FDA Addresses Device Constituents in New Draft Guidance on Container Closure Systems

FDA recently released a draft guidance titled Container Closure Systems for Human Drugs and Biological Products. The draft supersedes a 1999 guidance and its 2002 Q&A supplement—documents written before the prevalence of container closure systems (CCSs) like pre-filled syringes, metered dose inhalers, and autoinjectors blurred the line between container and device.  For Combination Product manufacturers, the new draft now explicitly acknowledges that a CCS may also be a device constituent or part of a device constituent and mentions, although with no specificity, that some recommendations may also be applicable to stand-alone drug-delivery devices.  However, the headline is that the draft guidance does not appear to introduce anything that has not already been covered in another guidance related to combination products.

The draft guidance organizes CCS evaluation around a risk-based framework covering safety of packaging materials, protection, performance, manufacturing process impacts, and storage.  It further provides recommendations for quality assessment and control, including an evaluation of protection; safety and compatibility, which includes extractables and leachables (E&L) assessments and nonclinical toxicological risk assessments; performance; stability; and tests for shipping, handling, and storage.  The draft guidance emphasizes that evaluation of a CCS is product-specific and that a CCS that is suitable for one drug product may not be an appropriate choice for another.  This is especially important for combination product sponsors to keep in mind when selecting a device constituent CCS.  Additional evaluation specific to the use of that device constituent CCS will be necessary to evaluate risk and conduct appropriate quality assessments beyond that which the developer of the device constituent has conducted.

As required by 21 C.F.R. Part 4, CCSs that are device constituent parts must comply with ISO 13485:2016 Clauses 7.3 (design and development) and 7.4 (purchasing), per 21 C.F.R. 820.10(c). The draft guidance also notes that Part 820 exemptions may not survive integration into a CCS.  As an example,  a dropper on its own might be exempt, but the same dropper built into a bottle cap would have a new use as part of the container closure and no longer be exempt.

For a CCS that is also a device constituent part, FDA expects appropriate testing to demonstrate the device’s function, delivery performance, and usability, consistent with other guidance, including for Essential Drug Delivery Outputs (see prior post here) and Human Factors.

The draft guidance also devotes significant attention to E&L and nonclinical toxicological risk assessments, including safety concern thresholds, qualification thresholds, and analytical evaluation thresholds. Notably, FDA recommends that for combination products, “the risk and extent and adequacy of testing should also take into account whether interactions between a CCS that is a device constituent part and the drug or biological product constituent part it holds (such as adsorption of the drug or biological product constituent part by the CCS) might negatively affect device performance.” This is a critical nuance: An E&L program needs to account not just for patient safety from leachables but also for the impact of drug-device interactions on the device’s ability to deliver the drug as labeled.

FDA also signals that more is coming. The guidance notes that FDA intends to issue additional topic-specific guidance, addressing methods for evaluating novel CCSs and providing information about specific quality attributes and testing requirements, including E&L evaluations and toxicological risk assessments. The pending ICH Q3E guideline on E&L assessments is also referenced.

FDA’s draft guidance on container closure systems represents an update that consolidates nearly three decades of regulatory evolution into its framework. For combination product sponsors, the guidance does not appear to break significant new ground beyond what existing combination product guidances already address, but it does place relevant threads—CCS quality assessment, device constituent part requirements, extractables and leachables evaluation, and design control obligations—under one roof. The explicit acknowledgment that a CCS may also function as a device constituent part, and the corresponding expectation that E&L programs account for drug-device interactions affecting device performance, warrant close attention during program design.

Affected parties should prioritize submitting comments before the deadline on October 13, 2026, conduct internal gap assessments, and monitor for the forthcoming topic-specific supplemental guidance documents.