Originally Published MDDI March 2005

Coatings

Risk Analysis of Coated Combination Products

Once a lead center has been assigned, the development path can be more clearly defined and documented in the design and development plan to satisfy design control requirements. The plan must address the safety and efficacy of the agent as well as the device parts of the product.

Risk analysis is an important element of design controls and should be performed early in the development cycle. Results of the analysis dictate requirements for the safe and effective performance and use of the combination product, including the incorporated agent.

The hazards associated with a coated combination product design include those of a coated medical device identified in the previous article. Additional hazards associated with the coated combination product include unacceptable biological response to the carrier or agent at the implantation site, side effects or toxicity of the agent, or unacceptable response to portions of the carrier or agent that separate from the device. This would include emboli of the coating that are released into the bloodstream or that constitute wear particles shed from coated orthopedic devices, or molecular fragments of biodegradable coatings. These fragments may concentrate locally or in distal organs. Also included is unacceptable performance of the coating—that is, the coated device or agent fails to perform as indicated in claims.

The potential failure modes for these hazards are also identified. These modes include unacceptable biological or toxicological properties of the carrier or agent, flaking or unintended removal of the carrier or agent from the platform surface, and inconsistent coating of the platform surface or irregular distribution of the agent in the carrier. In addition, deterioration of the uncoated platform materials or function by the coating or coating process, and deterioration of the performance of the carrier, agent, or platform before use are also included.

The specifications for coated combination products are created in part to address the potential failure modes identified in the risk analysis. These specifications include acceptable biocompatibility and toxicity of the combination product, including toxic side effects of the agent, thickness and uniformity of the carrier, and uniformity of agent distribution in the carrier. Adhesion of the carrier to the device surface; shelf life (stability), especially of the agent, which is typically less stable than the device or carrier; and durability of the carrier in the intended use environment should also be considered. Biological and/or clinical
performance of the coated product must justify any claims made. This specification includes delivery of a therapeutic dose of agent to the target tissue for a long-enough time to have the desired effect (release profile). Finally, physical performance of the combination product (reliability and durability) and physical dimensions of the product are included.

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