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This article was originally published in The Tan Sheet

Executive Summary

ICH IMPURITY STANDARDS MAY EXTEND TO OTC PRODUCTS in the future, FDA Center for Drug Evaluation & Research Associate Director Roger Williams, MD, indicated at a Nonprescription Drug Manufacturers Association conference on good manufacturing practices (GMPS) on Oct. 7 in Philadelphia. Referring to an FDA ad hoc advisory committee in June at which recent drafts of the ICH guidelines on impurities and stability testing were reviewed ("The Tan Sheet" June 28, p. 13), Williams hinted at the possibility that the committee's recommendation that ICH impurity standards apply to over-the-counter and generic products could be adopted by FDA. Williams predicted that "these [ICH] requirements, even if you try to confine them to new molecular entities or innovator products, inevitably tend to drift outward to other products, and we're just going to have to see how it sorts out in the coming years, and how much impact it will have" on OTC manufacturers. Currently, Williams explained, International Conference on Harmonization standards are "totally directed to new molecular entities and new drug substances after approval." However, he noted that the advisory committee recommended that impurities should be tested to ensure that they meet a.1% threshold limit for generic drugs and OTCs, particularly "where the route of synthesis may change [for an OTC drug]," Williams noted. A .1% standard for impurities identification is proposed in the current draft of the ICH impurities guideline. Calling the committee's recommendation to extend the impurities standard to OTCs "an interesting thought," Williams added: "I'm not saying that that is what we're going to do." He said he understood the committee's rationale "because it doesn't make any sense to create a double standard." If "the innovator bulk has to go through this," he queried, "why not a generic or OTC bulk?" In adopting ICH impurity standards, OTC firms would also have to begin to qualify impurities with pharmacology/toxicity testing, Williams suggested. However, he said that the agency was "not capable of dealing with [that] now," despite the logic behind the advisory committee recommendation. "But . . . it's certainly a problem perhaps for you as well as a problem for us," Williams told the group. "The concept of generics doing [pharmacology/toxicology] testing is certainly going to cause a lot of heartburn, perhaps with that industry as well as the agency [because] we don't really have a mechanism for doing this," he observed. "That is even more true for an OTC product subject to a monograph," Williams added. For OTCs, Williams asked rhetorically: "How would we do [pharmacology/toxicology] testing when it's not even part of the monograph?" He noted that FDA does not have an established process for submitting such data for OTCs to the agency for review. Currently, the agency is wrestling with ways to implement the stability requirements that it has decided to adopt from ICH, FDA's Office of Drug Evaluation I Assistant Director Charles Kumkumian, PhD, told the group. FDA is expected to adopt the ICH guideline, which contains standards for controlled room temperature, at an Oct. 27-29 ICH 11 meeting in Orlando, Fla. The guideline calls for controlled room temperature for long- term stability studies to be set at 25 (+/- 2) degrees Celcius with 60% (+/- 5%) relative humidity; and control room temperature for accelerated testing should be 40 (+/- 2) degrees, with 75% (+/- 5%) relative humidity. FDA had expressed concerns with the standards in publishing a former draft of the ICH guideline. However, reflecting the consensus of the advisory committee and industry comments, FDA agreed to support the ICH proposed testing standards in August. Addressing concerns expressed by industry members in the audience, Kumkumian assured the group that the changes in control room temperature -- currently set between 15 degrees and 30 degrees Celsius -- would not have to be translated into entirely new storage terms for the consumer. Kumkumian said that "it would be nice to put on the label exactly what control temperature means with short words, or with a small number of words" easily understood by the consumer, but in effect such labeling was "out of the question," he concluded. "The other point is, there's a lot of OTC products . . . with a lot of different temperatures out there: you have 15 degrees to 30 degrees, 25 degrees, 23 degrees. Should we standardize on this thing? Does the pharmacist know to store something at 23 degrees, 25 degrees, and 30 degrees differently? He doesn't," Kumkumian declared. The FDAer told the group that the agency would also "have to" put out a regulatory guidance on standardizing the new OTC labels. Donald Cadge, chairman of NDMA's manufacturing controls committee, said one of the primary goals of the committee is assisting FDA in implementing the new labeling control GMP regulations. Other goals of the committee include working with FDA and ICH on harmonizing stability standards internationally, standardizing child resistant packaging that would also be accessible to older Americans, and working with FDA to improve its process validation guidance. FDA Division of Manufacturing & Product Quality Director Paul Vogel pointed out to the audience that the revised GMP regulations to strengthen labeling controls, which were published in final form on Aug. 4, will become effective in August 1994. The regulations strengthen the controls necessary to prevent mislabeling by: prohibiting gang-printed labeling unless differentiated by size, shape or color; requiring special control procedures to be used for cut labeling; waiving existing labeling reconciliation requirements for cut or roll labeling if a 100% automated examination is performed; and requiring identification of unlabeled filled drug containers.





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