Rules Relaxed for Changes

In many cases, postapproval packaging changes will no longer have to be approved by FDA prior to implementation.

For years, industry has been asking FDA to allow more leeway with postapproval changes to packaging. It finally got its wish when FDA's Center for Drug Evaluation and Research (CDER) published the guidance document "Changes to an Approved NDA or ANDA" in November. Some of the new guidelines give industry even more latitude than what it originally asked for. The guidance is a result of the FDA Modernization Act (FDAMA) of 1997, which mandated fewer restrictions on changes.

Previously, in most cases firms could not make packaging changes to an existing product without prior FDA approval. The new document creates three reporting categories; two do not require prior approval. For major changes that have a substantial potential to adversely affect a drug's identity, strength, quality, purity, or potency, prior approval is still required. Changes that have a moderate adverse potential require the submission of a "Supplement—Changes Being Effected in 30 Days," known as a CBE-30. If FDA does not object within 30 days of receiving the supplement, the change may take effect. In a few cases, the change may take effect when FDA receives the supplement. Changes that have minimal adverse potential only need to be described in the firm's next annual report to the agency.

The biggest news is for users of blisters and other unit-dose packages for nonsterile solid-oral dosages. Any change to these packages is considered minor, provided that the new package has the same or better protective properties and that its components have previously been used with a CDER-approved product of the same type.

If the protective properties of the package are lessened for any dosage form, FDA automatically considers the change to be major. And if a component to be used is not already used for a CDER-approved product, the change requires at least the submission of a CBE-30. For liquids and semisolids, such changes require prior approval.

For bottled nonsterile solid-oral dosages, changes from one plastic container to another are considered minor provided that the new container is made of the same kind of plastic, offers the same or better barrier, and uses components that have been used for a CDER-approved product. Also considered minor are the addition of or change to a child-resistant closure, changes in the same type of bottle filler, and changes or additions to seals and cap liners.

For nonsterile semisolids and liquids, changes now considered minor include modifications to caps, cap liners, and seals and increases in the wall thickness.

Most packaging changes to sterile drugs are major, especially those that might affect sterility. Also considered major are changes to components that control dose delivery and the deletion of secondary packaging components that provide additional protection.

Changes in the size and shape of a container for a sterile drug product are considered moderate. Also in that category is any packaging change not specifically mentioned in the guidance. Changes to desiccants can be implemented once FDA has received notification.

Most labeling changes require prior approval. Those that require only a CBE-30 include adding or strengthening a warning or contraindication; adding or strengthening warnings about abuse and overdosage; adding information to increase safe use; deleting false, misleading, or unsupported claims; and making changes to meet specific FDA requests. Information in the product description that does not change dosage strength or form is considered minor.

The guidance also covers site changes. Moving the primary packaging site is often a major change. Moving the secondary packaging or labeling site is a minor one. If more than one change is involved, the most restrictive reporting category should be followed.

The guidance does not cover how a firm should go about proving that a new package is equal to or better than the old one and what the approved test methods are. That information may be covered in PACPAC, the Scale-Up and Post-Approval Change (SUPAC) guidance for packaging, a draft of which is currently being developed. A workshop for FDA and industry is scheduled for May 31—June 2 at the Crystal Gateway Marriott in Arlington, VA.

Also needed is a database of which packaging components have been used on CDER-approved products; currently, FDA has no such list.

Copies of the guidance can be obtained from the Center for Drug Evaluation and Research Drug Information Branch (HFD-210), 5600 Fishers Ln., Rockville, MD 20857; 301/827-4573.

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