Method Development for API manufacturing - Is your method the best method?

The FDA might not think so! See how one major API manufacturer kept their timeline intact…even when the FDA demanded additional data.

The Problem

The in-house HPLC-UV method used to carry out the analysis for impurities of a well-known generic antibiotic API was being questioned by the FDA. The manufacturer was worried. “How will this request affect our production timeline?” “How should the re-submission paperwork be handled?” “We don’t have experience with other detection techniques…who will do the actual testing?”

The Issues

In response to the initial ANDA submission, complete with supporting data of the in-house method, the FDA’s review sought additional data. Adding to the challenge was a request for a comparative study to the then current USP monograph method for the API and its impurities to demonstrate equivalence.

The Assignment

The manufacturer reached out to their customers for a trusted resource. Having extensive experience using complex or unique analytical methodologies, Quantum Analytics Group was recommended to develop the data and guide the paperwork for the client’s submission.

The Challenge

The USP method employed the use of a dual electrode coulometric (electrochemical) detector. Challenging to use for the uninitiated, the device is negatively affected by continuous use. It was clear to see why the manufacturer had developed an alternate, HPLC-UV method.

The Approach

Although the client asked us to deliver a greater volume of highly detailed results, we assured them that the standard approach of giving the FDA exactly what they needed (and nothing more) would be most beneficial. Many times, adding more data than necessary can kindle other questions that can complicate the problem at hand.

The Solution

The first step was to transfer the clients’ method to Quantum, through a protocol developed by Quantum. The transfer protocol covered detailed expected method performance, criteria for acceptance of data from each laboratory performing the method, and equivalency acceptance criteria between the originating and transferring laboratories. Once successfully transferred, a side by side comparison between the client’s method and the USP method was performed.

The Insight

“Coulometric detectors can pose challenges not common to other HPLC detectors. Some of the issues that can be encountered include problems with (a) oxidation of some impurity in the mobile phase, (b) deterioration of the working electrode surface, (c) electrode fouling, (d) subtle changes in the temperature of the room or mobile phase, as well as, the slow desorption of electro-active contaminants from the column, tubing or pump heads.”

The Result

Within 4 weeks, the tests were completed and a report in submission-ready format was provided to the manufacturer.

The Value

Shortly after Quantum’s submission of the additional data requested by the FDA, the client received approval of their ANDA submission.

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