The Food and Drug Administration is uncorking a new guidance on packaging information to accompany applications from pharmaceutical companies wanting to market new drug products. But pharmaceutical companies aren't ready to drink a toast yet over the draft guidelines on container closure systems, which will eventually replace guidelines last issued in 1987. The new version makes a number of changes ranging from the very welcome to the insignificant to the potentially troublesome. It categorizes products such as inhalants, injectibles, orals and topicals, then further identifies subcategories. Guidelines are established for the closure systems in areas such as safety, characterization, protection, compatibility, performance and quality control. Gerry Frank, a former top packaging executive for Rhone-Poulenc Rohrer, and now on his own as a consultant at MQS, Inc. (Jamesburg, NJ), says the draft guidelines are considerably clearer than their 1987 predecessor. He also likes the way the FDA used a rational system to rank dosage form, with potentially more dangerous systems of interaction ranked high, and conversely those with potentially low interaction ranked low. Having said that, though, Frank thinks the FDA may have gone too far in some areas. For example, the FDA suggests-and remember, even when final these will be guidelines, not requirements-that suppliers submit "a quantitative extraction profile for elastomeric or plastic components of metered dose inhaler (MDI) valves, and MDI container walls (coated or uncoated)." The 1987 guidelines do not mention extraction profiles, although Frank states the FDA has been asking for them more frequently over the past five years. Specifying extraction studies in black and white would be something that probably numerous companies would be unhappy about. The actual laboratory work is not that expensive. But for each component, a unique test method and validation process must be developed. "That can be a huge cost," says Frank. "A company may be looking at a cost of $5ꯠ to $10ꯠ per test for each compound extracted. An NDA [new drug application] can require testing on anywhere from two to 22 compounds, maybe more." Eric Sheinin, director of the FDA office of new drug chemistry, is a key policy maker with regard to the guidelines. "I can tell you that there have been problems with the safety of MDIs in the past, both fatalities and serious reactions. I am not sure that it has been proven that those problems were the result of something extracting out of the system. But many of these products are used in life-threatening situations, and we don't want to even risk adverse reactions. Perhaps we are erring on the side of caution." Comments on the draft were due September 15, after this was written; so it was impossible to know whether the draft unleashed a torrent of complaints or simply a dribble. Ron Jaketic, manager of Wallace Eng., a subsidiary of Carter Wallace, Inc., Cranbury, NJ, agrees that the proposed new guidelines are clearly written. The guidelines were discussed during an August 12 meeting of an ad hoc group comprising members of the Institute of Packaging Professional's Drug and Pharmaceutical Packaging Committee. Jaketic chairs the committee. The issue of quantitative extraction profiles was discussed a little. A bigger issue, though, according to Jaketic, was the FDA's seeming desire to see more information from the drug master files (DMF) of packaging suppliers. For example, the draft guidance says: "Manufacturers who supply raw materials or intermediate packaging components should inform customers and update DMFs concerning any intended changes to formulations or manufacturing procedures." Jaketic doubts that this is being done now, particularly with regard to manufacturing changes. "Vendors are reluctant to consider those kinds of changes significant," he explains. Another concern is the draft's suggestion that manufacturers submitting NDAs-or supplemental NDAs- should be able to prove that each of the container closure components has been approved by the FDA via a food additive regulation. This is especially suggested when a company wants to change an already-approved container for inhalation and liquid-based oral and topical drug products. These food additive regulations are notoriously time consuming. Moreover, it is somewhat perplexing that the FDA would want a food additive petition for a chemical used in a drug, although perhaps that would make sense for some products, such as cough syrups. Keller & Heckman, the Washington law firm that represents the Society of the Plastics Industry, said in its newsletter that a food additive application for a topical exposure may be "of little or no relevance. Furthermore, the level of exposure to a material resulting from its use in a drug packaging application is likely to be markedly different than the exposure resulting from a food packaging use." "We expect companies to prove that the components they use are safe," Sheinin answers. "One way to do that is if the component is cited in the Code of Federal Regulations via an approved petition. But if someone has a different approach that they can justify scientifically, they are welcome to take that approach. But they may want to come in and talk with us before spending a lot of time and money."
