Pre-Filled Syringes and Auto-Injectors: Combination Product Regulatory Strategy

Why Pre-Filled Syringes and Auto-Injectors Dominate Combination Product Development

The global autoinjector market reached USD 8.35 billion in 2023 and is projected to grow at a compound annual growth rate of 14.4% through 2030, according to Grand View Research. Pre-filled syringes (PFS) remain the dominant drug delivery format, while auto-injectors, on-body delivery systems, and dual-chamber devices are rapidly expanding as more biologics move toward self-administration.

In October 2025, Lasix ONYU received FDA approval as a drug-device combination for edema in adults with chronic heart failure — its infusor preprogrammed to deliver 30 mg in the first hour and then 12.5 mg per hour for the next four hours. The approval signaled that on-body infusion has moved beyond rare disease maintenance into practical at-home management of common chronic conditions.

For regulatory professionals, pre-filled syringes and auto-injectors present a unique challenge: they are regulated as drug-led combination products in most cases, yet they must satisfy both drug current Good Manufacturing Practice (cGMP) and device quality system requirements simultaneously. The FDA's Quality Management System Regulation (QMSR), effective February 2, 2026, has further tightened this interface by incorporating ISO 13485:2016 by reference.

This guide provides a practical regulatory strategy for developing and marketing pre-filled syringes, auto-injectors, pen injectors, and on-body delivery systems — from jurisdictional determination through design verification, human factors, stability, and lifecycle management.

Regulatory Jurisdiction: Determining Who Reviews Your Product

FDA Jurisdictional Framework

Under 21 CFR 3.2(e), a combination product is defined as a product comprising two or more regulated components (drug/device, biologic/device, or drug/biologic) that are physically, chemically, or otherwise combined. Pre-filled syringes and auto-injectors fall under 21 CFR 3.2(e)(1) as "single-entity" combination products.

The FDA's Office of Combination Products (OCP) assigns jurisdiction through a Request for Designation (RFD) process under 21 CFR Part 3. The primary mode of action (PMOA) determines which FDA center leads:

Section 503(g)(1)(B) of the FD&C Act requires FDA to "conduct the premarket review of any combination product under a single application, whenever appropriate." In practice, drug-led pre-filled syringes and auto-injectors are almost always submitted under a single NDA, ANDA, or BLA.

EU MDR Article 117 Interface

In the EU, drug-led combination products are regulated as medicinal products under Directive 2001/83/EC. However, the device constituent part must still comply with the General Safety and Performance Requirements (GSPRs) in Annex I of Regulation (EU) 2017/745 (EU MDR), per Article 117.

This means the Notified Body opinion (NBOp) is required for the device constituent part, even though the overall product is authorized through the medicinal product pathway. The NBOp evaluates whether the device part meets the relevant GSPRs.

The ISO 11608 Framework: Design Verification for Injection Systems

ISO 11608 Series Structure

The ISO 11608 series is the primary standard for needle-based injection systems (NIS). FDA recognized ISO 11608-1:2022 in May 2022 and encourages manufacturers to use it for demonstrating conformity. The series includes:

Primary Functions Under ISO 11608-1:2022

The 2022 revision introduced the concept of "Primary Functions" — those functions whose failure would cause the device to fail to accurately deliver the medicinal product via the correct route, or directly result in unacceptable harm. These primary functions form the basis of design verification:

The 2022 revision also introduced a flow chart (Figure 1 in the standard) mapping the interaction between all ISO 11608 parts and associated standards, providing a comprehensive roadmap for verification.

Pre-Filled Syringes vs. Auto-Injectors: Different Testing Expectations

A critical distinction exists between stand-alone pre-filled syringes and pre-filled syringes integrated into auto-injector systems:

FDA has not generally or systematically required ISO 11608 testing for stand-alone pre-filled syringes in NDA or BLA approvals over the past five years. However, when a pre-filled syringe is assembled into an auto-injector, the entire system falls under ISO 11608 requirements.

Human Factors and Usability Validation

FDA Expectations for Combination Product Human Factors

The FDA's guidance "Application of Human Factors Engineering Principles for Combination Products" (2023) establishes mandatory human factors validation testing for pre-filled syringes and auto-injectors. Key requirements:

For an auto-injector intended for home use, typical user groups include:

• Adult patients (15+ participants)

• Elderly patients with dexterity limitations (15+ participants)

• Caregivers (15+ participants)

The FDA expects discussion of planned user groups and sample sizes during a Pre-Submission (Q-Submission) meeting.

Smart Auto-Injectors and Connected Devices

The regulatory landscape is evolving to accommodate "smart" auto-injectors with connectivity features. In 2025, the SmartPilot YpsoMate accessory received FDA clearance as an injection data capture device that:

• Records device data, injection data, and process status

• Guides users through injection with visual and auditory step-by-step cues

• Detects errors such as partial injection or insufficient holding time

• Transmits data to a digital therapy management system for remote adherence monitoring

Smart accessories raise additional considerations around IEC 62304 (software lifecycle), cybersecurity (Section 524B), and data privacy.

Quality System Requirements Under QMSR

21 CFR Part 4: Streamlined CGMP for Combination Products

The FDA's 21 CFR Part 4 establishes a streamlined CGMP framework for combination products, allowing manufacturers to demonstrate compliance with either drug CGMP (21 CFR Parts 210/211) or device QMSR (21 CFR Part 820), supplemented by specific provisions from the other system where needed.

QMSR Changes Effective February 2026

The QMSR, effective February 2, 2026, replaced the former Quality System Regulation (21 CFR 820) and incorporated ISO 13485:2016 by reference. For combination product manufacturers, this means:

• Risk management must align with ISO 14971:2019

• Design transfer must be documented

• Supplier controls must be active and risk-based

• Management review must include combination product-specific inputs

FDA has indicated that investigators will assess compliance through the revised framework, with particular attention to supplier controls and risk-based decision making. Sponsors cannot treat contract manufacturers or component suppliers as distant partners — oversight must be active, structured, and documented.

Design Verification and Stability Testing

ICH and FDA Functional Testing Requirements

Stability Testing Strategy

Stability testing for pre-filled syringes and auto-injectors must address both the drug product and the device constituent part simultaneously:

Environmental conditioning per ISO 11608-1 requires testing across the full operating range — including temperature cycling, vibration, and free-fall drop testing.

EU Regulatory Pathway

Article 117 Notified Body Opinion

For drug-led combination products in the EU, Article 117 of the MDR requires a Notified Body opinion on the device constituent part. The process:

1. Manufacturer selects a Notified Body designated for the relevant device type

2. Notified Body evaluates the device part against GSPRs in Annex I

3. NBOp is issued (typically valid for the life of the marketing authorization unless significant changes occur)

4. NBOp is included in the Marketing Authorisation Application

The NBOp covers:

• Device description and specification

• GSPR checklist with evidence

• Risk management documentation

• Biocompatibility evaluation

• Sterilization validation (if applicable)

• Usability engineering file (IEC 62366-1)

• Software documentation (IEC 62304, if applicable)

Bridging Between Presentations

The FDA's draft guidance on "Combination Product Clinical Bridging" addresses the scenario where a drug initially developed in a pre-filled syringe presentation is later adapted to an auto-injector presentation. Key considerations:

When bridging from a pre-filled syringe to an auto-injector, the FDA expects the sponsor to:

• Generate design verification data on factors affected by the auto-injector (dose accuracy, injection time)

• Demonstrate the user interface supports safe and effective use

• Address quality considerations for the assembly process, including impacts on syringe resistance to breakage, functionality throughout shelf life, and expiration dating

Lifecycle Management and Change Control

ICH Q12 Application to Combination Products

ICH Q12 provides a framework for managing post-approval CMC changes, including Appendix A for combination products with device constituent parts. Key considerations:

EU Variation Framework

For EU marketing authorizations, changes to the device constituent part follow the variation regulation ((EU) 2024/1702). Device changes that affect the GSPR compliance require a new or updated Notified Body opinion submitted as part of the variation application.

Common Deficiencies and Enforcement Trends

FDA Warning Letter Patterns

FDA enforcement actions against combination product manufacturers have cited deficiencies primarily in:

The 2014 FDA Warning Letter to Amgen regarding PROLIA pre-filled syringe and ENBREL SureClick auto-injector remains a landmark case, demonstrating that legacy combination products may be held to a more rigorous standard, including retrospective application of device quality system requirements.

Submission Checklist

Key Standards Reference Table

Piston syringes are named in FDA's August 2026 CCS draft as a container closure that may also be a device constituent part. That draft does not replace ISO 11608, human factors, or this lifecycle page, and it does not yet supersede the May 1999 CCS guidance. See FDA 2026 container closure draft: device-constituent CCS.