【ECA新闻】FDA新发布指南:连续生产的质量考量

发布日期:2019-03-15

文章来源:ECA news

文章翻译:王孝东


In February 2019, the FDA published a new draft guideline that addresses quality aspects in the continuous manufacturing of medicinal products. It covers topics related to development, process validation, marketing authorisation and routine production.

2019年2月,FDA发布了一份新的指南草案,描述了在药品连续生产方面的质量考量。草案涵盖了有关研发、工艺验证、上市许可以及日常生产的主题。


The FDA sees continuous production as the most important tool in the modernisation of the pharmaceutical industry. In a statement released at the same time by FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock, there is meanwhile mention of five continuously manufactured products (from four companies) that have already been authorised. Four years ago it was only one authorised product. In total, twenty companies are working with the FDA on continuous manufacturing. These are both original and generic manufacturers. In order to further support the pharmaceutical industry, the present guideline has been developed. The development of an ICH guideline for continuous manufacturing of medicinal products was also initiated and its completion is planned for 2021.

FDA认为连续生产在制药工业现代化中是非常重要的工具。在同一时间由FDA局长Scott Gottlieb和CDER官员Janet Woodcock发布的声明中,提及已有来自四个公司的五个使用连续生产方式生产的产品得到了批准。而四年前仅批准了一个产品。总计有20家公司正与FDA一起推进连续生产。包括原研与仿制药的生产商。为了进一步的支持制药工业,起草了当前的这份指南。ICH也启动了关于药品连续生产的指南的准备工作并计划于2021年完成。


The draft guideline entitled "Quality Considerations for Continuous Manufacturing" is primarily aimed at manufacturers of solid medicinal products or small molecule medicinal products. Basically, the guidelines can also be used for the production of biologics, but these are not the focus of the paper.

指南草案标题为“连续生产的质量考量”,主要针对的是固体药品或小分子药品的生厂商。本指南也能用于生物技术产品的生产,但这并非本文的关注点。


The FDA defines a continuous process as a process consisting of at least two connected Unit Operations to which material is continuously fed and from which material (product) is continuously removed. According to the FDA, conventional batch processes consist of a sequence of individual process steps. Since the integrated, continuous procedure is new for the pharmaceutical industry, the new guideline describes the key elements that must be considered in continuous processes. Those elements are covered in the individual chapters:

FDA将连续工艺定义为至少两个连续单元操作组成的工艺,在该工艺中连续给料并连续出料。根据FDA的描述,传统批生产工艺由一系列连续的单个工艺步骤构成。由于整合连续的程序对制药工业是个新理念,新指南描述了在连续工艺中必须考虑的重要因素。这些因素分布在以下各个章节中:


A. Key Concepts of Continuous Manufacturing

1. Process Dynamics

2. Defining Batches for Continuous Manufacturing Processes

A.持续生产的重要概念

1. 工艺动态

2. 持续生产工艺中批次的定义


B. Control Strategy

1. Input Material Control

2. Process Monitoring and Control

3. Material Diversion

4. Real Time Release Testing

5. Specification

6. Equipment

7. System Integration, Data Processing, and Management

B.控制策略

1. 输入物料控制

2. 工艺监测和控制

3. 物料分流

4. 实时放行测试

5. 质量标准

6. 设备

7. 系统整合,数据处理和万兴彩票手机版下载


C. Process Validation

D. Additional Pharmaceutical Quality System Considerations

E. Scale-Up

F. Stability

G. Bridging Existing Batch to Continuous Manufacturing

C.工艺验证

D.制药质量体系的额外考虑

E.工艺放大

F.稳定性

G.现有批次到连续生产的桥接


In contrast to conventional batch processes, continuous processes are dynamic. In order to be able to characterize the process flow, it is necessary to determine the residence-time distribution (RTD). RTD is a probability distribution that describes how long a mass remains in the process. It can be determined by tracer studies, by online measurement of certain product properties and/or by mathematical methods (Process Modelling).

与传统批处理相比,连续工艺是个动态过程。为了能够确证工艺流,需要确定滞留时间分布(RTD)。RTD是描述物质留存在工艺中时间的概率分布。它可以由示踪研究、某一产品特性的在线监测和/或数学方法(工艺建模)来确定。


A very important aspect of the continuous process is the control strategy. The key elements for this are: control of input materials, process monitoring, material diversion, real-time release testing (RTRT), specification and process equipment.

控制策略是连续工艺中一个很重要的方面。这方面的要素是:输入的物料,工艺监测,物料分流,实时放行测试(RTRT),质量标准和工艺设备。


Since continuous processes must be continuously "fed" with input materials, their flow behavior plays a much greater role. This can lead to additional material properties having to be specified, e.g. particle size distribution or density of APIs or excipients.

连续工艺必须是物料的连续加入,因此物料的流动特性具有很大的影响。这决定了必须明确规定物料特性,例如APIs或辅料的粒径分布或密度。


Ideally, a continuous process is in the so-called "state-of-control". However, there will always be situations where this is not the case, e.g. due to incidents, start-up or shut-down of the process. Here, it has to be ensured that non-compliant material is diverted depending on the severity and duration of the failure and the process dynamics. Unexpected defects that lead to the diversion of product should be investigated before the batch continues to be used.

理论上,连续工艺应处于“受控状态”。但总会发生一些不在控制状态的情况,例如突发事件,工艺的启动或停止。因此,必须根据故障的严重性与持续时间以及工艺的动态性确保剔除不合格物料。应当在继续使用批次之前调查导致产品剔除的缺陷。


Through the use of PAT and the associated collection of in-process data, the establishment of a real-time release is possible (RTRT). According to the FDA, this is a "can" and not a "must" for continuous processes, but it is recommended.

通过PAT的使用以及过程数据的采集,使实时放行(RTRT)成为可能。根据FDA,这是“可能”而非“必须”,属于推荐的做法。


According to FDA CFR, a specification is required for finished medicinal products. The establishment of specifications for continuously manufactured products should follow the requirements of ICH Q6A and B. The FDA considers the data generated within the scope of an RTRT to be more meaningful than data determined within the scope of a final and offline testing of the product. Nevertheless, the specification should include offline test methods and acceptance criteria in order to be able to perform stability tests at a later time.

根据FDA CFR,成品应建立质量标准。应按照ICH Q6A和B的要求建立持续生产的产品质量标准。FDA认为实时放行中采集的数据要比最终和离线测试数据更有意义。质量标准应当包括离线检验方法和可接受标准,以便可在以后进行稳定性检验。


The FDA expects the performance of equipment used for continuous production to decline over time. To prevent this, additional aspects of qualification, maintenance and cleaning must be considered. The qualification of equipment must cover both individual manufacturing steps and the integrated overall process. Qualification should consider expected conditions (flow rates, pressures, speeds, duration). The diversion of non-compliant material should also be checked during qualification. The Quality Unit should establish acceptance criteria for the performance of equipment.

FDA认为用于连续生产的设备性能会随时间下降。因此为了防止出现这种情况,应考虑确认、维护与清洁的问题。设备确认必须涵盖单一生产步骤与整合过程工艺。确认应考虑预期条件(流速,压力,速度,持续时间)。不合格物料的剔除也应当在确认期间进行检查。质量部门应建立设备性能的可接受标准。

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