Since its creation in 2002, the Office of Combination Products (OCP) has been tasked with developing regulations and guidance documents for combination products . A combination product is a product composed of any combination of drug/device, drug/biologic, biologic/device, or device/drug/biologic . The three types of combination products recognized by the FDA are: 1) single entity products, 2) co-packages, which are two or more products packaged together, and 3) cross-labeled products, when the products are sold separately but intended to be used together . The complex nature of premarket and post market regulations for combination products has left manufacturers looking to FDA for answers on which current Good Manufacturing Practices (cGMPs) are required for specific types of combination products.
Until 2013, cGMP regulations for combination products were only intermittently, and vaguely, addressed by the OCP. In 2004, a draft guidance on cGMP for combination products was released . The guidance was only 8 pages long and strongly recommended discussing cGMP issues with FDA at a very early stage in product development . This recommendation indicated that confusion surrounding cGMP regulations for combination products persisted. The next step was to create a stand-alone final rule on cGMP regulations for combination products, 21 CFR 4. A draft of 21 CFR 4 was released in 2009 to collect comments from manufacturers in an effort to ensure that the final rule provided clear guidance . In January 2013, the final rule of 21 CFR 4 was released, not to create new cGMP requirements, but to clarify how the cGMP requirements for drugs, devices, biologics, and human cell and tissue products (HCT/P) apply to combination products . However, industry requested additional guidance on the implementation of 21 CFR 4. The FDA provided this additional guidance earlier this year with the release of a draft guidance on cGMPs for combination products.
The draft guidance has been well received by industry and commended for its detailed instruction and numerous examples. The ambiguous and subjective track record of FDA cGMP guidance documents makes this draft guidance revolutionary . One significant clarification of the guidance is how manufacturers can demonstrate cGMP compliance of different combination products. For cross-labeled products, establishing compliance is as simple as following the cGMP requirements for each constituent part. For drug/device single entity or co-packaged combination products, the guidance offers two acceptable approaches. Manufacturers may establish compliance with all drug cGMP and device Quality System Regulations (QSR) requirements that are relevant to each component of the combination product. The alternative is a streamlined approach, designed to allow manufacturers to determine which set of requirements to be in full compliance with, with an additional subset of requirements. Under the cGMP streamlined approach, manufacturers must demonstrate full compliance with drug cGMPs and a subset of device QSRs. Alternatively, the QSR streamlined approach requires manufacturers to demonstrate full compliance with device QSRs and a subset of drug cGMPs . Figure 1 provides a visual of the three approaches for demonstrating compliance. Manufactures are given the freedom to select the approach they want to utilize, regardless of which constituent part of the device is the primary mode of action (PMOA) .
Figure 1: Diagram of approaches for combination product manufacturers to demonstrate cGMP compliance.
Public comments regarding the draft guidance were accepted until March 30, 2015 and FDA is in the process of reviewing these comments to prepare the final version of the guidance document . In its comments’ submission, the Combination Products Coalition requested further clarification on nine topics, including Design History Files for combination products that were not developed under design controls, requests for cGMP information in marketing applications, and design controls for early-phase investigational combination products . These comments show that there remains room for improvement within the guidance document and it is in the hands of FDA to utilize this feedback to further the effectiveness of the final version.
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