Same Drug, No Room for Carelessness With the Injector: FDA Maps Out a Review Path for Biosimilar Devices

Whether a biosimilar can successfully replace the originator product depends on more than the protein in the vial. The force a patient uses to press an autoinjector, the way a cap is removed, and even a single line of instructions on the packaging can change the outcome of drug administration. The US Food and Drug Administration (FDA) has issued a new draft guidance that, for the first time, provides a more comprehensive framework explaining how differences in containers and devices should be incorporated into biosimilarity and interchangeability assessments.

The 16-page draft applies to combination products containing therapeutic protein biosimilars and interchangeable biosimilars submitted under the Section 351(k) pathway of the Public Health Service Act. What the FDA calls a product’s “presentation” encompasses the container closure system and device constituent parts, such as vials, prefilled syringes, and autoinjectors. The draft does not apply to drug-device combination products for conventional generic drugs.

Quality data remain the first threshold. Applicants must fully describe the container and device in their chemistry, manufacturing, and controls information and use studies of extractables and leachables, device performance, stability, and other factors to demonstrate that the device is compatible with the final biological product formulation. The FDA also notes that comparative in vitro performance testing may be used to support the assessment of the device constituent part.

The principal new focus is the user interface. The FDA recommends that developers conduct three types of comparisons: examine differences in the device’s visual, auditory, tactile, and internal mechanical features; break down every operational and cognitive task performed by patients or healthcare professionals; and then compare the device, outer carton, prescribing information, and instructions for use line by line. These analyses should be based on the final, launch-ready product rather than comparisons limited to early prototypes.

Differences do not necessarily prevent an application from proceeding. The key question is whether they affect a “critical task”—a step that, if performed incorrectly or omitted, could harm the user or delay medical care. If there are no differences, or only minor differences that do not affect critical tasks, the additional data required may be limited. If changes in factors such as button force, injection angle, or sequence of operation could cause use errors, the FDA may require a more comprehensive risk analysis, in vitro data, or a human factors validation study.

Background

The threshold is particularly sensitive for interchangeable products because, when conditions such as state law requirements are met, a pharmacist may substitute one for the reference product without the intervention of the prescriber. The draft therefore asks applicants to demonstrate that device differences will not prevent users from switching safely. Additional in vitro and human factors evidence may also be needed when a specific presentation of the reference product has been withdrawn from the market, or when a developer intends to replace the original vial with a prefilled syringe or autoinjector.

The document remains a Level 1 draft guidance open for public comment. Its contents are nonbinding recommendations and have not yet become final implementation standards. It also does not estimate the cost or review timeline associated with additional testing; the actual burden will depend on device differences, the user population, and the administration setting. However, for companies planning a Section 351(k) application, work on containers, labeling, and human factors clearly can no longer be left until the end of development.