WHO Draft Guidance: Continuous Manufacturing of Pharmaceutical Products- Points to Consider

The World Health Organization (WHO) has released the draft working document titled "Points to Consider in Continuous Manufacturing of Pharmaceutical Products". This guidance highlights the paradigm shift from traditional batch processing to continuous manufacturing (CM) in pharmaceutical production, emphasizing its advantages, challenges, and implementation strategies.

What is Continuous Manufacturing (CM)?

Continuous manufacturing is an advanced method where input materials are continuously fed into a system, and processed output materials are continuously removed.

Unlike batch processing, CM can be applied to specific unit operations or an end-to-end integrated process, ensuring increased efficiency, reduced downtime, and superior quality control.

Highlights from the Guidance:

1. Benefits of CM:

   • Efficiency: CM accelerates production timelines, improving output significantly.

   • Quality Control: The use of sensors and real-time analytical tools ensures consistent product quality.

   • Safety: Reduces operator exposure to hazardous materials.

2. Challenges of CM:

   • Technological Readiness: Lack of commercially available equipment for small-scale CM lines.

   • Regulatory Uncertainty: Harmonizing global regulatory requirements remains a significant hurdle.

   • Workforce Skills: Specialized training is needed for operators and regulators.

3. Good Practice Considerations:

   • CM necessitates adopting Process Analytical Technology (PAT) and Quality by Design (QbD) principles.

   • Premises, equipment, and computerized systems must meet stringent requirements to support continuous operations.

   • Pharmaceutical Quality Systems (PQS) must encompass new elements like real-time release testing and predictive analytics.

4. Risk Management:

   • Comprehensive risk assessment should be integrated into all stages of CM, focusing on material sourcing, process deviations, and equipment failures.

   • Methods like Failure Mode and Effects Analysis (FMEA) can aid in identifying and mitigating risks.

5. Control Strategies:

   • CM processes require a robust control strategy initiated during the development phase. It must address parameters such as raw material quality, process monitoring, and real-time corrective actions.

   • The use of advanced technologies, including in-line sensors and AI-driven analytics, is encouraged.

6. Validation and Verification:

   • Specific attention should be given to process validation, including startup and shutdown conditions, to ensure continuous quality assurance.

   • Stability testing protocols should be adapted for CM, incorporating real-time data.

Implementation Timeline: The WHO has outlined a comprehensive timeline for feedback, review, and finalization of this document, aiming for adoption by the Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) in October 2025. For a detailed review, the draft document can be accessed and commented on via the WHO Medicines Public Consultation Website or the WHO PleaseReview Platform.

This guidance provides a roadmap for the global pharmaceutical industry to adopt continuous manufacturing, a transformative step that enhances efficiency, ensures quality, and aligns with the evolving landscape of regulatory expectations. CM is poised to revolutionize pharmaceutical production worldwide by addressing challenges and implementing robust strategies.