文章来源:ECA news


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.


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.


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:


A. Key Concepts of Continuous Manufacturing

1. Process Dynamics

2. Defining Batches for Continuous Manufacturing Processes


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


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,数据处理和管理

C. Process Validation

D. Additional Pharmaceutical Quality System Considerations

E. Scale-Up

F. Stability

G. Bridging Existing Batch to Continuous Manufacturing






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).


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.


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.


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.


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.


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.


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