Medical Device Daily Washington Editor

FDA has published the final rule for good manufacturing practices for combination products, a move that was more than eight years in the making. The agency proposed a guidance in 2004, then re-filed the guidance as an appendage to the Code of Federal Regulations five years later. The agency released the final rule this past week, but at least one observer believes the final rule creates an enormous problem for contract manufacturing, one that may not be resolved by the time the final rule goes into force.

FDA's draft rule for "combo GMPs" indicated the agency was amenable to grafting subsets of GMP requirements from one area of regulation onto the entire set of requirements from another rather than force manufacturers to comply with all relevant GMP requirements (Medical Device Daily, Oct. 1, 2009). Under the rubric proposed in 2009, a combination device regulated primarily as a drug would have to address six items from the device quality systems regulations, including management and design controls, both of which appear in the final rule. The reverse situation includes a list of eight pharmaceutical GMP requirements when the item is regulated primarily as a device, including stability testing and testing for containers and closures.

Brad Thompson with the consultancy Epstein Becker Green (Washington) told Medical Device Daily the convenience kits discussion in the final rule is difficult "if for no other reason than the definition of a convenience kit is pretty uncertain." He explained that the difficulty "has less to do with the word convenience than it has to do with the word kit."

Thompson noted that the definition of a convenience kit is a drug and a device co-packaged, but a convenience kit "is still a combination product. What FDA is saying is that the GMPs don't come together for those kinds of kits when the only thing that binds them is that they are used together when there has been no re-labeling" and no change in intended use for any of the components.

Thompson said the extensive use of contract manufacturing has created an enormously complex supply chain/compliance picture, such as when one or more companies make components, another firm assembles them, and a third entity handles packaging and/or sterilization.

"The supply chain complexities involved in combination products are amazing, and we've been making the point that this very short rule doesn't really give us any guidance" for those arrangements, Thompson said. "Rather than try to address [those issues] in this rule, what they have been telling us is that they will try to address it in a companion guidance," he explained.

Thompson said industry has urged FDA to roll out a draft of the companion guidance promptly because "without the guidance, it's hard to get going on" the combo product rule for contract manufacturing purposes. "I think FDA is doing the best it can to get the guidance out soon" because compliance with the new portions of 21 CFR Part 4 commences in 180 days, he remarked.

One of the enforcement issues that will arise is that the FDA inspectorate comes from district offices and from FDA headquarters, which has fed complaints of inconsistent interpretations of regulations. Thompson said the Office of Regulatory Affairs at FDA has promised that inspectorate personnel will all receive the same training on this new rule. "One of the comments we made" was that the agency should provide "rigorous and specific training throughout the field force to make sure they're consistent in how they approach those rules," he said.

Thompson said, "there isn't any training" on how to address such circumstances at present, and "it's largely the inconsistency that worries us." He said it is difficult to tell whether ORA has some sort of template for training because "they treat training as an internal matter and they're not very transparent" on the subject. He indicated that FDA has communicated a need "to get the final rule out first," but there is some ambiguity as to whether the agency will wait until the supply chain companion guidance is out to train investigators in the relevant standards.

Combo changes guidance problematic

FDA also published a draft guidance dealing with changes to combination products, which does not address products based on 510(k) devices or abbreviated new drug applications (ANDAs). Thompson explained, "I don't know what the percent would be, but for true single-entity combination products – that is where the drug and device are so intertwined as to be inseparable – a lot of those products get to market through one of the three regulatory mechanisms," a list that includes biologics license applications (BLAs) as well as new drug applications (NDAs) and PMAs.

"The problem is that [the draft] treats every device component as though it ought to be subject to the PMA rules," Thompson asserted. He said most syringes "would be class II devices subject to the 510(k)," but noted that if a drugmaker opted to sell a drug packaged with a pre-filled auto-injector, "the drug company will file a supplemental NDA to add the pre-filled injection system."

"The problem is that the injectors are not PMA devices" and are subject to the iterative nature of devices in general. He said "what FDA is saying is that every time you change that injector, you have to use the rules written for class III devices," which under the draft would migrate into a requirement to address the rules for supplemental NDA filings.

"That tremendously ratchets up the number of changes that industry will have to file for that kind of combination product," Thompson said, adding, "that's part of the trend at FDA, to require more submissions for product changes." He mentioned the guidance for changes to 510(k) devices that was scuttled by the Food and Drug Administration Safety and Innovation Act of 2012, and remarked, "here we are confronting the exact same issue."

"There they were just ratcheting up requirements for 510(k) generally, and here they are ratcheting up to a class III product," Thompson observed. He said this approach is "completely out of synch with the risks associated with the changes."

"I do foresee a lot of comments objecting to that," Thompson predicted.

Mark McCarty, 703-361-2519

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