FDA Issues Final Rule on cGMP Requirements For Combination Products, Draft Guidance

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The Food and Drug Administration is issuing a final rule on the current good manufacturing practice (cGMP) requirements for combination drug-device products, according to a notice published Jan. 22 in the Federal Register (78 Fed. Reg. 4307).

The agency also is releasing a draft guidance for industry on submissions for post-approval modifications to a combination product approved under a new drug application (NDA), biologics license application (BLA), or premarket approval application (PMA). A notice announcing the draft guidance also appeared in the Jan. 22 Federal Register (78 Fed. Reg. 4417).

Final Rule

FDA said the final rule (FDA-2009-N-0435) clarifies which cGMP requirements apply when drugs, devices, and biological products are combined to create combination products. Additionally, the rule includes a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with cGMP requirements for “single-entity” and “co-packaged” combination products, the agency said.


FDA says that the streamlined approach set forth in the final rule “will help ensure that cGMP requirements for co-packaged and single-entity combination products are consistent and appropriate, without duplicative or otherwise unnecessary aspects.”  




The final rule defines co-packaged products as two or more separate products packaged together in a single package or as a unit and comprising drug and device products, device and biological products, or biological and drug products. A single-entity product is defined as a product comprising two or more regulated components (drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed.

The final rule is “largely identical” to the proposed rule that was issued in the Sept. 23, 2009, Federal Register (74 Fed. Reg. 48,423), FDA said (3 MELR 671, 10/7/09). Comments on the proposed rule originally were due in late December 2009, but the comment period was extended to Feb. 5, 2010 (4 MELR 90, 2/10/10). The agency said it received 25 sets of comments from regulated entities, trade associations, and individuals.

300 Manufacturers Affected

FDA said it estimates that approximately 300 manufacturers of combination products will be affected by the final rule. “These manufacturers of combination products should benefit from the greater clarity provided regarding what regulatory provisions apply to their products and how they may comply with them,” the agency said. “For both existing and future products, the streamlined approach set forth in the final rule will help ensure that cGMP requirements for co-packaged and single-entity combination products are consistent and appropriate, without duplicative or otherwise unnecessary aspects.”

In discussing the impacts of the rule, FDA said it believes that the rule “is not a significant regulatory action under Executive Order 12866.” The agency also said a number of comments “suggested that the regulatory impact analysis of the proposed rule underestimated the incremental cost to comply with this rule.”

FDA said it disagreed with the comments, adding that all manufacturers “are already responsible for compliance with the [cGMP] requirements that apply to each constituent part of their combination products,” such as a drug or device.

The final rule is effective July 22.

More Clarification Needed

Bradley Merrill Thompson, an attorney with Epstein Becker & Green in Washington, told BNA Jan. 18 that the final rule did not change significantly from the proposed rule and there were “a number of things that could have been clarified.”

Thompson said there were a lot of comments on the proposed rule and FDA offered explanations to these comments in the preamble to the final rule, “so you have to refer to the preamble to figure out what it means.”

FDA plans to publish another guidance document as a companion to the final rule, which is “where we will find a lot of answers to questions,” Thompson said. The final rule “ups the ante on getting the guidance out as soon as possible.”

Thompson said companies will need to have systems in shape for when the final rule becomes effective.

Additionally, Thompson pointed out two areas in the preamble where FDA departed from what it has said in the past. Specifically, he said the preamble states that syringes are considered devices and not container/closures. Thompson also said the final rule suggests design controls apply to combination products.

“We're very thankful” that the final rule is out, Thompson said. People at FDA “have been reluctant to talk about combination product cGMPs” and now there is no reason for them not to talk, he said.

Draft Guidance

The draft guidance, Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA, provides the underlying principles to determine the type of marketing submission that may be required for post-approval changes to a combination product that is approved under one marketing application, FDA said.

The agency said the draft guidance contains tables that may be helpful in determining what type of submission to provide for a post-market change.

Comments on the draft guidance are due April 22. The docket is No. FDA-2012-D-1240.

By Bronwyn Mixter  

The Federal Register notice on the final rule is at http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/html/2013-01068.htm. The notice on the draft guidance is at http://www.gpo.gov/fdsys/pkg/FR-2013-01-22/html/2013-01069.htm.