根据不同的生产工艺及用途，药包材的微生物限度或无菌应符合要求；注射剂用药包材的热原或细菌内毒素、无菌等应符合所包装制剂的要求。 |
| | 药品生产企业应根据药物的物理、化学性质以及相容性试验研究结果选择适合的药用玻璃容器。对生物制品、偏酸偏碱及对pH值敏感的注射剂，应选择121℃玻璃颗粒耐水性为1级及内表面耐水性为HC1级的药用玻璃容器或其他适宜的包装材料。 |
| 国家食品药品监督管理局办公室关于加强药用玻璃包装注射剂药品监督管理的通知 | | | 一、……注射剂产品与所用药用玻璃的相容性研究应符合国家食品药品监督管理局发布的《药品包装材料与药物相容性试验指导原则》（YBB00142002）等相关技术指导原则的要求。凡不符合的，必须立即停止使用该药用玻璃包装，并重新开展规范的研究…… 二、……对生物制品、偏酸偏碱及对pH敏感的注射剂，应选择121℃颗粒法耐水性为1级及内表面耐水性为HC1级的药用玻璃或其他适宜的包装材料。对注射剂类药品包装材料由达不到上述耐水要求的药用玻璃变更为符合上述耐水要求药用玻璃的补充申请…… |
| USP | | <1231> WATER FOR PHARMACEUTICAL PURPOSES | | 7.1 Chemical Tests for Bulk Waters In 1996, USP moved away from these chemical attribute tests, switching to contemporary analytical technologies for the bulk waters Purified Water and Water for Injection. The intent was to upgrade the analytical technologies without tightening the quality requirements. The two contemporary analytical technologies employed were TOC and conductivity. The TOC test replaced the test for Oxidizable Substances that primarily targeted organic contaminants. A multi-staged conductivity test that detects ionic (mostly inorganic) contaminants replaced, with the exception of the test for Heavy Metals, all of the inorganic chemical tests (i.e., Ammonia, Calcium, Carbon Dioxide, Chloride, Sulfate). Replacing the heavy metals attribute was considered unnecessary because 1) the source water specifications (found in the U.S. EPA’s NPDWR) for individual heavy metals were tighter than the approximate limit of detection of the Heavy Metals test for USP XXII Water for Injection and Purified Water (approximately 0.1 ppm), 2) contemporary water system construction materials do not leach heavy metal contaminants, and 3) test results for this attribute have uniformly been negative; there has not been a confirmed occurrence of a singular test failure (failure of only the Heavy Metals test with all other attributes passing) since the current heavy metal drinking water standards have been in place. Total Solids and pH were the only tests not covered by conductivity testing. The test for Total Solids was considered redundant because the nonselective tests of conductivity and TOC could detect most chemical species other than silica, which could remain undetected in its colloidal form. Colloidal silica in Purified Water and Water for Injection is easily removed by most water pretreatment steps, and even if present in the water, it constitutes no medical or functional hazard except in extreme and rare situations. In such extreme situations, other attribute extremes are also likely to be detected. It is, however, the user's responsibility to ensure fitness for use. If silica is a significant component in the source water, and the purification unit operations could fail and selectively allow silica to be released into the finished water (in the absence of co-contaminants detectable by conductivity), then either silica-specific testing or a total-solids type testing should be utilized to monitor for and control this rare problem. The pH attribute was eventually recognized to be redundant to the conductivity test (which included pH as an aspect of the test and specification); therefore, pH was discontinued as a separate attribute test. |
8.4 Endotoxin Endotoxins are lipopolysaccharides found in and shed from the cell envelope that is external to the cell wall of Gram-negative bacteria. Some grades of pharmaceutical waters, such as those used in parenteral applications (e.g., Water for Injection, Water for Hemodialysis, and the sterilized packaged waters made from Water for Injection) strictly limit the amount of endotoxins that may be present because these compounds are pyrogenic. |
8.5 Test Methods Microbes in water systems can be detected as exampled in this section or by methods adapted from Microbial Enumeration Tests <61>, Tests for Specified Microorganisms <62>, or the current edition of Standard Methods for the Examination of Water and Wastewater by the American Public Health Association. This section describes classical culture approaches to bioburden testing, with a brief discussion on rapid microbiological methods. |
| ICH* | | Specifications: Test Procedures and Acceptance Criteria for Biotechnological /Biological Products 质量规格：生物技术/生物产品的检验程序和可接收标准 | | 2.3.3 Raw materials and excipient specifications 2.3.3 原材料和辅料的质量标准 The quality of the raw materials used in the production of the drug substance (or drug product) should meet standards, appropriate for their intended use. Biological raw materials or reagents may require careful evaluation to establish the presence or absence of deleterious endogenous or adventitious agents. Procedures which make use of affinity chromatography (for example, employing monoclonal antibodies), should be accompanied by appropriate measures to ensure that such process-related impurities or potential contaminants arising from their production and use do not compromise the quality and safety of the drug substance or drug product. Appropriate information pertaining to the antibody should be made available. The quality of the excipients used in the drug product formulation (and in some cases, in the drug substance), as well as the container/closure systems, should meet pharmacopoeial standards, where available and appropriate. Otherwise, suitable acceptance criteria should be established for the non-pharmacopoeial excipients. 用于原液或成品生产的原材料质量应符合与其用途相适应的标准。生物来源的原材料或试剂应认真检测其是否携带内源性或外源性有害因子。生产工艺采用亲和层析(如，采用了单克隆抗体)时，应有适宜的检测措施以保证在生产和应用时，这类工艺相关杂质或潜在的污染物不致影响原液或成品的质量和安全性。所用抗体有关资料亦应提供。 如已有药典标准并适用时，用于成品(有时原液)的辅料质量和容器/密闭系统应尽量符合药典标准。对药典没有收载的辅料亦应建立合适的认可标准。 |
| Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients原材料药GMP指南 | | 7.3 Sampling and Testing of Incoming Production Materials 7.3 进厂生产物料的取样和检测 7.30 At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below in 7.32. 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. 7.30 除了 7.32 条款中所描述的材料之外，其它任何一批材料都应当经过至少一项检测以定性。假如生产者有一套评价供应商的系统，供应商的检验报告可用来代替其余检测。 7.31 Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Full analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis. Reliability of Certificates of Analysis should be checked at regular intervals. 7.31 供应商的批准书应当包括一个能够提供足够证据的评估（如以往的质量记录），以确保生产商能持续提供符合质量标准的物料。在减少厂内检测项目之前应至少进行3 个批次的全检。尽管如此，作为最低要求，在适当的时间间隔应进行全检并将结果与供应商的检验报告比较。应定期检查检验报告的可靠性。 7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit 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. 7.32 对于工艺辅助材料、有害或高毒性原材料、其它特殊材料或者在公司质量控制范围内转移到其它部门的材料，如果已有其生产商提供的符合要求的检验报告，则可免作检测，这些材料的免检应得到论证并记录在案。对容器、标签和批号记录进行目测检查有助于鉴别这些物料。对这些物料不作现场测试应当说明理由，并记录在案。 |
Questions and Answers 问答部分 | | A ‘full analysis’ should include all tests specified by the user of the raw material in the regulatory filing. “全检”应包括原材料使用者在监管申报文件中指定的所有测试。 |
| FDA 21CFR* | | Testing and approval or rejection of components, drug product containers, and closures. | | (d) Samples shall be examined and tested as follows:样品应按下列要求进行检查和检验 (1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used. 制剂各组分均应至少做一个鉴别检验，如有特殊鉴别检验，应进行特殊鉴别检验。 (2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals. 每一个组分均应进行检验，确保达到相关纯度、规格和质量的书面质量标准。如果生产企业至少完成一个特殊鉴别检验，且定期验证供应商的检验结果，确定其分析具有可信度，则该供应商的组分检验报告可以替代生产企业的此类检验。 (3) Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier's test results at appropriate intervals. 制剂容器和密封件应进行检验，确保达到相关书面质量标准。如果生产企业对制剂容器/密封件至少做了一次目检，且定期验证供应商的检验结果，确定其分析具有可信度时，该供应商的检验证书可替代生产企业的此类检验。 |
| IND content and format IND内容及格式 | | (7) Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process. (7)化学、制造和控制信息。 (i) 适用于IND所涵盖的特定调查的一节，描述药物物质和药物制品的成分、制造和控制。虽然在调查的每个阶段都需要提交足够的信息，以确保研究药物的正确鉴定、质量、纯度和强度，但做出这一保证所需的信息量将随着调查阶段、调查的拟议持续时间、剂型和以其他方式获得的信息量的不同而有所不同。FDA认识到，随着研究的进展，可能会修改新药物物质和剂型的制备方法，并改变剂型本身。因此，在最初的第一阶段提交中，通常应该把重点放在原材料和新药物的鉴别和控制上。药物物质和药物产品的最终规格预计要到调查过程结束后才会公布。 |
| Applications For Fda Approval To Market A New Drug | | Specification is the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved NDA or ANDA to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product. For the purpose of this definition, acceptance criteria means numerical limits, ranges, or other criteria for the tests described. 质量标准是经批准的NDA或ANDA中提供的质量标准(即测试、分析程序和验收标准)，用于确认用于生产药品或药品的原液、成品、中间体、原材料、试剂、成分、过程物料、容器封闭系统和其他材料的质量。在本定义中，验收标准是指所述测试的数值界限、范围或其他标准。。 |
(d) Changes to be described in an annual report (minor changes). (1) Changes in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with § 314.81(b)(2). …… （Vii）The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved NDA, or deletion of an alternative analytical procedure; |
| General Biological Products Standards | | The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and as approved in the biologics license application or supplement for that product. 测试：除本节第(H)款规定的外，生物制品制造商必须酌情对每批生物制品的最终容器材料或其他材料进行无菌检测，并按照该产品的生物制品许可证申请或补充中批准的方式进行无菌检测。 |
| | | (a) Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. |
| FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs (2008)* | V. Recommended Cgmp For Phase 1 Investigational Drugs | D. Control of Components, and Containers and Closures | | The manufacturer should establish acceptance criteria for specified attributes on each material. For some materials, all relevant attributes or acceptance criteria may not be known at the phase 1 stage of product development. However, attributes and acceptance criteria selected for assessment should be based on scientific knowledge and experience for use in the specific phase 1 investigational drug. The material attributes and acceptance criteria will be reviewed in the IND application (Refs. 1 through 6). 生产单位应基于每种材料特性建立可接受标准。对于某些材料，在产品临床I期可能不知道物料与产品相关的所有属性或可接受标准。然而，选择用于评估的属性和验收标准应基于用于临床I期研究药物的科学知识和经验。 We recommend that you examine the certificate of analysis (COA) and/or other documentation on each lot of material to ensure that it meets established acceptance criteria for specified attributes. For some (e.g., human and animal derived material), documentation should include information on sourcing and/or test results for adventitious agents, as appropriate. If documentation for a material is incomplete for a specified attribute, we recommend that you test for the incomplete specified attribute of the material. For each batch of the API (or drug substance), you should perform confirmatory identity testing. 我们建议您检查每批材料的分析证书(COA)和/或其他文档，以确保其符合指定属性的既定验收标准。对于某些物质(例如，人和动物衍生材料)，文件应酌情包括关于外来物质来源和/或测试结果的信息。如果指定属性的材质文档不完整，我们建议您测试该材质的指定属性是否完整。对于每一批API(或原材料药)，都要进行鉴定测试。 |
| EU GMP* | Part I - Basic Requirements for Medicinal Products | Chapter 5 production —Starting materials | | 5.27 ……The level of supervision should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product. The supporting evidence for each supplier / material approval should be maintained. 监督水平应与每种物料呈现的风险一致，并考虑其来源、生产工艺、供应链复杂性和物料在药品中的最终用途。应当保留每个供应商/物料批准的支持性资料。 |
Chapter 5 production —Starting materials —Excipients | | 5.31 If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release. 如一次交付物料由不同批次构成，必须考虑按批分别取样、检验及放行 5.35 Manufacturers of finished products are responsible for any testing of starting materials2 as described in the marketing authorisation dossier. They can utilise partial or full test results from the approved starting material manufacturer but must, as a minimum, perform identification testing3 of each batch according to Annex 8. 药品生产企业有责任按照上市许可档案中所描述的对起始物料进行任何测试。其可利用源于已批准的起始物料生产企业的部分或全部测试结果，但是，至少，按照附录8进行每批鉴定测试。 |
Chapter 5 production —Packaging materials | | 5.45 The selection, qualification, approval and maintenance of suppliers of primary and printed packaging materials shall be accorded attention similar to that given to starting materials. 内包材和印字包材供应商的选择、确认、批准和维护应参照起始物料要求进行。 |
Part II - Basic Requirements for Active Substances used as Starting Materials | 7 Materials Management （内容同ICH Q7） | | 7.30 At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below in 7.32. 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. 7.31 ……Full analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis…… 7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit 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. |
| Manufacture of Sterile Medicinal Products 无菌产品（征求意见稿） | | 7.7 Water treatment plants and distribution systems should be designed, constructed and maintained to minimize the risk of microbial contamination and proliferation so as to ensure a reliable source of water of an appropriate quality. Water produced should comply with the current monograph of the relevant Pharmacopeia. 应设计、建造和维护制水站和分配系统，以尽可能减少微生物污染和扩散的风险，以确保有 一个适当标准的可靠供水源。制备的水应符合相关药典的现行专论。 7.13 To prevent the formation of biofilms, sterilization or disinfection or regeneration of water systems should be carried out according to a predetermined schedule and also when microbial counts exceed action and alert limits. Disinfection of a water system with chemicals should be followed by a validated rinsing procedure. Water should be analyzed after disinfection/regeneration; results should be approved before the start of use of the water system. 为防止形成生物膜，应按照预定的时间计划或是当微生物计数超过行动限和警戒限时，对水 系统进行灭菌、消毒或重新制备。采用化学试剂对水系统进行消毒应遵循经验证的冲洗规 程。水在消毒/重新制备后应进行分析；应在水系统开始使用之前批准结果。 7.14 A suitable sampling schedule should be in place to ensure that representative water samples are obtained for analysis on a regular basis. 应制定合适的取样计划以确保定期对有代表性的水样进行分析。 7.16 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity. WFI 系统应当包含持续监测系统，比如总有机碳 CTOC) 和电导率。 7.18 Steam used for sterilization processes should be of suitable quality and should not contain additives at a level which could cause contamination of product or equipment. The quality of steam used for sterilization of porous loads and for Steam-In-Place (SIP) should be assessed periodically against validated parameters. These parameters should include consideration of the following examples: non-condensable gases, dryness value (dryness fraction), superheat and steam condensate quality. 灭菌工艺用蒸汽应具备合适的质量，且不应含可能导致产品或使设备污染的添加剂。对多孔负载和在线蒸汽灭菌 (SIP)用蒸汽的质量应根据已验证参数进行定期评估。这些参数应当包括如下范例的考虑：不凝性气体、干燥度、过热值、蒸汽冷凝水质量。 |
| 7.19 Compressed gases that come in direct contact with the produc container primary surfaces should be of appropriate chemical, particulate and microbiological purity, free from oil with the correct dew point specification and, where applicable, comply with appropriate pharmacopoeial monographs. Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22µm) at the point of use. Where used for aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of the batch release process. 与产品/容器内表面直接接触的压缩气体应有具备合适的化学、颗粒和微生物负载，在露点规范下应无油并且在适当情况下应符合适当的药典各论。压缩气体在使用点必须通过除菌过滤器过滤（最大标称孔径为0.22µm) 。当用于无菌工艺时，最终灭菌气体过滤器完整 性的确认应作为批放行过程的一部分。 |
| Sampling of starting and packaging materials 起始物料及包装材料取样 | | 2. The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample…… 通常情况下，只有从所有容器中逐个抽取样品并进行鉴定测试，才能确保整批起始物料无误。 |
| Investigational Medicinal Products 临床试验用药品 | | 6. Specifications (for starting materials, primary packaging materials, intermediate, bulk products and finished products), manufacturing formulae and processing and packaging instructions should be as comprehensive as possible given the current state of knowledge. （起始物料、内包材、中间体、半成品及成品）质量标准，生产配方及工艺过程，包装指令应尽可能体现当前知识水平。 |
| 15. Specifications and quality control checks should include measures to guard against unintentional unblinding due to changes in appearance between different batches of packaging materials. 质量标准和质量控制检查中应包括防止由于不同批次包装材料之间的外观变化而造成的无意揭盲的措施。 |
| WHO GMP* | | | | 17.14 An identity test should be conducted on a sample from each container of starting material (see also section 14.14). It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. 应对每个起始材料容器中的样品进行鉴定试验（另见第14.14节）。允许仅对已建立验证程序的容器的一部分进行取样，以确保没有单个起始材料容器的标签错误。 |
| WHO good manufacturing practices for investigational products* | | | | 10.1. The consistency of the production of investigational products may be influenced by the quality of the starting materials. Their physical, chemical and, when appropriate, microbiological properties should therefore be defined, documented in their specifications, and controlled. 试验产品生产的一致性可能受到起始材料质量的影响。因此，应定义其物理、化学性质，并在适当情况下，将其记录在规范中，并加以控制。 10.2. Existing compendial standards, when available, should be used. 应使用现有的药典标准（如有）。 10.3. Specifications for active ingredients and excipients should be as comprehensive as possible, given the current state of knowledge. 鉴于目前的知识状况，活性成分和辅料的质量标准应尽可能全面。 |
| PDA | Technical Report No. 54-4 | Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations | | 3.1.6 Excipients All excipients used in biologic formulations should be considered functional and should be controlled as part of the controlled manufacturing process. These excipients should also be monitored by inpro-cess and release testing. For excipients that play important roles in maintaining critical product quality attributes, testing methods can be developed and implemented to permit in-process or release testing. This testing ensures that levels of the excipients are acceptable. The majority of excipient evaluations focus on a drug substance and formulation solutions used to gen-erate a drug product. Drug products that do not undergo any further formulation processing may not require additional excipient-related testing. Excipient testing should be performed if there are filtration steps, excipients are added to the formulation during the filling process, or drug products are compound-ed. A nonspecific method may be chosen for some excipients or for a collection of excipients used for a single purpose to indicate that the excipient has an acceptable concentration in the formulation. In-process testing can sometimes be performed in real time to allow for corrective actions as needed. |
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