Provide a list of materials used in the manufacture of fermentation-derived drug substances, including:
提供用于发酵衍生原料药生产所用的物料清单，包括
l the microorganism
l 微生物
l cell bank system
l 细胞库系统
l media components
l 培养基成份
l solvents
l 溶剂
l reagents and auxiliary materials
l 试剂和辅助物料
l information on quality and control of materials.
l 物料的质量和检测资料
Microorganism 微生物
Provide information about the microorganism used for production (genus, species and type strain) and its known genotypic and phenotypic characteristics.
提供用于生产（种属和菌种类型）的微生物资料，和其已知基因型和表型特性资料。
Identify or describe the origin of the source material (or isolate), including methods used to improve the strain.
识别和描述源物料的来源（或分离），包括用于复壮菌种的方法。
Cell bank system – master cell bank 细胞库系统---母细胞库
Provide a brief description of the procedures used to generate the MCB and the criteria used for qualification, including:
提交用于产生MCB的方法和用于确认母细胞符合标准的简要描述，包括
l methods, reagents and media used in preparation
l 方法、试剂和制备中使用的培养基
l date of preparation
l 制备日期
l ?process controls
l 工艺控制
l storage conditions
l 存贮条件
l procedures used in testing for relevant phenotypic and genotypic markers, and determining culture purity
l 用于测试相关表型和基因型及测试培养物纯度的方法
l procedures used to ensure the absence of contamination with adventitious agents (e.g. microbial contamination and cross-contamination by other cell types), with tests and acceptance criteria specified.
l 用于保证无外源性试剂污染的程序（例如，微生物污染和被另一类型细胞交叉污染），检测方法和指定的可接受标准。
Cell bank system – working cell bank 细胞库系统---工作细胞库
Preservation of the microbial purity of the MCB is an important factor in maintaining the production strain, and a WCB can be created to lower the likelihood of the MCB being compromised.
MCB微生物纯度的维护是保持生产用菌种的重要因素，可以建立一个WCB以降低MCB变差的可能性。
A WCB is created by propagating the MCB through defined culture conditions, and then keeping aliquots of the resultant homogeneous culture suspension in individual storage containers of an appropriate size for routine production purposes.
WCB是在指定的培养条件下对MCB进行培养得到的，培养物保存在均匀混悬液中，放入适当规格的单个存贮容器中用于日常生产。
l Provide a brief description of the procedures used to derive a WCB from the MCB and the criteria used for qualification.
l 提交从MCB制备WCB的程序及用于确认的标准简述
l Submit information similar to that submitted for the MCB for the WCB.
l 提交与MCB类似的关于WCB的资料
Media components 培养基成分
l Provide a list of the media components used at each stage of the fermentation process.
l 提供发酵工艺各步骤所用培养基的成分清单
l Provide the specifications for each component that are used to verify that the material is of suitable quality for its intended use.
l 提供确认成分中各物料符合其用途的质量标准
l Describe the identity and source of any animal-derived materials used in the fermentation media, and how the risk of transmission of transmissible spongiform encephalopathies (TSEs) is controlled.
l 描述所有发酵培养基中动物来源物料的鉴别和来源，以及控制其TSE风险的方法
Solvents, reagents and auxiliary materials 溶剂、试剂和辅助物料
l Provide a list of solvents, reagents, and other auxiliary materials used in the fermentation process.
l 提供所有用于发酵工艺的溶剂、试剂和其它辅助物料的清单
l Include the specifications for each material that are used to verify that the material is of suitable quality for its intended purpose (including water).
l 包括用于确认物料适合其用途的质量标准（包括水）
11.4.4.4 Control of critical steps and intermediates 关键步骤和中间体的控制
Controls are essential during the fermentation process to ensure consistency of the drug substance.
在发酵工艺中必须进行控制以保证药用物质的一致性。
l Identify and justify all critical process controls and their associated numeric ranges, limits or acceptance criteria.
l 识别并论述所有关键工艺控制及其数字化的范围、限度或可接受标准。
l Include a brief description of the test. Include experimental data to support the justification.
l 包括对测试的简要描述，包括支持论述的实验数据。
The manufacturing processes should be controlled to ensure that the drug substance meets previously identified quality attributes.
生产工艺应受到控制，以保证药用物质符合既定的质量属性。
l Identify all controls used in determining an isolated intermediate's acceptability for downstream processing.
l 识别所有用于被分离中间体的控制，以使其达到可接受标准，可以用于后续工艺。
Note 注 When the intermediate represents the end of the fermentation process and the beginning of a synthetic scheme, the controls warranted are generally more extensive than those used for other types of intermediates. 如果中间体代表发酵工艺结束，合成过程开始，则这些控制保证一般不会比那些用于其它类型中间体的控制要求更高。 |
11.4.4.5 Noncritical in-process controls 非关键中控
Identify and describe noncritical in-process controls. 识别并描述非关键中控项。
Note 注 These controls may not directly demonstrate that a process produces a quality product; however, a description of the tests being conducted and why they are not critical demonstrates understanding of the process. 这些可能不能直接证明工艺可以生产出一定质量的产品，但是，对所进行检测的描述及为什么它们不关键证明了生产商对自己工艺的理解。 |
11.4.4.6 Process validation and/or evaluation 工艺验证和/或评估
When a fermentation-derived drug substance is sterilised:
如果对发酵衍生药用物质进行灭菌，则：
l provide the process validation information and data in support of the sterilisation process(es) as per sterile drug substances.
l 提供工艺验证资料和数据，以支持无菌药用物质的灭菌工艺
Note 注 Non sterile process validation is conducted before commercial marketing. 非无菌工艺验证要在商业销售前完成。 |
11.4.4.7 Characterisation 特性描述
Provide confirmation of the structure and characterisation data for fermentation-derived drug substances.
提交对发酵衍生原料药的结构确认和特性数据。
Note 注 If the fermentation product is a mixture of active components, it may be appropriate to isolate and purify individual components for structural analysis and characterisation. 如果发酵产品是活性成分的混合物，可能不能将单个成分进行分离和纯化进行结构分析和定性。 |
Structural characterisation 结构确证
l Provide structural confirmation using physical and chemical techniques (e.g. elemental analysis, mass spectrometry, infrared spectroscopy) for the intermediate or drug substance.
l 提交采用物理和化学技术（例如，元素分析、质谱、红外光谱）对中间体或原料药所做的结构确认资料
l Include the data and details of its interpretation.
l 包括数据和详细的解析资料
Note 注 The extent of data needed to confirm the structure can vary, depending on the complexity of the molecule. 对结构进行确认的要求程度可能会由于分子的复杂性不同而不同。 |
Physicochemical characterisation 理化特性
The type and extent of the physicochemical characterisation information that should be provided depends on:
要提交的理化特性资料类型和程度取决于：
l the type of drug substance (e.g. semisynthetic molecule, protein)
l 原料药类型（例如，半合成分子、蛋白质）
l the type of dosage form in which the drug substance will be used
l 原料药将要用于生产的剂型
l the ability or tendency of the drug substance to occur in one or more solid-state forms
l 原料药形成一个或多个固体形态的能力或趋势
l the importance of differences in the physical characteristics of the different forms to the stability, dissolution or bioavailability of the drug product.
l 不同形态的物理特性差异对制剂的稳定性、溶出度或生物利用度的重要性
Biological activity 生物活性
When a biological assay (e.g. antimicrobial activity for antibiotics) is used to assess the potency or strength of the intermediate or drug substance:
如果采用了生物效价含量（例如抗生素的抗微生物活性）来评估中间体或原料药的效价或剂量：
l provide the biological activity data to complete the characterisation profile.
l 提交生物活性数据，将特性概况描述完整
l provide data on the reference standard lot or other relevant lots to demonstrate the potency/strength of the intermediate, drug substance or drug product.
l 提交对照品批的数据，或其它相关批的数据，证明中间体、原料药或制剂的效价/剂量。
In some cases, the product of fermentation is a complex mixture of major and minor components that together make up a product's biological activity.
在有些情况下，发酵产品是主要成分和次要成分在一起的复杂混合物，它们一起形成一个产品的生物活性。
When evaluating the impurity profile for these fermentation products, try to identify and characterise the active components (major and minor) that contribute to the product's overall potency and distinguish them from impurities. This may not be practical or feasible in all cases.
在对这些发酵产品的杂质概况进行评估时，要尽力将对产品总体效价做出贡献的活性成分进行定性（主要的和次要的），将它们从杂质中识别出来。这种要求可能在有些情况下不实际，无法实现。
Impurities 杂质
Provide information about impurities in the fermentation-derived drug substance, such as:
提交关于发酵衍生原料药的杂质资料，如：
l organic impurities
l 有机杂质
l inorganic impurities
l 无机杂质
l residual solvents.
l 残留溶剂
Impurities may be either: 杂质一般是：
l derived from the manufacturing process (e.g. residual media components, protein and nucleic acids from microbial cells, processing reagents, inorganic salts, filter aids, solvents)
l 在生产工艺（例如残留培养基成分、微生物细胞蛋白和核酸、工艺试剂、无机盐、助滤剂、溶剂）中产生的物质
l structurally related to the desired fermentation product but not share the same properties with respect to biological activity, efficacy and safety (e.g. other microbial metabolites, precursors, byproducts).
l 与目标发酵产物结构相关，但在生物活性、效价和安全性方面具有不同特性（例如，其它微生物代谢产物、前体、副产物）的物质
Process-related impurities derived from fermentation and downstream processing should be minimised through the use of a well-controlled and reproducible manufacturing process.
在发酵过程中和后续加工过程中产生的工艺相关杂质应通过采用控制良好且可重复的生产工艺来降到最低。
Structurally related impurities should be identified, tracked and controlled throughout the fermentation, isolation and purification processes.
结构相关杂质应在整个发酵、分离和纯化工艺中进行识别、追踪和控制。
Provide a summary of the impurities that are most likely to arise during:
提交在以下过程中最可能产生的杂质总结：
l fermentation
l 发酵
l isolation
l 分离
l purification and storage (e.g. holding time) of the intermediate and the drug substance
l 中间体和药用物质的精制和存贮（例如，存贮时间）
Include: 包括
l impurity profiles (i.e. chromatograms)
l 杂质概况（例如，色谱图）
l test results from representative batches
l 代表性批次的检测结果
l results from forced degradation studies used to identify the potential impurities that may arise during storage.
l 用于鉴别存贮期间会生成的潜在杂质的强降解研究的结果
For impurities of known structure, partially characterised or unidentified:
对于已知结构的杂质、结构部分确定或未鉴别的杂质：
l summarise any studies carried out to characterise the structure of impurities.
l 总结所有对杂质结构特性所做的研究工作
l include documentation to show that the analytical procedures used in quantifying impurities are properly validated or qualified.
l 放入文件记录以显示所用的定量杂质用的检测程序已经过适当验证或确认
For specifications for fermentation-derived intermediates, drug substances or medicines include:
对于发酵衍生的中间体、药用物质或制剂质量标准，应包括
l limits for organic impurities
l 有机杂质的限度
l inorganic impurities
l 无机杂质
l residual solvents.
l 残留溶剂
Present a rationale for the inclusion or exclusion of impurities in the specifications. As appropriate, this rationale should include a discussion of the impurity profiles observed in batches used for clinical, safety and stability testing, as well as batches representative of the proposed commercial process.
提交在质量标准中包括或不包括杂质的理由。适当时，该理由中应包括对临床批次、安全和稳定性测试批次以及代表拟定的商业化工艺批次中观察到的杂质概况的讨论。
For complex fermentation products 对于复杂的发酵产品
For complex fermentation products that are not well characterised in terms of structure, physicochemical properties, biological activity and purity, the levels for organic impurities should be determined on a case-by-case basis.
对于结构、理化特性、生物活性和纯度未经确证的复杂发酵产品，有机杂质的水平要各案确定。
The acceptable levels for organic impurities 有机杂质可接受标准
The acceptable levels for organic impurities will depend on how the fermentation product is to be used.
有机杂质的可接受标准取决于发酵产品的使用方法。
The levels will likely be less stringent for a drug substance or an intermediate that will be subjected to further modification and/or purification than for a drug product that does not undergo further processing.
如果原料药或中间体会经进后续修饰和/精制，则其杂质水平可以不需要象没有后续加工的原料药那么严格。
For most fermentation products (e.g. antibiotics) 大多数发酵产品（例如，抗生素）
The purification and downstream processing is expected to effectively remove process-related impurities, such as:
纯化和后续处理应能有效去除与工艺有关的杂质，例如：
l residual media components
l 培养基成分残留
l residual protein and nucleic acid derived from microbial cells
l 从微生物细胞产生的蛋白和核酸残留
l other processing reagents.
l 其它工艺用试剂
Therefore, in most cases, limits do not need to be included in the specifications for these impurities.
因此，在大多数情况下，这些杂质的限度不需要放入质量标准中。
However, when studies suggest that process-related impurities are not effectively removed during the purification process, these impurities should be controlled with limits in the specifications, as appropriate.
但是，如果研究表明工艺相关的杂质在精制过程中不能被有效去除，则需要时，这些杂质应在质量标准中采用适当的限度进行控制。
Note 注 Microbial impurity tests (e.g. for endotoxins) for medicines may be required. 可能需要对药品进行微生物杂质检测（例如，内毒素）。 |
Degradation products 降解物
Summarise details of the degradation products observed during stability studies of the drug substance or drug product, including:
总结在原料药或制剂的稳定性试验中观察到的降解产物的详细资料
l product-related impurities arising from degradation of the drug substance, and reaction products of the drug substance with an excipient and/or a component of the container/closure system
l 原料药降解中产生的有关物质，原料药与辅料和/或包材反应产生的杂质
l test results from representative batches and results from forced degradation studies on the drug substance or product
l 原料药或制剂具有代表性批次的检测结果，以及强降解试验的结果
l studies done to characterise the structure of the degradation products.
l 对降解产物结构所做的定性研究
Provide documentation to show that analytical procedures used in quantifying degradation products are properly validated or qualified.
提交资料证明用于降解产物定量检测的分析方法经过适当验证或确认。
Include limits for degradation products that are expected to occur under recommended storage conditions in the specifications for the drug substance or drug product.
在原料药或制剂的质量标准中包括在推荐的存贮条件下会产生的降解产物的限度。
Provide a rationale for excluding a degradation product from the specifications.
提交质量标准中不包括降解产物的理由。
11.4.4.8 Control of intermediates and drug substances 中间体和原料药的控制
Specifications 质量标准
Provide the proposed specifications for the fermentation-derived intermediate, drug substance or drug product, including:
提交发酵衍生中间体、原料药或制剂的拟定质量标准，包括：
l the tests that will be performed on each batch
l 每批所要进行的检测项目
l a reference to the analytical procedure used in performing the test
l 检验所用方法依据
l the acceptance criteria for each test.
l 各测试项目的可接受标准
Focus the specifications on those characteristics found to be useful in ensuring the safety and efficacy of the intermediate or drug substance.
质量标准应关注已知在在保证中间体或原料药安全有效性方面有用的特性。
Provide a justification for the proposed specifications for the intermediate, drug substance and drug product.
提交对拟定中间体、原料药和制剂的质量标准的论述。
For some fermentation-derived drug substances, a nonspecific bioassay (e.g. microbiological assays for antibiotics) may be proposed to determine the content of the drug substance.
对于有些发酵衍生原料药，可以用非专属性的生物含量（例如，抗生素的微生物含量）来检测原料药的含量。
In these cases, the development of a specific, stability-indicating assay (e.g. high-performance liquid chromatography [HPLC]) is encouraged because it offers considerable advantages in terms of separation of components, accuracy and precision.
在这种情况下，鼓励开发具有专属性和稳定指示性的含量方法（例如，HPLC），因为它在成分的分离、精密度和准确度方面具有很大的优势。
Analytical procedures 分析方法
Provide copies of the analytical procedures used in testing the fermentation-derived intermediate, drug substance or drug product.
提供用于发酵衍生中间体、药用物质或制剂的分析方法的复印件。
Use specific citations when the analytical procedure is from an official compendium and is not modified in any way.
如果分析方法来自于正式的药典，未做任何修订则进行引用。
Validation of analytical procedures 分析方法的验证
Provide validation data for the analytical procedures used in testing the fermentation-derived intermediate, drug substance or drug product.
提供用于发酵衍生中间体、药用物质或制剂的分析方法的验证数据。
Reference standards or materials 对照品或标准物质
Provide information about reference standards or reference materials used for testing.
提交用于检测的对照品或标准物质的资料。
Relevant information includes: 相关资料包括
l characterisation
l 鉴定
l storage conditions
l 存贮条件
l working solutions
l 工作溶液
l stability of the reference standard.
l 对照品的稳定性
Batch analyses 批分析
Provide batch analysis data, using the proposed analytical procedures and specifications, for:
提供以下批次的批分析数据，采用拟定的分析方法和质量标准
l all relevant batches of the drug substance (pharmacology and/or toxicology)
l 所有相关的药用物质批次（药学和/或毒性）
l clinical batches for safety and efficacy
l 安全和有效性临床试验批次
l bioavailability/bioequivalence batches
l 生物等效性批次
l stability batches
l 稳定性批次
l batches representative of the proposed commercial process.
l 代表拟定的商业化工艺的批次
11.4.4.9 Container/closure system 容器/密闭系统
l Describe the container/closure system for fermentation-derived intermediates, drug substances and drug products, as well as the storage containers for the MCB and WCB.
l 描述发酵衍生中间体、原料药和制剂的容器/密闭系统，以及MCB和WCB存贮用容器
l Identify the supplier of each component (except for MCB and WCB containers).
l 标明每个组件的供应商（除MCB和WCB容器外）
l Provide letters of access to master files for raw material component manufacturing.
l 提交一份原料组件生产主文件的授权信
l Include schematics and raw material specification sheets for the components.
l 包括组件所用原料的质量标准清单和图表
l Include information to support processes for components that are irradiated, pre-sterilised by other means or pre-washed.
l 包括用于支持经过辐射照射、经其它方式预先灭菌或预清洗的组件工艺的资料
11.4.4.10 Labelling 标签
Provide copies of primary and secondary packaging labels for:
提交以下产品的内包装和外包装标签复印件：
l fermentation-derived intermediates (for resale)
l 发酵衍生中间体（转售）
l drug substances
l 药用物质
l medicines.
l 制剂
Include the following information on the label for intermediates and drug substances:
中间体和原料药标签应包括以下信息：
l name of the chemical entity
l 化学实体的名称
l number of units or micrograms of activity per milligram when activity is expressed in biological terms
l 如果活性采用生物术语来表示，以每毫克数量表示的活性单位或微生物数量
l number of grams or kilograms in the immediate container
l 中间体容器
l batch or lot number
l 批号
l statement 'Sterile' or 'Nonsterile'
l “无菌”或“非无菌”申明
l expiration or retest date, as supported by appropriate stability studies
l 有效期或复验期，由适当稳定数据支持
l storage conditions.
l 存贮条件
11.4.4.11 Stability summary and conclusions 稳定性试验总结和结论
Provide information relating to the stability of the fermentation-derived drug substance.
提交与发酵衍生原料药稳定性试验相关的资料。
For intermediates 对于中间体
l the recommendations for stability are applicable to intermediates intended for resale, but generally not otherwise.
l 稳定性方面的推荐适用于销售用的中间体，但其它情况下一般并不需要。
Provide a summary of the types of:
提交以下内容的总结：
l studies conducted
l 所实施的稳定性研究内容
l protocols used
l 使用的方案
l results from the studies for fermentation-derived intermediates, drug substances and medicines.
l 发酵衍生中间体、杂质和制剂的稳定性研究的结果
For intermediates and drug substances 对于中间体和原料药
Provide conclusions regarding appropriate storage conditions and an appropriate retest or expiration date.
提交在适当存贮条件下，适当复验期或有效期的结论。
Batch selection for stability studies for fermentation–derived substances 发酵衍生物质用于稳定性研究的批次选择
Studies should be conducted on three separate batches (if feasible, generated from three different WCB vials).
要对3个独立批次实施研究（如果可行，一般来自3个不同WCB瓶）。
The batches can be pilot scale; however, the manufacturing process for the pilot-scale batches should fully represent and simulate the proposed full-scale production process.
稳定性试验用批次可以是中试批量的，但是，中试规模的生产工艺要能完全代表并模拟拟定的全规模生产工艺。
Expiration date or retest date 有效期或复验期
For fermentation-derived drug substances 对于发酵衍生原料药
A retest period or date may be appropriate in cases where the drug substance shows little change in potency and/or degradation products throughout the proposed shelf life.
如果原料药显示出在拟定的货架期内效价和/或降解物变化很小，则可以适用制订复验期。
Use an expiration date if there is a marked change or trend in the potency and/or degradation profile, such that there is a concern that an out-of-specification test result could occur during stability studies.
如果产品效价和/或降解产物概况呈现显著的变更或趋势，在稳定性研究中可能会发生超出质量标准的结果，则应采用有效期。
Expiration date 有效期
When an expiration date is assigned to a fermentation-derived intermediate or drug substance, the material is not to be used beyond that date and is to be discarded if that date has passed.
如果一个发酵衍生中间体或原料药被赋予了有效期，则在超出有效期后，该物料不能再使用，必须丢弃。
Retest date 复验期
A retest date is a date before which the material meets all applicable specifications.
复验期是指在该日期前，物料符合所有适用标准。
Beyond that date, the material may be retested and, if acceptable, used within a reasonable amount of time (e.g. within 30 days).
超出复验期后，可以对物料进行复测，如果结果可以接受，则在一个合理的时间段时可以使用（例如，在30天内）。
The retest date should include the test attributes that are critical to the fermentation-derived intermediate or drug substance (e.g. potency, moisture content).
复验期应包括发酵衍生中间体或原料药（例如，效价、水分）关键的检测项目。
Expiration dates and retest dates should both be established based on supportive stability data.
复验期和有效期均应建立在具有支持性的稳定性试验数据上。
For fermentation-derived medicines 对于发酵衍生药品
l An expiration date should be established based on supportive stability data.
l 应基于支持性的稳定性试验数据建立有效期
l Retest dates are not appropriate for fermentation-derived medicines.
l 发酵衍生药品不适用复验期
11.5 When to include a certificate of suitability in an application 在申报中包括CEP
A CEP may be submitted instead of a DMF:
可以提交CEP来代替DMF
l for a Category 1 application to register a new prescription medicine.
l 对于1类申报，申请注册新的处方药
l for a request to make a variation to include an additional site of drug substance manufacture.
l 变更申报，要求包括原料药生产商的新增场所
l when a drug substance manufacturer ceases the operation of a DMF and refers to a CEP instead.
l 原料药生产商停止DMF操作，转而引用CEP
For ingredients of animal or human origin 动物或人来源成分
A CEP does not contain sufficient information and will not alone be accepted.
由于CEP中包括的信息不充分，因此仅提交CEP是不会被接受的。
Related information and guidance 有关资料和指南 l Therapeutic goods that contain or are produced from human blood or plasma l 含有或由人用血液或血清制备的治疗用品 l Adventitious agent safety of medicines l 药品中外源性试剂安全性 |
11.6 How to include a certificate of suitability in an application 如何在申报中包括CEP
Sponsors need the written permission of the drug substance manufacturer to refer to a CEP in an application.
申请人需要原料药生产商出具允许引用CEP的书面申明，并放入申报资料中。
A proforma for a Letter of Access (available in Module 1.6.3 of the CTD) from the drug substance manufacturer, addressed to the TGA and indicating clearly the product sponsor to which it applies, should be sent directly to the TGA, either with the CEP or separately.
原料药生产商要将给TGA的授权信，在其中清楚说明授权给谁给哪个产品，与CEP一起或分别提交给TGA。
Note 注 The proforma for Letters of Access used in Europe is not acceptable. TGA不接受欧洲格式的授权信。 |
11.7 Sponsor's obligations regarding certificates of suitability 申请人在CEP方面的责任
Sponsors: 申请人
l have an obligation under the standard conditions of registration, imposed under s. 28(3) of the Act, to ensure that no changes are made to the product, including the drug substance, without the sponsor's knowledge and TGA approval (if required).
l 在由法案赋予的标准注册条件下，保证所有变更，包括对原料药的变更，在变更前均要通知申请人，并在必要时获得TGA的批准
l need a formal agreement with the manufacturer of the drug substance to ensure they are notified before any changes are made to the drug substance.
l 需要与原料药生产商有正式协议，以保证对原料药做出任何变更前都会被通知
l are required to seek approval for any changes made to the drug substance after the CEP has been issued.
l 在CEP签发后，要将原料药的所有变更提交批准
Note 注 Amendments to the CEP that are allowed by the EDQM are not automatically accepted in Australia. An amended CEP can be submitted in support of a request to make a variation to an Australian Register of Therapeutic Goods (ARTG) entry. 澳大利亚不会自动接受EDQM允许的CEP增补。增补后的CEP可以提交给TGA以支持对ATRG的变更。 |
Related information and guidance 有关资料和指南 l Minor variations to registered prescription medicines: Chemical entities l 已注册处方药的轻微变更：化学实体 |
11.8 Additional information regarding certificates of suitability for some drug substances 某些CEP原料药要提交的额外资料
Further information is required by the TGA for the following types of drug substances.
TGA对以下类型原料药要求的额外资料。
11.8.1 Nonsterile drug substances 非无菌原料药
Sponsors provide: 申请人要提交
l written authorisation from the drug substance manufacturer in the form of a Letter of Access (available in Module 1.6.3 of the CTD) for the TGA to refer to the CEP.
l 原料药生产商采用TGA引用CEP的格式（在CTD模块1.6.3中）制作的书面授权信
l written assurance that no significant changes have been made to the manufacturing method since the CEP (or its last revision) was issued by the EDQM, including to the scale of the final purification step.
l 书面保证在EDQM签发CEP后（或从上次修订后），生产方法无重大变更，包括纯化步骤的批量
l written assurance that the drug substance complies with all conditions and additional tests attached to the CEP by the EDQM.
l 书面保证原料药符合EDQM附录于CEP的所有条件和附加测试项目
l written assurance that for currently registered drug products, any tests and limits required by the TGA in addition to those in the Ph. Eur. monograph (e.g. particle size distribution, specific polymorphic form) that are relevant to the intended use of the substance will be applied to each batch of the drug substance that is destined for the Australian market.
l 书面保证对于正在注册的原料药，如果目的地是澳大利亚市场，会每批检测TGA所要求的EP各论以外，与原料药用途有关的项目和限度（例如，粒径分布、特定晶型），
l certificates of analysis (or equivalent analytical data) for at least three production-scale batches demonstrating that the drug substance complies with the monograph, any additional tests or limits attached to the CEP and, for currently registered drug products, any agreed additional tests or limits for the drug substance.
l 证明原料药符合各论的至少3批生产规模批次的检验报告书，附录于CEP的所有附加测测或限度；对于目前已注册的原料药，原料药所有经同意的附加测试或限度
l the chemical structures of the impurities if the CEP refers to impurities as a code number.
l 如果在CEP中，列出杂质是一个代码，则需要杂质的化学结构式
l a list of the changes between the previously approved version of the DMF or CEP and the current version of the CEP for an updated CEP or for a change from a DMF to a CEP.
l 之前批准的DMF或CEP与现行版本之间的变更清单，或从DMF到CEP之间的变更清单
Note 注 If this information is confidential from the sponsor, the TGA may obtain this information from the CEP holder. 如果这些资料对于申请人是保密的，则TGA可能需要从CEP持有人那里获得这些资料。 |
11.8.2 Sterile drug substances 无菌原料药
In addition to the nonsterile drug substances requirements listed above, a CEP is not sufficient for the TGA to assess the quality of a sterile drug substance (and/or excipients) that does not undergo further processing. Information regarding sterile manufacture, as specified in What to include in a Drug Master File for sterile drug substances, must be provided, but a full DMF is not required.
对于后期没有进一步处理的无菌原料药（和/或辅料），除了上述非无菌原料药所需资料外，在TGA评估时，仅CEP是不够的，无菌原料药生产商必须提交“无菌原料药DMF中应包括的内容”所述的资料，但不需要提交整个DMF文件。
11.9 Other information that may be requested by the TGA in relation to certificates of suitability TGA可能需要的与CEP有关的附加资料
The TGA may request:
TGA可能需要：
l additional information about the manufacture and quality control of the drug substance
l 关于原料药生产和质量控制的附加资料
l additional information about how the impurity limits specified in the CEP have been justified by the manufacturer and assessed by the EDQM
l CEP中列明的杂质限度方面生产商的论述和EDQM的评估的附加资料
l copies of the EDQM evaluation report parts A and B and any related correspondence between the manufacturer and the EDQM
l EDQM评估报告A和B部分复件，生产商和EDQM之间的所有通信内容
l validation data for use of the drug substance in the drug product, where relevant.
l 必要时，提交药品中使用原料药的验证数据
Therapeutic Goods Administration |
PO Box 100 Woden ACT 2606 Australia http://www.tga.gov.au |
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发表于 2014-10-15 15:56:17
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