• Replies 4 replies
  • Subscribers 5 subscribers
  • Views 1251 views
  • Users 0 members are here
Related Content

What’s one adjustment that made a big difference in your CM process?

Kaitlin Baumer

What’s one small adjustment that has had a big impact on your CM process? This could be anything—from cleaning procedures and process control strategies to equipment modifications or team workflows.

Your input is valuable - share it below so we can learn from each other!

  • I recently read a two-part study published by Amgen researchers. It described a conversion of the penultimate step of the synthesis of Apremilast, which is the API in Otezla (a PDE4 inhibitor for inflammatory diseases).

    The traditional batch process for the penultimate step in apremilast synthesis had three main challenges:

    1. Long reaction time (>18 hours).
    2. Low solubility of starting materials/intermediates in THF.
    3. Multiple post-reaction operations, leading to significant solvent waste.

    By switching to continuous mode using a higher temperature plug flow reactor they realized several benefits:

    • Plug-Flow Reactor (PFR): Enabled higher reaction temperatures (up to 130 °C), reducing reaction time from >18 hours (batch) to 30 minutes (flow) (*this is huge in my opinion).
    • Solvent Switch: Replaced THF with DMSO, greatly improving solubility of 3-acetamidophthalic anhydride and intermediates. (*highly impactful from a distributed manufacturing, diversified supply chain perspective)
    • Process Safety: Careful thermal analysis (ARC) and modeling ensured safe operation at elevated temperatures, with built-in safety protocols for lab and production scale. (*always a concern)

    The two part study is published in: A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles | Organic Process Research & Development

    A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy | Organic Process Research & Development

  • The value of having chemists and chemical engineers together in meetings.  Its a small team action that dramatically accelerates development work.
    Also, it's important to have analytical chemists in any meeting for planning a production campaign.  Their input for where and when to sample can provide so much value afterwards.

    Another big unexpected positive impact is the significant reduction in cleaning solvent required as more and more unit operations are integrated - one cleans at the end of the campaign instead of after every batch.

  • Intentional Information, Meaningful Impact: Implementing a deliberate, consistent, and collaborative method for sharing project updates, data insights, literature reviews, and guidelines to strengthen stakeholder engagement and knowledge exchange.

  • I quote a friend from industry who told me: “The change that has had the biggest impact to our CM operation is organizational. We had a dedicated team (and not a cross-operational site or global team) that was responsible for commissioning and qualification of our units. The same team then became the operations team upon completion of qualification activities. This dramatically reduced the learning curve for the team. The analogous change was also implemented in the quality organization – the team responsible for installation and qualification of the unit transitioned to being the operational quality team upon completion of qualification. Besides reducing learning curve for a new technology, a single team now has deep knowledge of the machine and operation. This has also resulted in much smoother pre-approval inspections (PAIs)”.