Scenario - Active Substance Solvent Change

Your API manufacturer tells you that they intend to switch one of their recrystallization solvents.

First thought

  • Change! Changes bring risk. Will the product perform as before? How could the solvent impact the API properties and its stability, purity, safety, efficacy, potency? Same question for any product that uses the API.

How would you manage this?

The core management process would be a change control to document the change and plan responsive actions. This permits a pre change impact assessment to be done. Expect to use subject matter experts from the following groups

  • Formulations / Research and development:

  • Regulatory Affairs

  • Production / Technical support / Process Validation

  • Purchasing / procurement

  • Supplier Quality Assurance

  • Quality control (Incoming materials testing)

There would also be an expectation that other parts of the business should be notified as they may be impacted such as the sales or planning team.

What are areas of concern?

The change is not a small insignificant change and would require full investigation prior to progressing change. These will broadly track the departments required to help manage the implementation of the change but include:

Formaulations:

Impact on residual solvents of the finished product – some solvents will have a lower limit than others. There are prescribed limits for residual solvents in ICH Q3C.

Clinical development (R&D):

Does this impact the polymorph of the AS? Also considering whether there are any bioavailability concerns relating to the polymorphism etc and whether this would have an impact on the finished product.

Production / Technical support:

Consideration of the impact of the solvent on the final crystal form and polymorph of the Active Substance being manufactured and whether there is any impact on flow properties, crystal shape or particle size of the API. May require repeated validation of a production process if so.

Regulatory Affairs

Is the solvent part of any registration? Unlikely but some countries may include?

Sales and Production Planning

There may be an impact on AS availability during the change implementation.

Supplier Quality Assurance

Supplier Auditing team. Does the current audit cover the use of this solvent? Does the risk based plan for supplier audit need to be updated.

Quality control (Incoming materials testing)

Does the AS incoming need tested independently for residual solvent? On vendor maintenance? Does a method need to be transferred in?

What do you need to see happen?

Actions captured in the change management plan would typically include:

  • Formulations impact assessment which informs a…

  • Clinical impact assessment

  • Regulatory filling updates (if required) which probably mean

  • API stability studies and Finished Good Stability Studies

  • Some level of comparative lab analysis

  • Some level of process revalidation using the new API.

  • A summary report of the change post testing.

  • Batches made using the material placed in quarantine control until relevant testing is complete.