Originally Published PMPN May 2001
The agency has published a guidance document answering some of the most frequently asked questions on postapproval changes for drugs.
FDA's guidance on postapproval changes for drugs, issued in November 1999, was one of the agency's most significant regulations affecting drug packaging in recent years. It divided potential postapproval changes into three main categories. The guidance called on the agency to approve major changes before implementation. Moderate changes, however, could be implemented 30 days after notifying FDA as long as the agency had not issued any complaints. And minor changes only needed to be documented in a firm's annual report to the agency.
After such a sweeping change in procedure, it was inevitable that some companies would seek clarification on various issues related to it. In response, FDA has published a guidance document answering some of the most frequently asked questions. The document, which raises several issues specific to packaging, can be viewed at http://www.fda.gov/cder/guidance/4163fnl.htm.
The following are some of the document's packaging-related highlights:
- Changing to a different site for the fabrication of packaging components or materials does not in and of itself require prior approval from FDA as long as there is no change in the dimensions, composition, specifications, or processing aids for the package. However, packaging-related site changes that are also related to the processing of the drug, such as the sterilization, washing, and irradiation of the drug, do require prior approval.
- Tertiary packaging sites, for example, those that package sample cartons and promotional material into a larger carton or box with the product name on it, are considered the same as secondary packaging sites for the purpose of the postapproval changes guidance. If the site is not required to be registered with FDA or to be subject to GMP inspection, the company does not need to notify FDA of changes related to it. However, attaching inserts and handling cartons that contain product labels are functions that do require FDA registration and GMP inspection.
- Changing to a different in-house or contract sterilization site for packaging components only requires a mention in the annual report as long as the process is not materially different from that described in the approved application and the facility has passed the appropriate GMP inspection.
- The addition of a new aseptic filling line requires prior approval.
- For a sterile product, changing the filling speed by adding or adjusting fill heads just needs annual report documentation as long as total processing time does not extend beyond the approved application's validated limits.
- A decrease in fill volume is a specification change and therefore requires prior approval.
- Changes in the plastic canister of a desiccant used in a solid oral dosage form product are subject to the same standards as changes to the plastic of a container-closure system.
- Deletion of a cotton filler or desiccant is considered to be a moderate change and requires immediate FDA notification but not prior approval.
- Equivalency or comparability protocols are defined as "tests, validation studies, and acceptable limits to be achieved to demonstrate the absence of adverse effects on the identity, strength, quality, purity, and potency of the drug from specific types of changes." Such protocols are needed for many of the changes to container-closure systems that do not require prior approval. They are not the same as the approved stability protocol, though the stability protocol may be a part of them.
- A change from a trilayer to a bilayer blister package only requires an annual report mention when the product contact surface remains the same and data show the bilayer package has the same or better protective properties.
- If a firm has notified FDA of a moderate change to be effective after 30 days, FDA will notify the firm within 30 days on whether prior approval is required or if required information is missing from the report. But it does not expect to complete substantive reviews and action letters within 30 days. The absence of information from the report does not automatically change the reporting category to prior approval, but distribution of the product made with the change has to be delayed until the missing information is submitted.
The full text of the November 1999 guidance can be viewed at http://www.fda.gov/cder/guidance/2766fnl.htm.
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