FDA's proposed "streamlined approach" to combination product manufacturing raises a number of practical questions such as what elements are actual components of a combo product and at what stage the streamlined system kicks in, firms say.

Combination product makers and other industry reps met with FDA officials Jan. 12 to discuss the combination products current Good Manufacturing Practices ¹ proposed rule and work through case studies to test the rule in action.

FDA extended the comment deadline on its Sept. 23, 2009, proposed rule to Feb. 5 to give firms more time to provide meaningful feedback.

An FDA working group, including cGMP staff from all the product centers, the Office of Regulatory Affairs and the Office of Chief Counsel, will craft the final rule, as well as companion guidance and a training program for FDA staffers to help them apply the new policy consistently.

Firms Call For Clarifications

The rule attempts to streamline GMP requirements for the various parts of a combination product by allowing firms to adopt either the device or drug quality system as a baseline and tack on certain additional requirements for the rest of the product component types (² Also see "Proposed Rule Defines Good Manufacturing Practices For Combo Products" - Medtech Insight, 28 September, 2009.).

"The goal is to ensure that the rule provides for the manufacture of safe and effective combination products while avoiding redundant regulatory requirements," John Weiner, associate director for policy at FDA's Office of Combination Products, said at the workshop, hosted by the Regulatory Affairs Professionals Society and the Combination Products Coalition.

Weiner said industry has been generally supportive of the proposed rule, but wants more clarity on certain points. For example, companies are unclear on what constitutes a "constituent part" of a combination product, he said.

"The issue here seems to be distinguishing between what is a component of a drug or a component of a device, as opposed to a constituent part of a combination product," Weiner said.

"This is a tricky issue, of course, because combination products combine things in ways such that the final drug isn't going to be in a nice little bottle or pill," he said, but rather may "be stuck on a stent or something."

This confusion "raises questions about applying GMPs for components and ingredients even before they arrive at a combination product manufacturing facility," noted Nancy Kazantzis, senior principal scientist at Pfizer, at the workshop.

Is There Wiggle Room In The Rule?

Manufacturers also want more flexibility in deciding whether the specified additional requirements should apply to their product.

While working through the case studies, for example, the workshop participants found that following the streamlined approach sometimes led to "overkill," Combination Products Coalition Director Bradley Thompson said.

FDA's Weiner explained that, of course, the specified cGMP requirements "apply to your product only when they apply to your product."

"If your product isn't an [over-the-counter] product, for example, the OTC tamper-evidence packaging requirements ... wouldn't apply," he said.

Firms may also want to avoid added requirements that just don't make sense, Weiner said.

"There still is a basic notion in the cGMP regime that you do what makes sense for your type of product," he said. If companies can justify why certain parts of the reg don't apply or seem sensible, they may be able to depart from the regulation at face value, he said.

When Is The Streamlined Approach Triggered?

There is also ambiguity as to when the streamlined approach is "triggered."

According to the rule, the streamlined approach kicks in when different component product types - drug, device or biologic - are manufactured at the same facility.

Some companies questioned the "facilities"-based approach. For very large companies with in-house drug and device manufacturing businesses, for example, it might not make sense to operate under one combined quality system, industry reps said.

Companies "should be able to choose between a separate system or a streamlined system, whatever works for the firm and their product," Pfizer's Kazantzis said.

Further, other GMP aspects, such as purchasing and installation, are not tied to a facility, per se.

"We clearly should distinguish those that really are pre-facility or post-facility requirements and how they get managed," FDA's Weiner agreed.

Companion Guidance Is Critical - Firms

FDA and the industry reps agreed that the companion guidance to the final rule will be critical.

"The plan all along has been to issue some kind of an accompanying guidance with the final rule," Weiner said, but he wondered whether FDA should wait until the final rule is issued so it can use the guidance to address new questions that arise.

More likely, he said FDA will probably issue draft guidance concurrently with the rule, "with the expectation that we may well want to revise it or amend it."

Companies, on the other hand, recommend that FDA put out guidance now.

"The sooner a draft guidance document can go out, the better off we'll be," said Leighton Hansel, director of regulatory affairs at Abbott Laboratories.

The draft guidance could address comments on the proposed rule, and elicit comments that could help FDA in finalizing the rule, Hansel suggested.

Implementation Questions

Finally, the industry reps raised questions about how and when the final rule would be implemented.

FDA has not yet determined whether the rule will apply to already approved or cleared products, or whether those products might be grandfathered in.

Companies also said the suggested implementation date - 180 days after publication of the final rule - might not be feasible.

Some firms say a yearlong implementation period would be more appropriate.

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

Company Questions Remain Unanswered In FDA's Combo Products GMP Rule

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