FDA released its long-awaited proposed rule on good manufacturing practices for combination products Sept. 22.

The ¹ draft regulation, about four years in the making, is intended to help firms comply with necessary parts of device, drug and biologics manufacturing regulations. FDA estimates that about 300 combination product manufacturers will be affected.

But until companion guidance is developed, a number of nitty-gritty questions will remain unanswered, some industry reps say.

In particular, it is unclear which FDA center will oversee compliance by the maker of a particular combination product, and how FDA will integrate principles of the proposed rule into its manufacturing facility inspections, says regulatory law expert and former FDA official Jim Cohen, of the law firm Buchanan Ingersoll and Rooney.

FDA Describes Streamlined GMP Approach

Combo products include two or more categories of regulated components combined into a single entity; two or more distinct product categories that are co-packaged; or products of a different category packaged separately but only intended for use with each other, where both products are required for the intended use or effect.

Each component of a combination product retains its unique regulatory status, even after combined, according to FDA. This means that, technically, a drug is required to meet all pharmaceutical current GMP regulations and a device all aspects of the quality system regulation, even if the two elements are combined into a single product.

But some products may use a "streamlined approach," intended to avoid duplicative manufacturing processes, given the overlap between device QSRs and drug cGMPs, the draft rule states.

Under the streamlined approach, firms that make single-entity or co-packaged combo products at the same facility can adopt one operating system as the baseline, and then tack on certain additional procedures as needed, the agency explains.

Specifically, combo products that comply with drug cGMPs must also comply with the following device requirements: management responsibility; design controls; purchasing controls; corrective and preventive action; and installation and servicing, if the product involves hardware that requires installation and/or servicing.

If the firm adopts device QSRs as its baseline, it must comply with the following drug regulations: testing and approval or rejection of components, drug product containers and closures; calculation of yield; tamper-evidence packaging for over-the-counter drug products; expiration dating; testing and release for distribution; stability testing; special testing requirements; and reserve samples regs.

The added requirements should be incorporated in the firm's operating system where "most appropriate," and should be included in the company's written procedures, FDA says.

When combo product parts are manufactured at separate facilities, the streamlined approach does not apply: each part is subject only to device QSRs or drug cGMPs. If the parts are then packaged together at a third facility, the streamlined approach can be used during that portion of the production process only.

Guidance Will Follow Final Rule

The proposed regulation elaborates on a 2004 draft guidance on the topic (² Also see "Combination Product Rules Clear OMB, To Be Released In Weeks" - Medtech Insight, 21 September, 2009.). Combination product makers say the proposal answers some of the questions raised by that draft guidance, but not all.

"I'm pleased that, number one, they've got it up because that starts a dialogue process that we really haven't had for the last several years," Brad Thompson, head of the Combination Products Coalition industry trade group, said in an interview.

Once the rule is finalized, FDA intends to issue companion guidance on the streamlined approach, which Thompson said is "welcome news." "The proposed rule is at such a high level ... that it leaves a lot of questions to interpretation," he said.

For example, FDA refers to device and drug components handled in the same facility, but "for some larger companies with larger facilities, they may have drug and device processes ongoing in the same facility but really not connected to each other," Thompson said. "There the streamlined approach wouldn't make sense."

Buchanan's Cohen said FDA will also need to flesh out its oversight procedures. "Within headquarters, between CDER, CBER and CDRH, who is going to be responsible for the compliance oversight of the product, and how are they going to talk to each other? What kind of guidance will be given to field investigators?"

These sorts of issues will not be clear even when the final rule is published, Cohen said. "They have to do a draft guidance as soon as they can when they issue the rule."

- Jessica Bylander ( ³ j.bylander@elsevier.com )

Proposed Rule Defines Good Manufacturing Practices For Combo Products

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