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By Laura O’Brien

Laura O'Brien-finalWe all probably know somebody who uses a drug-device combination product, whether it is insulin in a pen injector, an inhaled drug for asthma, or a liquid antibiotic given to a child in a spoon. The device part of the combination product may measure the dose and/or deliver it.

Current best practice for sponsors is an integrated, systematic approach to the development and manufacture of safe and effective drug-device combination products. A combination product should be intuitive to the end-user (patient or care-giver), deliver the right dose with the right quality, and have low risk of user errors causing over/under dosing or injury.

In the U.S., regulation of combination products was historically complex due to the involvement of more than one Food and Drug Administration (FDA) center (Center for Drug Evaluation and Research [CDER], Center for Biologics Evaluation and Research [CBER], Center for Devices and Radiological Health [CDRH]), sometimes resulting in unclear requirements or inconsistent implementation.

FDA finalized regulation (21 CFR 4) in 2013 to clarify which current good manufacturing practices (cGMP) requirements apply when drugs, devices, and/or biologic products are combined to create combination products.

The U.S. definition of combination products from a regulatory standpoint includes:

  • “Single entity” or “integral” product comprising two or more different regulated components (drug/device/biologic) that are physically, chemically, or otherwise combined or mixed;
  • “Copackaged” or “kitted” unit in a single package comprising drug and device, device and biologic, or biologic and drug products;
  • “Cross-labeled” drug, device, or biologic product packaged separately that according to its investigational plan or proposed labeling is intended for use only with another individually specified drug, device, or biologic product where both are required to achieve the intended use, indication, or effect.

FDA has stated that the final rule does not create new cGMP requirements, but clarifies how to apply them to drug-device combination products. The cGMP requirements that apply to each of the constituent parts of the combination product continue to apply when they are combined, thus 21 CFR 210 and 211 apply to the drug constituent part(s), and 21 CFR 820 applies to the device constituent part(s). The final rule sets forth a streamlined regulatory framework to implement cGMP requirements for copackaged and single-entity combination products.

In the cover article in the February issue of the AAPS Newsmagazine, we review several facets of the new rule, including ways to comply with GMP requirements, regulatory challenges within FDA, design control requirements, human factor study requirements, sponsor implementation challenges, and compliance for legacy products (especially with design controls). Also included in this issue is a sidebar article on EU Regulatory Approach for Drug-Device Combination Products. Read Regulatory Requirements for Drug-Device Combinations: Are We Clear?, from the RS section, and then participate in the discussion point below.

What discussion framework is available to resolve the implementation challenges for drug-device combination products?

Laura O’Brien, Ph.D., is senior research fellow in Boehringer Ingelheim’s Global CMC Experts group. She has broad expertise in her responsibility for the scientific planning and review of documents authored by CMC Development scientists for the Quality section of regulatory submissions, from early drug development through global product registration and approval.