FDA to Publish Stability Guidance

After a lengthy delay, the agency has pared down a final version and prepared it for publication.

The long-awaited final version of FDA's stability guidance is scheduled for publication in the first quarter of 2003, an FDA official told attendees at a recent industry conference.

The agency published a draft guidance in June 1998 and intended to publish a final version shortly thereafter but ran into delays. The main reason it has taken so long for the final version to come out is that the agency wanted to wait for the International Conference on Harmonization (ICH) stability documents to be published to make sure the FDA document did not conflict with them, said Richard C. Adams. Adams is chair of the stability technical committee for FDA's Center for Drug Evaluation and Research (CDER) and an antibiotic drug review team leader for CDER's Office of Generic Drugs. 

Another reason for the delay, Adams said, was the sheer volume of comments received. More than 70 entities provided over 3000 specific comments to the agency, covering every single section of the draft guidance. Of those comments, 131 pertained to container- closure systems.

The draft document was more than 100 pages, but the final version has been shortened to about 70, as quotations from the ICH documents have been replaced with references, Adams told the audience at the Parenteral Drug Association's (PDA; Bethesda, MD) annual meeting. The meeting was held December 9-12, 2002, in New Orleans. This change reflected comments that the draft guidance was too long and unwieldy.

The agency agreed with comments that much of the information sought should be addressed in drug development but disagreed with assertions that "harmonization efforts are undermined if topics outside of Q1A [ICH's main stability document] are needed for filing in the U.S.," Adams said. Industry also expressed concern that the requested information should have scientifically sound justification, and the agency believes that it does.

Significantly, Adams said, some container-closure information that industry might have expected to be in the document will not appear. That is because the agency would prefer to address certain container-closure issues, especially those relating to post-approval changes, in the forthcoming PACPAC document, he said. It is hoped PACPAC will show what tests, in lieu of stability studies, must be performed if a firm makes a packaging change to an existing product. Efforts on PACPAC had stalled for a while, but work has commenced again, and the agency hopes to have a draft ready "before too long."
The new guidance will address stability issues for physician samples and pharmacy bulk packs, as well as specifications for containers storing bulk product for more than 30 days. 

All package sizes must be included in the stability test unless bracketing or matrixing is used. Bracketing and matrixing designs should be submitted in the original application to the agency.

There is no need for stability studies relating to extractables and absorption issues if levels are acceptable during container-closure qualification, but all relevant information should be included in the application. 

The document includes new labeling storage statements. Products intended to be stored at room temperature should be labeled with "Store at 20-25 degrees C (68-77 degrees F) [see USP CRT]" or "Store at 25 degrees C (77 degrees F) [see USP CRT]" along with "excursions permitted to 15-30 degrees C (59-86 degrees F)."

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