2025 FDA 483 Review: Why Combination Products Are Disproportionately at Risk

Combination products sit at the intersection of drug CGMPs, device QSR/QSMR, and Part 4 integration requirements. FDA 483 data across both sectors show that organizations continue to manage these requirements in parallel rather than within an integrated quality system, a structural weakness that QSMR will further expose.

MEDICAL DEVICES:2025 FDA 483 OBSERVATIONS DESCRIPTION	Frequency
Lack of or inadequate procedures	279
Lack of or inadequate complaint procedures	211
Purchasing controls, Lack of or inadequate procedures	115
Documentation	98
Nonconforming product, Lack of or inadequate procedures	95
Lack of or inadequate process validation	93
Lack of Written MDR Procedures	63
Quality audits – Lack of or inadequate procedures	57
Label to bear a unique device identifier	54
Training – Lack of or inadequate procedures	50
Management review – Lack of or inadequate procedures	49
DRUGS: 2025 FDA 483 OBSERVATION DESCRIPTION	Frequency
Procedures not in writing, fully followed	243
Investigations of discrepancies, failures	164
Absence of Written Procedures	162
Scientifically sound laboratory controls	121
Cleaning / Sanitizing / Maintenance	95
Computer control of master formula records	87
Equipment Design, Size and Location	81
Written procedures not established/followed	70
Procedures for sterile drug products	68
Testing and release for distribution	44
Calibration/Inspection/Checking not done	38
Validation lacking sterile drug products	37

Under QSMR:

• FDA expects a single, coherent QMS
• Risk management, CAPA, and management review must span the entire product lifecycle
• Fragmented ownership (drug vs. device vs. supplier) is no longer defensible

Common FDA 483 Failure Themes: Combination Product Lens

Fragmented Quality System Architecture

Observed Failures

• Procedures exist but are product-type specific (drug OR device)
• Inconsistent definitions of deviations, complaints, and nonconformances
• Duplicate or conflicting SOPs across functional silos

483 Signals

• Devices: Inadequate procedures, complaint handling, and purchasing controls
• Drugs: Procedures not followed, absent, or inconsistently applied

Combination Product Impact

• Part 4 requires demonstrable integration, not coexistence
• FDA increasingly challenges “we follow both systems” without evidence of harmonization

Ineffective Exception Management Across the Lifecycle

Observed Failures

• Deviations investigated in drug system; device impacts not assessed
• Device complaints evaluated without drug stability, sterility, or dosing risk
• CAPAs are limited to functional root cause, not systemic

483 Signals

• Devices: Complaint handling, nonconforming product, CAPA
• Drugs: Investigation failures, sterile product deviations

Combination Product Impact

• FDA expects end-to-end issue escalation
• Failure to assess cross-constituent impact is a frequent trigger for:
  • Repeat 483s
  • Warning Letters
  • Field actions

Validation Gaps at Constituent Interfaces

Observed Failures

• Device validated independently of drug formulation or fill/finish
• Software validation ignores drug dosing or sterility risk
• Changes assessed in one constituent without holistic revalidation

483 Signals

• Devices: Process and software validation deficiencies
• Drugs: Sterile processing, lab controls, equipment qualification

Combination Product Impact

• FDA focuses on interface failure modes (delivery accuracy, container/closure, human factors)
• QSMR emphasizes lifecycle validation, not one-time qualification

Supplier and Contract Manufacturer Misalignment

Observed Failures

• Supplier quality agreements scoped to only one constituent
• Inadequate oversight of CMOs managing drug fill or device assembly
• Poor change notification and risk assessment

483 Signals

• Devices: Purchasing control deficiencies
• Drugs: Equipment, cleaning, calibration failures

Combination Product Impact

• FDA holds the combination product owner fully accountable
• “Supplier error” is no longer an acceptable rationale

Weak Management Review and Quality Governance

Observed Failures

• Drug and device metrics are reviewed separately
• Management reviews informational, not decision-driven
• Risks not escalated across QMS, products, processes

483 Signals

• Devices: Management review deficiencies
• Drugs: Recurrent procedure failures, repeat observations

Combination Product Impact

• FDA increasingly probes:
  • How leadership integrates quality signals
  • How cross-functional risks are evaluated and mitigated

What FDA Is Signaling for Combination Products Under QSMR

FDA 483’s indicates a clear shift:

Legacy Expectation	QSMR / Current FDA Expectation
Separate drug and device compliance	Unified, process-based QMS
Procedural compliance	System effectiveness
Functional investigations	Product-level risk assessment
Static validation	Lifecycle validation
Siloed management reviews	Enterprise quality governance

For combination products, QSMR becomes the forcing function that exposes integration weaknesses long tolerated under Part 4.

Priority Readiness Actions for Combination Product Manufacturers

To mitigate inspection and enforcement risk, organizations should prioritize:

1. Single Integrated QMS
   • Harmonized definitions, workflows, and escalation paths
   • One CAPA, one complaint system, one management review
2. Exception Management at the Product Level
   • Cross-constituent impact assessment mandatory
   • Risk-based escalation aligned with ISO 13485 and ICH Q10
3. Interface-Focused Validation Strategy
   • Delivery accuracy, container/closure, software, and usability
   • Lifecycle change impact is explicitly documented
4. Supplier Quality Integration
   • Combination-product-specific quality agreements
   • Risk-tiered supplier oversight
5. Executive Quality Oversight
   • Management review outputs tied to decisions and actions
   • Quality metrics aligned to patient risk, not just compliance

Executive Bottom Line

FDA 483 trends show that combination product failures are rarely technical—they are governance and system failures. QSMR raises the bar by demanding proof that integrated systems work in practice, not just on paper.

Those who use QSMR to finally unify drug, device, and supplier quality systems will materially improve inspection outcomes and patient safety.

Consult Wing LLC partners with life sciences companies to design, remediate, and sustain robust Quality Management Systems across medical devices, pharmaceutical, biotech, and combination product portfolios. We align regulatory compliance with business objectives to support product lifecycle execution, inspection readiness, and long-term operational performance.

For further discussion on how we can support your organization’s Combination Product strategy, visit www.ConsultWing.com