ICH publishes Guideline Q13 on Continuous Production

End of July, the ICH (International Council for Harmonisation) published the long-awaited draft guideline on continuous manufacturing. The ICH had already announced in June 2018 that it was working on a new ICH Guideline on Continuous Manufacturing with the abbreviation Q13. In addition to batch definitions, the document describes three different continuous manufacturing approaches and provides guidance on control strategy and approval issues. The new guideline ICH Q13 Continuous Manufacturing of Drug Substances and Products covers active ingredient and drug production manufacturing as well as the production of therapeutic proteins and combined or integrated active ingredient and drug production. It comprises the development, implementation and operation of continuous manufacturing processes as well as life cycle management.

The actual guideline comprises 15 more general pages and a second part, which in 24 pages contains five annexes with more specific instructions. The document lists three possible batch definitions: a quantity of consistent quality defined by the quantity of input materials, the quantity of output from the manufacturing process, or by the manufacturing time (at a defined mass flow rate).

PART I: Guideline with 6 Chapters

1. Introduction
2. Continuous Manufacturing Concepts
3. Scientific Approaches
4. Regulatory Considerations
5. Glossary
6. References

The fourth chapter, Regulatory Considerations, also contains a section on process validation. Here it is stated that in addition to the traditional batch-based approach, validation can also be performed through continuous process verification. For this purpose, the system performance and the material quality must be continuously monitored and it must be proven by means of the real-time data that the system has been kept in the state of control throughout. According to ICH Q10, this state is one that ensures continuous process performance and product quality.

A controlled condition (as defined by ICH Q10) is a condition that ensures continuous process performance and product quality....
The fourth chapter also contains the helpful Table 1 with specific information on the contents for the authorisation application.

PART II: Five Annexes with concrete indications

• Annex 1: Continuous Manufacturing of Drug Substances for Chemical Entities 
• Annex 2: Continuous Manufacturing for Drug Products 
• Annex 3: Continuous Manufacturing of Therapeutic Protein Drug Substances
• Annex 4: Integrated Drug Substance and Drug Product Continuous Manufacturing

Each of these four parts contains an exemplary flow chart with the individual unit operations, notes on process equipment, process control and validation. Special regulatory issues are also addressed.

• Annex 5: Perspectives on Managing Disturbances

The last appendix deals with the important topic of process deviations. For example, product from the startup and shutdown phases of the process must be handled differently, and product from phases with process behavior that deviates from the target must be safely discharged. The strategies for this are already defined during process development and are based on DoE (Design of Experiments), RTD studies or a combination of both. RTD (residence time distribution) indicates the residence time of material in the process and is an important aspect in determining the material to be discharged. So-called funnel plots indicate how severe a process disturbance can be or how long it can last to still produce conforming material. In this way, acceptance criteria for disturbances can be defined. The chapter contains three examples for further explanation: irregularly occurring disturbances with deviations within and outside the disturbance acceptance criteria as well as frequently occurring disturbances within the acceptance range.

Current Status

The document is now in Step 2 (Step 2) of the ICH procedure and open for comment. In Step 2 of the ICH process, a draft Guideline, based on comments received from the relevant ICH Expert Working Group (EWG), is circulated by ICH to the regulatory authorities in the ICH regions for review in accordance with national or regional procedures. A meeting of the EWG is planned in November 2021 to discuss the comments received. The final Guideline is expected to be signed in November 2022 (Step 3).

Please visit the ICH website to find the draft of the Guideline ICH Q13 Continuous Manufacturing of Drug Substances and Products.