Combination Products: No Orphaned DHFs

Combination products succeed only when drug and device documentation move in

lockstep. Too often, the drug dossier flies ahead while the design history file

(DHF) drifts behind—setting the stage for inspection findings.

This playbook keeps drug and device teams aligned. You will create an integrated

plan, maintain DHF checklists, synchronize risk files, and share governance so

nothing falls through the cracks.

Why drug-device alignment matters

Regulatory confidence: Agencies expect cohesive evidence that drug, device,

and combination perform safely together.

Inspection readiness: Auditors review DHF, design controls, and quality

system records alongside drug submissions.

Patient safety: Integrated risk management ensures user needs and design

mitigations align with clinical outcomes.

Speed to market: Coordinated timelines avoid last-minute scrambles to fill

DHF gaps before submission or approval.

Step 1: Build an integrated master plan

Combine clinical, CMC, design control, human factors, and regulatory milestones

into one plan.

Highlight dependencies (e.g., device verification completion before pivotal

clinical batches).

Assign owners for each deliverable from drug and device teams.
Use shared project management tools so status updates stay synchronized.

Step 2: Maintain comprehensive DHF checklists

Detail required artifacts: design inputs, design outputs, verification reports,

risk analyses, usability studies, manufacturing controls, change records.

Link each item to the integrated plan, recording status and storage location.
Track progress in the same RIM or QMS used for drug submissions to prevent

siloed information.

Conduct periodic DHF health checks to confirm completeness and traceability.

Step 3: Synchronize risk management files

Align device risk management (ISO 14971) with drug safety assessments.
Ensure combination-product risk files cross-reference device FMEAs, human

factors studies, and post-market surveillance data.

Document mitigation strategies and verification/validation evidence in both

DHF and regulatory dossiers.

Review risk files in joint meetings to keep messaging consistent across teams

and regulators.

Step 4: Integrate change control and lifecycle management

Use unified change-control processes so device modifications trigger drug

assessments and vice versa.

Update labeling, IFUs, and training materials in sync with device changes.
Maintain merged post-market surveillance summaries covering complaints, device

history records, and pharmacovigilance data.

Step 5: Govern together and document evidence

Establish joint governance forums with Regulatory, QA, device engineering,

clinical, and manufacturing.

Review metrics, open risks, and submission readiness at each meeting.
Capture minutes, actions, and decisions in controlled repositories accessible to

both teams.

Train cross-functional leaders on combination regulatory pathways (EMA, FDA,

MDR) so they anticipate documentation needs.

Metrics that signal success

On-time completion of DHF milestones versus plan.
Number of combination-product risks open versus mitigated.
Audit or inspection findings related to DHF alignment.
Time to close change controls affecting both drug and device components.

45-day roadmap

Days 1-10: Review active combination projects, identify misalignments

between drug and device timelines, and collect existing DHF status reports.

Days 11-20: Draft the integrated master plan with representatives from CMC,

device engineering, regulatory, and quality.

Days 21-30: Populate DHF checklists, migrate artifacts to controlled

systems, and schedule joint risk reviews.

Days 31-45: Launch governance meetings, monitor metrics, and close priority

gaps before upcoming submissions.

Frequently asked questions

Who leads combination oversight? Shared ownership between Regulatory and QA

with device SMEs and drug development leads actively involved.

How do we store DHF artifacts? Use validated QMS or document control systems

with cross-functional access. Avoid personal drives or siloed tools.

What about contract device partners? Include them in planning, require DHF

documentation, and integrate their change control with yours.

How do we handle differing regulatory pathways? Map requirements for FDA,

EMA, and MDR early; tailor submissions while maintaining a core evidence set.

Sustain the win

Hold joint governance meetings monthly, refresh checklists after inspections, and

rotate leadership roles between drug and device teams. Celebrate submissions

where aligned evidence impressed regulators. When DHFs never go orphaned, your

combination product launches stay smooth.