FDA to require cleanrooms for all nasal solutions in new rule
By Myron Struck
Washington — The Food and Drug Administration said by early next year it would require manufacturers of all prescription and over-the-counter inhalation solutions to make their products in a cleanroom “to ensure the safety and effectiveness of these solutions.” The action was taken in a Sept. 23 proposed rule issued in the Federal Register.
The ruling affects all manufacturers of “fine aqueous mists” that are created by devices known as atomizers or nebulizers. About half of the products now on the market are manufactured in sterile environments, but the FDA said it has received too many reports of adverse drug experiences from contaminated non-sterile inhalation solutions, and is taking action to protect public safety.
Public comments are being accepted on the rule through December 22. A final rule is expected to be in place by March 23, the FDA said.
The inhalation products are widely used to help correct breathing disorders. To ensure safety, those products not manufactured in a cleanroom now must meet microbial count limits.
William K. Hubbard, the FDA`s associate commissioner for policy coordination, said the agency has determined that “current manufacturing methods and purported safeguards against contamination, including the microbial limits test, have not prevented dangerous microbial contamination of non-sterile inhalation solutions for nebulization. A sterility requirement is needed to prevent such microbial contamination.”
Contaminated inhalation solutions can cause lung infections because the chemicals bypass many of a patient`s natural defense mechanisms. According to the FDA, some patients using inhalation solution products have developed a chronic obstructive airway disease or cystic fibrosis.
“Microbial contamination of these products may result in serious health consequences due to opportunistic pathogens entering the lungs or to the possible inactivation of the drug product by these microorganisms,” Hubbard stated.
The FDA said that manufacturers choosing to convert in-house manufacturing operations from their present configuration to meet the new regulations “would need to set up an in-plant sterilization process by constructing a cleanroom especially designated for the inhalation solution product.”
The Federal Register notice said that the FDA has determined that the cost of building a new cleanroom may amount to $600 per square foot, and cleanrooms may have to cover from 200 to 2,500 square feet. Each manufacturer affected, therefore, may face costs of $120,000 to $1.5 million. Businesses that create cleanrooms would then have to revalidate the safety of the inhalation solution manufactured through this process at an estimated cost of $75,000 to $100,000 per product, the Register notice states. Because each existing manufacturer not using a cleanroom creates an average of two products each, the FDA estimated that the cost per firm would be twice that amount for validation, plus the cost of manufacturing the cleanroom. Any manufacturer constructing a cleanroom will also be called on to hire technicians who know how to operate the sterile facilities.
The change in manufacturing requirement comes in the aftermath of a January, 1994, scare in which an albuterol sulfate inhalation solution was found to have been contaminated with a bacteria known as Pseudomonas fluorescens/putida. While the unspecified manufacturer voluntarily recalled the product, the red-flag was already up, and the latest incident laid a foundation for the new rulemaking.
Two years earlier, a manufacturer had recalled a metaproterenol sulfate inhalation solution after the product was found to contain excessive microbial growth identified as P. gladioli/cepacia. FDA investigators have also identified Aspergillus glaucus and Chrysosporium in other solutions that were headed to the market.
By requiring sterilization, the proposed rule is expected to provide health benefits and a reduction of liability claims, the government claimed in justifying the stiff requirements to go with cleanroom environments.
The FDA stated that it believes there are now 28 generic and over-the-counter firms manufacturing inhalation solutions, and five of them are now using non-sterile manufacturing processes. (Some of the remainder contract out work to facilities that provide a sterile manufacturing environment, the FDA said. That procedure will continue to be accepted.)
The FDA said it generally would give affected businesses six months, after a file rule is issued, to comply with the findings. Because all of the businesses affected are considered small firms, and protected under one or another government standard, the proposal will allow the firms to have one year for the conversion to take place. In the meantime, solutions manufactured in non-sterile environments will continue to be allowed to go to the market.
The FDA said it was justifying its proposed new requirement because it believed that “adherence to current good manufacturing practice (cGMP) regulations without appropriate sterilization procedures does not provide an adequate level of assurance that inhalation solutions for nebulization will not be contaminated.”
One solution that some manufacturers have turned to is an antimicrobial preservative. The FDA said that these may not be effective, and some bacteria are becoming resistant to them.
According to the Federal Register notice, the albuterol sulfate product recalled in 1994 contained benzalkonium chloride, an antimicrobial preservative. The proposal said that any manufacturer not using a cleanroom could be cited for producing a drug product that is adulterated under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351(a)(2)(B)), and misbranded under section 502(j) of the act (21 U.S.C. 352(j)). Failure to comply with the sterility requirement would also result in the agency`s refusal to approve a new or abbreviated application for the product, pursuant to section 505(d)(1), (d)(2), (d)(3), and (j)(3)(A) of the act (21 U.S.C. 355(d)(1), (d)(2), (d)(3), and (j)(3)(A)).
To comment on the rule, write: Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., Rm. 1-23, Rockville, MD 20857. For more information, contact: Carol E. Drew, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, (301) 594-2041.