Mark A. DeSorbo
BETHESDA, MD—A task force from the Parenteral Drug Association (PDA) has submitted a draft of “change tables” to the U.S. Food and Drug Administration (FDA) for consideration in developing the first-ever post approval change (PAC) guidance for sterile products.
“There are no PAC guidelines for sterile products,” says William H. Stoedter, PDA's director of regulaory affairs. “Sterile liquids are one of the most scientifically challenging products to make. To make any sterile product, you have to sterilize everything, and personnel in the manufacturing facility have to know how to work in a cleanroom.”
While there is general PAC guidance for pill form drugs, like aspirin, and liquid medicines, like cough syrup, Stoedter says the process establishing guidelines for sterile products has been difficult for the FDA.
“The agency can't get its arms around what kinds of changes are appropriate,” he adds. “We want to start a dialogue with the agency as well as save the industry time, money and help it improve products.”
According to the FDA's Center for Drug Evaluation and Research (CDER), PAC guidelines indicate how to classify various types of modifications, namely filing categories and what types of data are required to understand the impact of the change. When pharmaceutical manufacturers make changes after the product and process has been federally approved, they must do one of three things, depending on the type of change.
A manufacturer must note the change in an annual report; notify the FDA in writing that the change will be made within 30 days notice; or get prior approval from the FDA before the change can be made. In any case, a manufacturer must always validate the change and follow current Good Manufacturing Practices (cGMP).
The protocol, Stoedter says, makes it easy for a cough-syrup maker to switch from plastic to glass bottles, but it's a different story if a sterile liquid manufacturer wants to make that same modification.
“It could take sterile product manufacturers six months to a year to make a change that might even improve the process. If there is no incentive to improve sterility insurance levels, the process will just remain the same,” he says. “Having PAC guidelines for sterile products is an incentive for the industry and the [FDA].”
The PDA's PAC proposal for sterile products was submitted to CDER's Office of Pharmaceutical Science last October.
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Using the same FDA change criteria, PDA has made recommendations that address changes to components and composition; location within a site; location to a different site; in process controls; terminal sterilization process; equipment; sterile filtration; sterilization of equipment and components; and processing time. The tables also recommend chemical, physical and microbial informational requirements; change examples and impacts; the level of the modifications (minor, moderate, major); and the proper federal filing requirements.
According to the proposed change tables, PDA classifies the addition of another filter or the selection of a tighter pored filter in the filtration process as a “minor change.” That modification would require a mention in an annual report.
If, however, the drug maker decides to reduce the number of filters or switch the filter medium, that change would be considered “moderate” and that would require a letter of intent to the FDA indicating that the change will occur within 30 days.
An example of a major change to sterile filtration would be altering the method of filtration, which would require prior approval from the FDA.
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“This is very helpful. We will study this and see where it fits into our current thinking,” says Ajaz S. Hussain, deputy director of CDER's Office of Pharmaceutical Science, declining further comment.
Stoedter, however, says it is too soon for CDER to respond, although it's in the agencies best interest to do so.
“PAC has been successful for other types of drugs, so that's why we don't want this to drop off the FDA's radar screen,” he adds. We don't want to be pedantic. We just wanted to lay some ideas out on the table and say, “Here's a point to start discussion.”