This API Method Validation Checklist Helps Avoid Common Mistakes


A few years ago, a surgeon at Brigham and Women’s Hospital in Boston, Dr. Atul Gawande, became a viral sensation with his best-selling book, The Checklist Manifesto: How to Get Things Right. I remember seeing him on TV talking about the increasing complexity that technology and other factors have brought to all our jobs. They cause even the most expert professionals in their field to make grievous errors. His solution: a simple and humble technique, the checklist.

Checklists aren’t new. They were commonly used decades ago by U.S. Air Force, enabling pilots to fly planes of “mind-boggling sophistication.” They are still used by military and civilian pilots today.

Dr. Gawande’s book resulted in checklists being widely adopted in hospitals around the world that weren’t already using them, helping doctors and nurses respond to everything from avalanches to drownings to epidemics. In operating suites, checklists have been credited with cutting the rate of fatalities by more than a third, and for helping fight hospital-acquired infections. And the checklist phenomenon hasn’t been limited to healthcare or aeronautics – it is equally helpful in other complex endeavors such as investment banking and skyscraper construction.

API development, scale-up and manufacturing are among these highly complex undertakings. They too have become more sophisticated and require working under time and budget constraints. Consequently, we constantly endeavor not only to get things right, but to get things right the first time. We’ve written in the past on implementing a right-first-time approach to synthetic route selection, and to choosing the right team for your project in order to come as close to getting things right the first time as is possible when developing new chemistry.

We’ve also discussed the importance of project management skills in keeping projects on time and on budget, and all that function entails – it’s such a critical part of assuring everything that needs to get done is done.

In the course of API development, method validation is among the most critical CDMO functions given its importance to seeking regulatory approval.  We thought a simple checklist of questions and tasks would be helpful as a quick-glance double-check for those charged with Quality Assurance and Quality Control.

Method Validation Checklist

Physiochemical Properties

  • Solubility
  • pH
  • pKA
  • Reactivity
  • Melting point
  • Boiling point
  • Moisture sensitivity
  • Light sensitivity
  • Heat sensitivity
  • Corrosivity
  • Polymorphism
  • Dissociation
  • Other physical or chemical properties unique to the molecule of interest

Validation purpose

  • Release of raw material?
  • In-process control?
  • Final product release testing?

Product questions

  • Route of administration?
  • Maximum daily dose?
  • Length of administration?
  • Components to be monitored for each sample?
  • Specifications?
  • Genotoxic impurities?
  • Impurities profile?
  • Maximum daily dose?
  • Robustness against various parameters?
  • Acceptance criteria?
  • Filter studies
  • Forced degradation testing/degradants
  • Testing conducted under cGMP and ICH guidelines?
  • Column challenge/column performance
  • Upper and lower pH limits
  • Limit of detection values
  • Limit of quantitation values
  • Method transfer
  • Column cleaning procedure

Are these drug substance attributes supported in method validation?

  • Identity
  • Strength
  • Quality
  • Purity
  • Potency
  • Reproducibility
  • Are all observations captured in methods validation report?
  • Has method validation been peer reviewed?
  • Has method validation been approved by QA?

Add your method validation checklist suggestions

Are there other items you would add to this checklist? We would be happy to consider them for inclusion.

You can download the checklist here and please check back periodically for updates.

We’ve written about checklists and standard operating procedures before. Check out: “Transferring API Technology to a CMO? Use This Checklist,” “Three Questions to Ask Your CMO about Standard Operating Procedures,” and “4 Questions to Ask Your CMO about Standard Operating Procedures.