WHO publishes Guideline on Continuous Manufacturing

Following the first guidelines on continuous manufacturing (ICH, FDA), the WHO has now also published its first paper on the topic, initially as a draft. The FDA's draft guideline "Quality Aspects for Continuous Manufacturing" had already been published in 2019. The ICH issued its final guideline "Continuous Manufacturing of Drug Substances and Drug Products (Q13)" in 2022.

The recently published draft of the WHO guideline "WHO Points to consider in continuous manufacturing of pharmaceutical products" is intended to provide a global framework for the implementation of continuous manufacturing processes in the pharmaceutical industry. It is aimed at manufacturers as well as regulatory authorities.

The new document is made up of 10 chapters:

1. Introduction
2. Glossary
3. Benefits and challenges in continuous manufacturing
4. Good practices considerations
5. Risk management
6. Control strategy
7. Process dynamics
8. Computerized systems
9. Validation and verification
10. Stability testing

 The main contents include:

• Fundamentals of continuous production: Continuous production is defined and distinguished from traditional batch processes. Advantages such as increased efficiency and improved product quality are illustrated. 
• Regulatory requirements: Necessary adaptations of GMP principles in continuous processes, such as the conversion of batch size from quantity to times or the conversion from random sampling to real-time analytics, are stated. Requirements for process validation and verification are described, with the WHO placing great emphasis on dynamic validation concepts which require continuous data analyses and documentation in order to ensure product quality in real time. The importance of data integrity and real-time monitoring is emphasized.
• Quality risk management (QRM): The use of QRM methods to identify and control potential risks and the integration of PAT to monitor critical quality attributes are highlighted.
• Technical aspects: The use of automation and digitalization in continuous processes as well as the requirements for equipment and infrastructure are mentioned. Equipment should be able to maintain stable production conditions over long periods of time without the need for frequent interventions or shutdowns. It should include integrated control systems that can monitor critical parameters such as temperature, pressure, flow rates or particle sizes in real time. Equipment must be easy to clean. Modular equipment that can be completely disassembled and adapted for different product types is mentioned. In addition, the handling of process disruptions and deviations is discussed.
• Training and skill building: The need for specialized training for personnel and the promotion of knowledge sharing between industry and regulators are emphasized.

A comparison of the ICH and WHO guidelines reveals significant differences. The ICH Q13 guideline provides technical details and is aimed at countries with advanced regulatory systems and available technology. The WHO guideline, on the other hand, places particular emphasis on global applicability and flexibility in order to meet the different needs and capabilities of the member countries. It provides general recommendations and an overarching framework that can be adapted to different scenarios.

The draft guideline "WHO Points to consider in continuous manufacturing of pharmaceutical products" is available on the WHO website. The deadline for comments is March 7, 2025.