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LONG-TERM STABILITY TESTING SHOULD BE AT 25 degrees C/45% RELATIVE HUMIDITY, FDA ADVISORY COMMITTEE CONCURS; TESTING STANDARD SHOULD ONLY APPLY TO NEW DRUGS

Executive Summary

FDA should propose that long-term testing of new drug entities and new drug substances be conducted at 25 degrees Celsius and a relative humidity (RH) of 45%, an ad hoc advisory committee assembled by the agency's Office of Generic Drugs recommended June 21. The advisory committee also voted four to two that accelerated stability testing for new drugs and substances should be conducted at 40 degrees C/75% RH for six months, and if a "significant change" occurs, the drug should be tested at 30 degrees C/60% RH for six months. The testing conditions recommended by the ad hoc committee would bring FDA's position in line with that proposed in the International Council on Harmonization's third draft stability guideline. When FDA published ICH's draft guideline in the Federal Register May 19, the agency expressed concern with the proposal, suggesting instead a temperature of 30 degrees C for long-term testing. A group of FDA chemists sent an anonymous letter to FDA May 15 criticizing FDA's stance on stability testing ("The Pink Sheet" May 24, T&G-4). FDA Office of Generic Drugs Director Roger Williams and Office of Drug Evaluation I Assistant Chemistry Director Charles Kumkumian, PhD, reported the advisory committee's discussions and conclusions to the ICH steering committee at its meeting in Washington, D.C. June 24. The agency hopes to have finalized its views on ICH's draft stability guideline by the second major ICH meeting, scheduled for Oct. 27-29 in Orlando. Regarding long-term testing, committee member Christopher Rhodes, PhD, University of Rhode Island, concluded that "because of our need and desire to harmonize...the onus of proof is upon those who would argue we have to go to 30 degrees." In addition, "we can make exceptions for individual products. We are developing a criteria which should be applied to most products," Rhodes said. Summing up a number of concerns about drug stability brought up at the meeting, FDA's Williams said: "There's a progressive loss of control in [the distribution chain from manufacturer to patient].... We get to a point where really there is no control on a pharmaceutical product." There is "some hope" that the Prescription Drug Marketing Act, which went into effect last autumn, "will institute better controls on the warehouse," he added. However, Williams does not believe "those warehouse controls are in place now" or that "the controls on a pharmacy in the United States are all that they could be." As an example, he noted that when FDA looked at how pharmacies in Maryland were inspected, the agency found that "there are no temperature controls in Maryland pharmacy, nor are they inspected for temperature controls." Office of Generic Drugs Associate Director of Chemistry Robert Jerussi, PhD, added that "it's estimated by the Puerto Rico district of the FDA that up to 50% of American drugs are made in Puerto Rico. It's pretty humid and not every plant is automatically controlled. And many drugs are stored in Puerto Rico for shipment to the United States." Williams concluded that "I don't think any of us would be terribly surprised if we said that at a certain point in the life of a pharmaceutical product it's exposed to extremes of temperature and humidity above 30 degrees for unknown periods of time and humidity conditions above 60% relative humidity." Some sampling from the marketplace is "critical," Rhodes stressed. "After all, all...obtained temperature data, be it at 25 or 30, has to some extent at least an element of artificiality. These are products which have been coddled, have never gone out in the real marketplace. So I think...concern [about drug shipping and transport] would be answered if we had some more testing of marketplace samples." The committee agreed that generic drugs should not be subject to the proposed stability testing requirements. Committee Chair Leslie Benet, PhD, University of California at San Francisco, summed up the sense of the committee, concluding that the current requirement of "three months [of] accelerated stability [testing] and a commitment for long-term evaluation of the formulation is appropriate for major formulation changes and for ANDA drugs." Current Office of Generic Drugs policy for accelerated testing is three months at 40 degrees C/75% RH. Storage condition labeling should be based on the U.S. Pharmacopoeia's proposed definition of controlled room temperature, the committee recommended in a five-to-one vote. USP plans to change its definition of "controlled room temperature" to a mean kinetic temperature of not more than 25 degrees C with allowance for "temperature excursions" between 15 and 30 degrees. The organization plans to implement the change through a general notice effective Nov. 15 for all USP monographs not specifying other temperature parameters. The other labeling option before the committee was a storage temperature of 15 to 25 degrees. The ad hoc group did not specify in what detail the drug label should describe "controlled room temperature." Committee consultants Joel Davis, a retired FDAer, and Sanford Bolton, PhD, St. John's University, expressed concern that the full USP definition would confuse patients.
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