持续生产质量管理 FDA这样要求

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DRAFT GUIDANCE

指南草案

 This guidance document is being distributed for comment purposes only.

本指南文件仅为讨论稿。

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852. All comments should be identified with the docket number listed in the notice of availability when published in the Federal Register. For questions regarding this draft document, contact (CDER) Sau L. Lee at 301-796-2905.

关于本指南文件草案的意见和建议应在FDA公布指南草案的通知后90天内以电子方式向https://www.regulations.gov.提交。向美国马里兰州洛克维尔市菲舍巷5630号食品药品监督管理局档案管理人员(HFA-305)提交书面意见。所有意见都应与联邦登记册上公布的可用性通知中列出的摘要编号一致。有关本文件草案的问题，请致电301-796-2905与(CDER) Sau L. Lee联系。

 Additional copies are available from: Office of Communications, Division of Drug Information  Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  Silver Spring, MD 20993-0002  Phone: [phone] or 301-796-3400; Fax: [phone]  

Email: [e-mail]  https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

其他文件可从以下地址索取:美国食品药品监督管理局药物评价和研究、药物信息中心办公室，希兰代尔大道10001号，马里兰州银泉大厦4楼，电话:855-543-3784或301-796-3400;传真:301-431-6353，Email: [e-mail]

https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U. S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

美国公共卫生事业部 食品与药品监督管理局 药物评估与研究中心(CDER)

February 2019 Pharmaceutical Quality/CMC Pharmaceutical Quality/Manufacturing Standards (CGMP)

2019年2月药品质量/CMC药品质量/制造标准(CGMP)

 

 I.INTRODUCTION

一. 概述

This guidance provides information regarding FDA’s current thinking on the quality considerations for continuous manufacturing of small molecule, solid oral drug products that are regulated by the Center for Drug Evaluation and Research (CDER). The guidance describes several key quality considerations and provides recommendations for how applicants should address these considerations in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental NDAs and ANDAs, for small molecule, solid oral drug products that are produced via a continuous manufacturing process. FDA supports the development and implementation of continuous manufacturing for drug substances and all finished dosage forms where appropriate, including those submitted in NDAs, ANDAs, drug master files (DMFs), biologics license applications (BLAs), and nonapplication over-the-counter (OTC) products. Scientific principles described in this guidance may also be applicable to continuous manufacturing technologies used for these drugs. However, this guidance is not intended to provide recommendations specific to continuous manufacturing technologies used for biological products under a BLA.

本指南提供了有关FDA目前关于持续生产由药物评估和研究中心（CDER）监管的小分子固体口服药物产品的质量考量的信息。该指南描述了几个关键的质量考量，并为申报人如何应对新药申请（NDAs），简短新药申请（ANDAs）以及补充的NDAs和ANDA中的这些考虑提供了建议，用于生产的小分子固体口服药物产品通过持续的生产过程。 FDA支持药物物质和所有成品剂型的持续生产的开发和实施，包括在NDAs，ANDA，药物主文件（DMF），生物制剂许可证申请（BLA）和非应用非处方药物中提交的剂型（ OTC）产品。本指南中描述的科学原理也可适用于用于这些药物的持续生产技术。但是，本指南并非旨在提供BLA下用于生物制品的持续生产技术的具体建议。

For purposes of this guidance, FDA considers “continuous manufacturing” to be a process in which the input material(s) are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system. Although this description can be applied to individual unit operations or a manufacturing process consisting of a series of unit operations, as described in this guidance, continuous manufacturing is an integrated process that consists of a series of two or more unit operations.

出于本指南的目的，FDA认为“持续生产”是一种过程，其中输入物料持续地进料到过程中并在过程中转化，并且处理的输出物料被持续地从系统中移除。尽管该描述可以应用于单个单元操作或由一系列单元操作组成的生产过程，如本指南中所述，但持续生产是由一系列两个或更多个单元操作组成的集成程。

This guidance focuses on scientific and regulatory considerations that are specific or unique to continuous manufacturing. These considerations include process dynamics, batch definition, control strategy, pharmaceutical quality system, scale-up, stability, and bridging of existing batch manufacturing to continuous manufacturing. Recommendations broadly applicable to both continuous and batch processes are generally not covered in this guidance and the reader should refer to other FDA and International Council on Harmonization (ICH) guidance documents for such information.

本指南重点关注持续生产特定或独特的科学和法规考量。这些考量包括过程动态，批次定义，控制策略，制药质量体系，放大，稳定性以及现有批次生产与持续生产的桥接。本指南通常不涉及广泛适用于持续和批处理过程的建议，读者应参考其他FDA和国际协调委员会（ICH）指导文件以获取此类信息。

In general, FDA’s guidance documents do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency’s current thinking 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.   

 一般而言，FDA的指导文件并未建立法律上可执行的责任。相反，指南描述了该机构目前对某一主题的看法，应仅视为建议，除非引用了具体的法规或法定要求。 在机构指南中使用“应该”一词意味着建议或推荐某些内容，但不是必需的。

 

II. BACKGROUND 

二.背景

FDA is committed to supporting and enabling pharmaceutical innovation and modernization as part of the Agency’s mission to protect and promote public health. The Agency hopes that these efforts may also help reduce the number of drug shortages, as noted in FDA’s drug shortage strategic plan. In 2002, FDA launched an initiative entitled “Pharmaceutical CGMPs for the 21^st Century: A Risk-Based Approach,” to encourage the implementation of a modern, science-and risk-based pharmaceutical quality assessment system. One goal of the initiative is to ensure that regulatory review, compliance, and inspection policies continue to support continuous improvement and innovation in the pharmaceutical manufacturing industry. Since publication of that initiative document, FDA has promoted a vision of a maximally efficient, agile, flexible manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.  

作为保护和促进公共卫生使命的一部分，FDA致力于支持和促进制药创新和现代化。如FDA的药物短缺战略计划所述，本机构希望这些努力也可能有助于减少药物短缺的数量。2002年，FDA启动了一项名为“面向21世纪的药物CGMP：基于风险的方法”的倡议，以鼓励实施现代的，基于科学和风险的药品质量评估系统。该计划的一个目标是确保监管审查，合规和检查政策继续支持制药行业的持续改进和创新。 自该倡议文件发布以来，FDA推出了一个最高效、敏捷、灵活的生产业的愿景，可以可靠地生产高质量的药品而无需广泛的监管。

FDA supports the adoption of modern manufacturing technology as a foundation for improving the overall quality of products and availability to patients. FDA recognizes that continuous manufacturing is an emerging technology that can enable pharmaceutical modernization and deliver potential benefits to both industry and patients. Continuous manufacturing can improve  pharmaceutical manufacturing by, for example, using an integrated process with fewer steps and  shorter processing times; requiring a smaller equipment footprint; supporting an enhanced  development approach (e.g., quality by design (QbD) and use of process analytical technology  (PAT) and models); enabling real-time product quality monitoring; and providing flexible  operation to allow scale-up, scale-down, and scale-out to accommodate changing supply  demands. We also expect that this operational flexibility may decrease the need for some postapproval regulatory submissions. Therefore, FDA expects that adopting continuous manufacturing for pharmaceutical production will reduce drug product quality is issues, lower manufacturing costs, and improve availability of quality medicines to patients.  

FDA支持采用现代生产技术作为提高产品整体质量和患者可用性的基础。FDA认识到，持续生产是一项新兴技术，可以实现制药现代化，并为行业和患者带来潜在利益。持续生产可以通过例如使用具有更少步骤和更短处理时间的集成工艺来改进药物生产;需要更小的设备占地面积;支持增强的开发方法（例如，设计质量（QbD）和过程分析技术（PAT）和模型的使用）;实现实时产品质量监控;并提供灵活的操作，以比例放大，缩小规模和扩大规模，以适应不断变化的供应需求。我们还预计，这种操作灵活性可能会减少对某些批准后监管提交的需求。因此，FDA预计采用药品生产的持续生产将降低药品质量问题，降低生产成本，并提高患者对优质药品的可用性。

 

III. QUALITY CONSIDERATIONS  

 三．质量考量 

A.Key Concepts of Continuous Manufacturing  

A.持续生产的关键概念

1.Process Dynamics 

1.过程动力学

Product and process understanding form the foundation for effective risk management. The expectations regarding the science- and risk-based approach to the control of processes and  product quality based on process understanding are the same for continuous manufacturing as for  traditional batch manufacturing. 

产品和流程理解是有效风险管理的基础。 基于流程理解控制流程和产品质量的基于科学和风险的方法的期望，与持续生产和传统批量生产相同。 

Continuous manufacturing processes are dynamic systems, unlike batch manufacturing processes. During normal operation, a set of critical process parameters and/or quality attributes are kept close to the target values, rather than at a steady-state condition. Transient disturbances may occur during normal operation. These are usually small enough to be controllable (i.e., being kept within a desired range). Larger changes in process parameters and quality attributes can happen when a process is in a transient state, such as during start-up and shutdown, a change from one operating condition to another, or significant deviations such as those due to equipment failure or unexpected change in material attributes. Understanding of process dynamics as a function of input material attributes (e.g., potency, material flow properties), process conditions (e.g., mass flow rates) or equipment design elements (e.g., blade types for a continuous blender) enables material traceability (the ability to preserve and access the identity and attribute of a material throughout the system) during and after production. This knowledge is essential for identification and mitigation of risks to product quality. Therefore, due to the dynamic nature of continuous processing, the risk assessment for a continuous manufacturing process should consider process understanding of the integrated system in addition to each unit operation.

 与批量生产过程不同，持续生产过程是动态系统。在正常操作期间，一组关键过程参数和/或质量属性保持接近目标值，而不是在稳态条件下。在正常操作期间可能发生瞬态干扰。它们通常足够小以便可控（即，保持在所需范围内）。当过程处于过渡状态时，例如在启动和关闭期间，从一个操作状态到另一个操作状态的变化，或者由于设备故障或意外变化导致的重大偏差，过程参数和质量属性的更大变化可能发生在物料属性。根据输入物料属性（例如效能，物料流动特性），工艺条件（例如，质量流速）或设备设计元素（例如，持续搅拌器的叶片类型）来理解过程动力学，从而实现物料可追溯性（能力）在生产期间和之后保留和访问整个系统中物料的标识和属性。这些知识对于识别和减轻产品质量风险至关重要。因此，由于持续处理的动态性质，持续生产过程的风险评估应考虑除了每个单元操作之外的集成系统的过程理解。

A suitable scientific approach should be used to characterize how a material flows through the process. One common approach is characterization of residence time distribution (RTD) for the individual unit operations and integrated system. An RTD is a probability distribution that describes the amount of time a mass or fluid element remains in a process, and can be measured through a tracer experiment, online process measurements of appropriate product attributes, and/or process modeling. The shape of the RTD reflects the degree of axial dispersion or back mixing within that system, which affect the propagation of disturbances, material traceability, and the control strategy (e.g., material diversion and sampling frequency). The RTD is dependent upon several factors such as input material attributes, mass flow rates, process parameters, and equipment design and operation. It is important to understand how the RTD varies over the range of planned operating conditions in addition to characterizing the RTD at the nominal/target operating conditions. This information serves as a basis for material traceability and determination of appropriate sampling plans and is essential to designing a control strategy for continuous manufacturing processes.

应该使用适当的科学方法来表征物料如何流过整个过程。一种常见的方法是表征各个单元操作和集成系统的停留时间分布（RTD）。 RTD是描述质量或流体元素在过程中保留的时间量的概率分布，并且可以通过示踪剂实验，适当产品属性的在线过程测量和/或过程建模来测量。 RTD的形状反映了该系统内的轴向色散或反向混合的程度，其影响干扰的传播，物料可追溯性和控制策略（例如，物料转移和取样频率）。 RTD取决于若干因素，例如输入物料属性，质量流速，工艺参数以及设备设计和操作。除了在标称/目标工作条件下表征RTD之外，了解RTD如何在计划工作条件范围内变化也很重要。该信息可作为物料可追溯性和确定适当抽样计划的基础，对于设计持续生产过程的控制策略至关重要。

翻译：黄昭曦，邓玲玲，maywen，蓝宇

校对与排版：蓝宇