Confusion Abounds in Elemental Impurities Testing for Pharma, Excipients

USP General Chapters <232> and <233> are set to be implemented in May 2014, despite calls from IPEC (International Pharmaceutical Excipients Council) to extend the deadline as not enough information is known to begin setting specifications, David Schoneker, chairman of the Coalition for the Rational Implementation of USP Elemental Impurities Requirements, told attendees of Excipient Fest in Baltimore on Wednesday. 

And when the chapters take effect and pharmaceutical companies attempt to place new specifications on their excipients, the ingredient suppliers “may not be willing or able to agree with those specifications​” because of the added cost and work required to meet them, Schoneker said.

Companies have told Schoneker in private that they know some of their products will fail these new specifications, though none are willing to step forward and begin discussions with the FDA on which products might be affected, he added. Some of the companies have also told him that they may just stop selling their chemical products to the pharma industry because of the heightened regulations.

Some drugs may end up being re-formulated, though the additional testing and data collection could also drive up prices for excipients if significant amounts of new work are required, Schoneker speculated.

Furthermore, it will take significantly more data and time to develop enough data to understand what the normal variations are to conduct science-based risk assessments of the impurities, he said.

For excipients derived from natural sources -- such as cellulose derivatives, alginates or carrageenans – metal impurities are inherent in a lot of the raw materials, Schoneker noted. Similarly, many metal impurities are in mined excipients, such as titanium dioxide and calcium carbonate, and will not be further processed out of them, he said. But synthetic excipients, such as povidone and silicones, “will probably be the easy ones​” to meet any new specifications, he added.

ICH and FDA​

The ICH’s Q3D, which governs metal impurities, is slated to advance to Step 2 of the international organization’s process in June, which means it will be open for public comment.

But neither the ICH guideline nor the new USP chapters lay out specific requirements for excipient manufacturers. The USP leaves the testing up to the finished dose manufacturers, whereas the ICH requires excipient suppliers to “share what they know and don’t know​” with their customers, Schoneker said.

The FDA’s efforts in metal impurities continued last year when the agency requested blinded samples of excipients to test them for impurities at its lab in St. Louis, he noted. IPEC's work with the FDA and the industry -- from obtaining the samples from the companies, blinding them and then obtaining preliminary data on the impurities -- has been a collaborative process, Schoneker told In-Pharmatechnologist.com. He added that results from the first round of samples have been provided to the companies and that the blinding mechanism took into account the sensitivity around the issue of impurities.

IPEC has begun drafting a Q&A for the FDA on what issues still need to be considered before any progress is made, he said.

But with very little data to work with and a lot of “unknown unknowns​,” it will take a lot more work to establish concrete plans for how to track the impurities, Schoneker added. He also said that depending on the company, it could take between 10 and 85 weeks to comply with the new USP chapters, which means a number of companies would not make the deadline set for next May.

[Editor's note: A previous version of this article inaccurately said the FDA's lab in St. Louis had not sent back to companies excipient samples that were tested.  The first round of excipient samples were blinded and sent back to the companies. In-Pharmatechnologist.com regrets the error.]