Q7a

19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

19.24 Process and quality problems should be evaluated.

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.

19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

19.4 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.

19.41 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.

19.51 Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

19.23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对工艺和质量问题应当进行评估。

19.25临床实验用原料药的贴签应当有适当的控制，并将物料标明用于研究。

19.3 设备和设施

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 原料的控制

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有时，原料的适用性可以在使用前根据其在小规模反应（如使用测试）中的可接受程度而定，而不单凭分析测试。

19.5 生产

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。

61

Q7a

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.

19.61 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.

19.7 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.

19.8 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.

19.81 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.

19.82 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.

19.9 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.

19.91 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

19.6 验证

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 变更

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 实验室控制

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 文件

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。

62

Q7a

appropriately documented.

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.

20. Glossary

Acceptance Criteria

Numerical limits, ranges, or other suitable measures for acceptance of test results.

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.

API Starting Material

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.

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.

Batch Number (or Lot Number)

A unique combination of numbers, letters, and/or

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. 术语 认可标准

接收测试结果的数字限度、范围或其它合适的量度标准。

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。

原料药的起始物料 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。

批

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。

批号

用于标识一批的一个数字、字母和/或符号的唯

63

Q7a

symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

Bioburden

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.

Calibration

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

A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

Computerized System

A process or operation integrated with a computer system.

Contamination

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.

Contract Manufacturer

A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer.

Critical

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.

一组合，从中可确定生产和销售的历史。

生物负载

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。

校验

证明某个仪器或装置在一适当的量程范围内所测得的结果与一参照物，或可追溯的标准相比在规定限度内。

计算机系统

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。

计算机化系统

与计算机系统整合的一个工艺或操作。

污染

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。

协议制造商

代表原制造商进行部分制造的制造商。

关键的

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。

64