近日，FDA发布了《21 CFR 211.110 的合规性考虑 草案》（21CFR 211：即药品CGMP条款，21 CFR 211.110款内容为中间产品及药品的取样），其中描述了FDA当前对符合 CGMP法规中中间产品及药品取样要求的考虑，以确保批次一致性和药品完整性。此外，该指南还讨论了使用先进制造技术制造的药品的相关质量考虑。还讨论了制造商如何将过程模型整合到商业制造控制策略中。

I.  INTRODUCTION

介绍

This guidance, when finalized, will describe considerations for complying with the requirements in 21 CFR 211.110 to ensure batch uniformity and drug product integrity. In addition, this guidance discusses related quality considerations for drug products that are manufactured using advanced manufacturing. It also discusses how manufacturers can incorporate process models into commercial manufacturing control strategies.2,3

本指南最终确定后，将描述遵守 21 CFR 211.110 中要求的注意事项，以确保批次一致性和药品完整性。此外，本指南还讨论了使用先进制造技术制造的药品的相关质量考虑。还讨论了制造商如何将过程模型整合到商业制造控制策略中2,3。

This guidance appliesto the manufacture of human drug products,including biological products, and animal drug products;these will be collectively referredto as drug products in this guidance. This guidance does not apply to the manufacture of active ingredients.

本指南适用于人用药品（包括生物制品）和动物药品的制造;在本指南中，这些商品统称为药品。本指南不适用于活性成分的制造。

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describethe Agency’s currentthinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

一般来说，FDA 的指导文件没有规定法律上可执行的责任。相反，指南描述了FDA当前对某个主题的看法，除非引用了特定的监管或法定要求，否则应仅将其视为建议。在机构指南中使用 should 一词表示建议或推荐某事，但不是必需的。

II. BACKGROUND

背景

To ensure batch uniformity and drug product integrity, the current good manufacturing practice (CGMP) regulations4 require, among other things, that manufacturing processes are designed and controlled to ensure that in-process materials consistently and reliably meet predetermined quality requirements.5This guidance explains the requirements for drug product manufacturing in § 211.110. This guidance also describes considerations for the use of advanced manufacturing (e.g., 3D printing, continuous manufacturing)6and the use of process models as a part of commercial manufacturing control strategies. FDA supports the adoption of advanced manufacturing as a foundation for improving the overall qualityand availability of drug products for patients.

为确保批次一致性和药品完整性，现行药品生产质量管理规范 （CGMP） 法规要求设计和控制制造过程，以确保中间产品始终如一地可靠地满足预定的质量要求。本指南解释了 § 211.110 中的药品生产要求。本指南还描述了使用先进制造（例如 3D 打印、连续制造）6 的注意事项，以及将工艺模型用作商业制造控制策略的一部分。FDA 支持采用先进制造作为提高患者药品整体质量和可用性的基础。

Advanced manufacturing is a term for an innovative pharmaceutical manufacturing technology or approach that has the potential to improve the reliability and robustness of the manufacturing process and supply chain and increase timely access to quality medicines for the American public. Advanced manufacturing can integrate novel technological approaches, use established techniques in an innovative way, or apply production methodsin a new domain wherethere may be limited experience or no defined best practices. Advanced manufacturing can potentially be used for new or currently marketed large or small molecule drugs.7

先进制造是指一种创新的制药技术或方法，该技术或方法有可能提高制造过程和供应链的可靠性和稳健性，并增加公众及时获得优质药物的机会。先进制造可以整合新的技术方法，以创新的方式使用现有技术，或将生产方法应用于经验可能有限或没有明确最佳实践的新领域。先进制造技术可能用于新的或目前上市的大分子或小分子药物。

All manufacturers, regardless of whetherthey are using advanced manufacturing, should apply a scientific- and risk-based approach to controlling processes and ensuring drug product quality.

所有制造商，无论是否使用先进制造，都应采用基于科学和风险的方法来控制工艺并确保药品质量。

This approach should be based on robust product and process understanding. Manufacturers must maintainthe process in a state of controlover the life of the process to ensure drug product quality, even as materials, equipment, production environment, personnel, and manufacturing procedures change.8Planning and executing a system that monitors process performance and drug product quality helps ensure that a state of control is maintained. An effective monitoring system helps maintain a state of control in multiple ways, which include helping manufacturers:

这种方法应基于对产品和工艺的深刻理解。制造商必须在工艺的整个生命周期内保持工艺处于受控状态，以确保药品质量，即使物料、设备、生产环境、人员和制造程序发生变更。规划和执行监控工艺性能和药品质量的系统有助于确保保持控制状态。有效的监控系统以多种方式帮助保持控制状态，其中包括帮助制造商：

(1) ensure that processes and controls are continuously capable of producing a drug product of desired quality; and (2) identify areas for continual improvement.9 In addition, § 211.110(a) requires that manufacturers establish and follow writtenprocedures “that describethe in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch.” Section 211.110(c) also requires that in-process materials are “tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit,during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.”

确保工艺和控制能够持续生产出所需质量的药品;以及 （2） 确定需要持续改进的领域。此外，§ 211.110（a） 要求制造商建立并遵循书面程序，“描述对每批中间产品的适当样品进行的过程控制、测试或检查”。第 211.110（c） 节还要求中间产品“在生产过程中（例如，在重要阶段开始或完成或长期储存后）经过适当的特性、强度、质量和纯度测试，并由质量控制单位批准或拒绝。

III.  GENERAL CONSIDERATIONS FOR IN-PROCESS SAMPLING AND TESTING

过程中（中控）取样和检测的一般考虑

Under section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, a drug is deemedto be adulterated if it is not produced in accordance with CGMP. The CGMP regulations for drug products are in 21 CFR parts 210 and 211, and FDA monitors drug product manufacturers' compliance with these regulations.10The CGMP regulations contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, packing, and holding of drug products. The CGMP regulations also provide flexibility for manufacturers to use better, more efficient methods to meet CGMP requirements because these innovative methods benefit patients.11The determination of whether in-process controls, and tests, or examinations meet the regulatory requirements in § 211.110 primarily depends on the nature of the drug product (e.g., dosage form) and the type of process used by the manufacturer. Knowledge and understanding that manufacturers gain from robust product and process development are an important basis for establishing and maintaining control strategies throughout the lifecycle of a drug product. This helps ensure that drug products have the required quality attributes.12

根据FDC法第 501（a）（2）（B） 条，如果药品未按照 CGMP 生产，则视为掺假。药品的 CGMP 法规载于 21 CFR 第 210 和 211 部分，FDA 负责监督药品制造商对这些法规的遵守情况。CGMP 法规包含对药品制造、加工、包装和储存中使用的方法、设施和控制措施的最低要求。CGMP 法规还为制造商提供了灵活性，让他们可以使用更好、更有效的方法来满足 CGMP 要求，因为这些创新方法使患者受益。确定过程控制、测试或检查是否符合 § 211.110 中的法规要求，主要取决于药品的性质（例如，剂型）和制造商使用的工艺类型。制造商从稳健的产品和工艺开发中获得的知识和理解是建立和维护药品整个生命周期控制策略的重要基础。这有助于确保药品具有所需的质量属性。

To ensure conformance to drug productquality requirements, the manufacturer should identify which critical quality attributes13and in-process material attributes to monitor and control.

为确保符合药品质量要求，制造商应确定需要监测和控制的关键质量属性和中间产品的属性。

Section 211.110allows flexibility in the in-process controls, and testing,or examinations that are employed to ensure that processes deliver in-process materials and drug products with the appropriate quality attributes. To ensure that drug products have the properties that they are represented to possess, the in-process materials used throughout the manufacturing process should be of consistent quality.

211.110 允许在过程控制和测试或检查方面具有灵活性，以确保工艺交付具有适当质量属性的中间产品和药品。为确保药品具有其所具有的特性，在整个制造过程中使用的加工物料应具有一致的质量。

In addition to identifying which critical quality attributes and in-process material attributes to monitor, the manufacturer should define and justify where and when the proposed in-process controls, and testing, or examinations that are used to monitor those attributes should occur. The definition and justification should be based on the manufacturer’s understanding of the product and the process. Under§ 211.110(c), “[i]n-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the qualitycontrol unit, duringthe production process, e.g., at commencement or completion of significant phases or after storage for long periods.” As noted in the preamble of the final rule, “Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding,” FDA declined to define the term significant phase.14Instead, FDA stated that “significant phases in the processing of drug products can vary greatly depending on the methods used and nature of the individual products.”15 Therefore, the regulations generally allow flexibility in the determination of significant phases depending on the manufacturing process and the drug product. Manufacturers should define the significant phases in their manufacturing processes; however, FDA evaluates the adequacy of these determinations and the supporting scientific rationale during application assessment and on inspection. The manufacturer shoulduse a scientific- and risk-based approach to determine what constitutes a significant phase and to justify when and where the appropriate tests or examinations should occur relative to a significant phase. It is important to choose the appropriate in-process controls, and tests, or examinations to ensure the quality of in-process materials as well as the performance of the manufacturing process. Process monitoring and control decisions that result in minor equipment and process adjustments do not typically need additional quality unit16 approval if all of the following conditions are met: (1) the adjustments are within the preestablished and scientifically justified limits; (2) these limits have been approved by the qualityunit in the master production and control recordand the controlstrategy; and (3) the production data is reviewed by the quality unit before approval or rejection of a batch.17,18

除了确定需要监控的关键质量属性和中间产品的属性外，制造商还应定义并论证所建议的工艺控制以及用于监控这些属性的测试或检查的位置和时间。定义和论证应基于制造商对产品和工艺的理解。根据 § 211.110（c），“在生产过程中，例如，在重要阶段开始或完成或长期储存后，应酌情对中间产品进行特性、强度、质量和纯度测试，并由质量控制单位批准或拒绝。正如最终规则“当前制造、加工、包装或保存的良好生产规范”的序言中所述，FDA 拒绝定义“重要阶段”一词。相反，FDA 表示，“药品加工的重要阶段可能会因所使用的方法和各个产品的性质而有很大差异。因此，法规通常允许根据制造工艺和药品灵活地确定重要阶段。制造商应定义其制造过程中的重要阶段;但是，FDA 会在申请评估和检查期间评估这些决定的充分性以及支持科学依据。制造商应使用基于科学和风险的方法来确定什么是重要阶段，并证明相对于重要阶段应在何时何地进行适当的测试或检查的合理性。选择适当的工艺控制、测试或检查以确保中间产品的质量和制造过程的性能非常重要。如果满足以下所有条件，则因设备和工艺的微小调整而导致的工艺监测和控制决策通常不需要额外的质量部门批准：（1） 调整在预先设定且经论证的范围内;（2） 这些限值已在主生产和控制记录和控制策略中得到质量单位的批准;（3） 质量部门在批准或拒绝批次之前审查生产数据。

In-process testing strategies should be dictated by the nature of the drug and the manufacturing processes. Manufacturers should ensure that innovative strategies that streamline in-process testing provide sufficient assurance of product quality. The manufacturer should employ a scientifically sound and appropriate sampling and testing strategy for quality attributes at appropriate points19 in the process that are adequate to ensure drug product quality. The manufacturershould employ time-based sampling plans for quality attributes, where appropriate (e.g., time-based measurement of the change in dryer outlet temperature during powder drying processes, which can be used as a surrogate measurement for moisture content).

过程中（中控）的检测策略应由药物的性质和制造过程决定。制造商应确保简化过程测试的创新策略为产品质量提供足够的保证。制造商应在流程中的适当点采用科学合理且适当的质量属性抽样和测试策略，以确保药品质量。制造商应在适当的情况下对质量属性采用基于时间的抽样计划（例如，在粉末干燥过程中对干燥机出口温度的变化进行基于时间的测量，这可以用作水分含量的替代测量）。

In addition to appropriate flexibility in where and when in-process sampling and testing should occur, the regulations provide flexibility in how in-process material and drug product testing is conducted. The preamble to the final rule states that a sampling plan “can mean both a plan for collection of physical units for testing, or it can mean a schedule by which an examination of some sort is done.”20 Although in-process controls, and tests, or examinations of in-process materialsare required,21 sampling does not necessarily require steps for physically removingin- process materials to test their characteristics. Innovative technologies allow in-line, at-line, or on-line measurements in place of physical sample removal for laboratory testing,22and these measurements can be used in conjunction with process models.

除了在何时何地进行过程中（中控）取样和检测方面具有适当的灵活性外，这些法规还在如何进行中间产品和药品检测方面提供了灵活性。最终规则的序言指出，取样计划“既可以指收集物理单元进行测试的计划，也可以指进行某种检查的时间表。尽管需要对中间产品进行工艺控制、测试或检查，但取样并不一定需要物理取出中间产品以测试其特性。创新技术允许在线测量代替物理取出样品以进行实验室测试，并且这些测量可以与工艺模型结合使用。