A Hybrid Approach to Combination Products

As manufacturers focus more efforts on acquiring or manufacturing biologics, the popularity of prefilled syringes continues to rise. This product format is replacing vials, which are less convenient for caregivers and patients to use. FDA considers prefilled syringes to be combination products because they contain two regulated constituent parts (i.e., a biologic and a medical device). Even though manufacturers are responsible for ensuring the quality of combination products, some companies may not be certain about what quality system to apply to their production.

In the absence of a final rule that governs combination products, manufacturers should contact the agency if they have questions. “The individual constituent parts [of a combination product] must be manufactured in accordance with the cGMPs applicable to that type of article,” says John Barlow Weiner, associate director for policy in FDA’s Office of Combination Products. “For example, if a facility makes an autoinjector, it must comply with the quality-system regulation at 21 CFR 820, and a facility that makes the drug for inclusion in the injector must comply with drug cGMP requirements at 21 CFR 210 and 211,” he adds.

On Sept. 23, 2009, FDA published a proposed rule for combination products that draws on existing quality systems for drugs and devices. The most important message of the proposed rule “is that while the constituent parts are separate, the individual regulations that pertain to those constituent parts apply to those constituent parts,” says Mike Gross, senior consultant for combination products at Biologics Consulting Group. “At the point where the constituent parts are combined, both regulations apply.”

From that point onward, manufacturers have the option of applying a streamlined quality system that combines the regulations for drugs and those for devices, according to the proposed rule. FDA considers drug and device regulations to be similar, but recognizes that they do not overlap in certain areas, says Gross. To create a streamlined quality system, a firm can use one regulation as its basis, then add the elements unique to the other regulation as necessary to ensure the quality of the combination product.

For example, if a combination product’s primary mode of action is its drug, then a firm can base its quality system on 21 CFR 210 and 211. But to be fully compliant, the firm’s quality system would have to address provisions in 21 CFR 820 regarding management responsibility, design controls, purchasing controls, installation, and servicing, according to the proposed rule. Likewise, a firm could opt to base its quality system on 21 CFR 820 if the combination product’s primary mode of action were its device (e.g., a drug-eluting stent). But to be fully compliant, the firm would have to address provisions in 21 CFR 210 and 211 regarding stability testing, expiration dating, and reserve samples, among other topics.

Although the proposed rule provides details about how to comply with applicable regulations, some companies find parts of it ambiguous. One source of uncertainty includes the quality-system requirements for the manufacture of components (e.g., syringe barrels) and constituents of prefilled drug-delivery systems, which some manufacturers view as drugs in functional container-closure systems, says Gross. Some manufacturers believe that drug-delivery system components should be regulated as components of a drug-product container-closure system, rather than as components of the device constituent of a drug–device combination product. But this interpretation is controversial, and companies are seeking official clarification and hope to see this point addressed in the final rule or in a subsequent guidance, says Gross.

“The proposed rule is not in force and, therefore, is not itself a regulation with which manufacturers must comply,” says Weiner. FDA inspections will continue to evaluate whether makers of combination products are operating in accordance with cGMP, based on existing regulations, “as well as with associated Agency Staff Manual Guides relating to manufacturing facility inspections,” says Weiner.

And despite its potential ambiguities, the proposed rule has found acceptance within industry. “Based on the comments received, it appears that stakeholders generally support the approach of the proposed rule with most comments seeking clarification rather than major substantive revision,” says Weiner. By the time the rule becomes final, drug manufacturers should have the information they need to produce increasingly popular products, such as prefilled syringes, in full compliance with FDA regulations.