21 CFR Part 4 – Combination Products (cGMP & PMSR)

This topic is part of the SG Systems Global regulatory glossary series.

Updated October 2025 • FDA / cGMP • Combination Products

21 CFR Part 4 explains how FDA cGMP and postmarketing safety reporting apply to combination products (drug–device, biologic–device, drug–biologic, or drug–device–biologic). It maps which parts of Parts 210/211 (drugs), Part 820 (devices), and biologics cGMPs apply—and provides a “streamlined” path so you don’t duplicate equivalent quality system controls. Part 4 also sets postmarketing safety reporting (PMSR) obligations specific to combination products.

“Part 4 lets you build one quality system for a combination product—then plug in the drug and device requirements that matter, without duplicating work.”

1) What It Is

Part 4 has two pillars: Subpart A (cGMP for combination products) and Subpart B (PMSR). Under Subpart A, a manufacturer may operate primarily under drug cGMP (210/211) or device QSR (820) and then add specified provisions from the other rule set—this is the streamlined approach. Subpart B aligns combination product safety reporting timelines and content across drug and device paradigms.

Subpart A — cGMP options. You may:

• Use a single integrated QS that fully complies with 210/211 and 820; or
• Use a streamlined QS primarily under drug cGMP with specified 820 provisions (e.g., design controls, purchasing controls, CAPA, complaint files); or
• Use a streamlined QS primarily under device QSR with specified 210/211 provisions (e.g., stability, expiration dating, testing/approval of components, MBR/BPR-equivalents).

Subpart B — PMSR. Defines how to report serious adverse events and malfunctions for combination products using harmonized timelines and formats drawn from drug and device reporting frameworks.

Documentation and data integrity. If you keep required records electronically, Part 11 applies (validation, audit trails, e-signatures, security, retention).

Where it shows up by industry. Auto-injectors, prefilled syringes, drug-eluting stents, on-body injectors, antimicrobial wound dressings, and diagnostic–therapeutic kits are classic combination products. Your QS must show how both drug and device risks are controlled end-to-end.

2) FAQ

Q1. Drug-led vs device-led—what changes?
The primary mode of action (PMOA) determines the lead center and which QS you base on. Drug-led systems add key 820 provisions (design controls, CAPA, complaint handling, purchasing). Device-led systems add key 210/211 provisions (stability, sampling/testing, master/batch record rigor).

Q2. Do I need separate CAPA and deviation systems?
No. A single, integrated CAPA system is acceptable if it meets both paradigms (investigation, root cause, effectiveness checks) and links to batch/device history.

Q3. Are design controls always required?
For device-led or streamlined drug-led systems adding 820 elements, yes—design planning, inputs/outputs, verification/validation, risk management, and a DHF are expected.

Q4. What about labeling and UDI?
Device-centric requirements (e.g., UDI, label reconciliation controls) still apply where relevant; drug labeling rules also apply for the medicinal constituent.

Q5. How does Part 11 fit?
If electronic records/signatures are used for required activities (e.g., eBMR/eDHR, lab data, CAPA, complaints), Part 11 governs validation, audit trails, and e-signatures.

Q6. What is PMSR in Part 4?
Postmarketing Safety Reporting harmonizes drug/device reporting for combination products—timelines, what to submit, and how to handle malfunctions and serious adverse events.

Q7. Where can I read the full rule?
See the eCFR text for 21 CFR Part 4.

3) How It Relates to V5

V5 by SG Systems Global lets combination-product manufacturers operate one integrated digital QS that satisfies both drug and device expectations with full traceability.

• Dual-paradigm records. Execute eBMR/eBR for drug steps and eDHR for device steps in one platform, with Part 11 audit trails and e-signatures.
• Design controls & risk. Manage DHF artifacts, verification/validation evidence, and change control within QMS.
• CAPA & complaints. Single CAPA process mapped to both paradigms; complaint files link to batches/devices and feed PMSR reporting.
• Specifications & release. LIMS scheduling, test results, and CoA generation tied to lot/device genealogy.
• Warehouse & labeling. WMS enforces status/FEFO, blocks unreleased lots, and helps reconcile labeling to reduce mix-up risk.
• ERP & ecosystem. Integrations via V5 Connect API (e.g., NetSuite, Dynamics 365, Sage X3, QuickBooks Desktop).

End-to-end example. A prefilled injector (drug–device) is produced under a streamlined, drug-led QS with 820 design controls and CAPA added. V5 captures eBMR and eDHR data, QC tests post to CoA, complaints link into CAPA and PMSR, and WMS blocks shipment until QA release—yielding an inspection-ready trail.

Primary References:
• FDA eCFR: 21 CFR Part 4
• Drug cGMPs: 21 CFR 210/211
• Device QSR: 21 CFR 820
• Electronic Records: 21 CFR Part 11