Premarket Notification Requirements for Aerosol Delivery Devices: Nebulizers, Metered Dose Inhalers, Spacers and Actuators

What You Need to Know? 👇

What is the regulatory pathway for nebulizers and metered dose inhalers in the US?

Nebulizers and MDIs are regulated as prescription medical devices requiring FDA 510(k) premarket notification clearance before marketing. CDRH reviews nebulizers and spacers, while CDER reviews MDIs and actuators when distributed with specific drugs.

What particle size testing is required for aerosol delivery devices?

Particle size distribution testing must include at least three different drugs (bronchodilators, steroids, anti-allergics, mucokinetic agents, or antivirals) using cascade impactor method plus one additional sizing technique. Testing must determine MMAD and geometric standard deviation.

Are clinical studies required for 510(k) submissions of inhalation devices?

Clinical studies may be required for devices with new technological characteristics or new intended uses. Most submissions rely on in vitro performance testing demonstrating substantial equivalence to predicate devices through comprehensive bench testing protocols.

What environmental testing is needed for portable inhalation devices?

Environmental testing must demonstrate safety and effectiveness in intended use environments. This includes electrical safety standards (IEC 601-1), electromagnetic compatibility testing, and environmental conditions testing per applicable IEC and MIL standards for portable devices.

How should spacer devices be evaluated for 510(k) clearance?

Spacers require particle size distribution comparison to both predicate spacers and MDI alone, testing with each intended drug classification. Small in vivo confirmational trials assessing safety and effectiveness versus MDI alone are also required.

What biocompatibility testing is required for inhalation device components?

Biocompatibility testing must follow ISO 10993-1 standards when material changes are involved. Testing requirements depend on patient contact duration and body contact type, with protocols, pass/fail criteria, and results analysis required for submission.

---

What You Need to Do 👇

Recommended Actions

1. Determine if device falls under CDRH or CDER jurisdiction based on intended use
2. Prepare comprehensive device description including:
   • Engineering drawings
   • Materials
   • Operating principles
   • Specifications
3. Conduct required performance testing:
   • Particle size distribution using multiple methods
   • Spray pattern/plume geometry for MDIs
   • Life-cycle testing if reusable
   • Environmental testing for portable devices
4. Perform biocompatibility testing per ISO 10993-1
5. Develop complete labeling including:
   • Instructions for use
   • Prescription statement
   • Warnings/cautions
   • Drug compatibility information
6. For software-driven devices, prepare complete software documentation
7. Prepare comparison to predicate devices showing substantial equivalence
8. Conduct clinical trials if required (especially for spacers)
9. Submit 510(k) with all required testing data and documentation
10. Include either 510(k) summary or statement per SMDA requirements

Key Considerations

Clinical testing

• Small in vivo confirmational trials required for spacers to assess relative safety and effectiveness compared to MDI alone
• At least two trials per drug classification type needed:
  • One trial for effectiveness
  • One trial for safety
• Clinical trials must follow 21 CFR Part 812, Part 50, and Part 56 requirements

Non-clinical testing

• Particle size distribution testing required using at least two different methods
• Cascade impactor testing mandatory to determine:
  • Total drug mass released
  • Drug quantity at each impactor location
  • Mass median aerodynamic diameter (MMAD)
  • Geometric standard deviation (GSD)
• For MDIs/actuators:
  • Spray pattern and plume geometry testing
  • Testing at different fill levels (full, half, end of life)
  • Potency testing for each claimed drug
• Life-cycle testing for reusable devices

Labelling

• Must include prescription statement per 21 CFR 801.109
• Instructions for use including:
  • Operating principles
  • Drug-specific instructions if applicable
  • Cautionary statements
  • Single use/reuse statements
  • Patient and physician instructions as needed

Software

• For software-driven devices:
  • Hazard analysis
  • Software requirements and design information
  • Test plans/protocols with data
  • Development process documentation
  • Quality assurance activities
  • Configuration management plan
  • Verification activities

Biocompatibility

• Testing per ISO 10993-1 requirements
• Must include test protocols, pass/fail criteria, results and analysis

Safety

• Electrical safety testing for electronic devices
• Environmental testing for portable/home use devices
• Sterility information if applicable

Other considerations

• Device description including engineering drawings
• Comparison to predicate devices
• Performance testing in intended environment
• Documentation of Good Laboratory Practices compliance

---

Relevant Guidances 🔗

• Use of ISO 10993-1 for Biological Evaluation and Testing of Medical Devices
• Content of Premarket Submissions for Device Software Functions
• Content and Decision-Making Process for 510k Submissions: Determining Substantial Equivalence
• Refuse to Accept Policy for 510k Submissions: Minimum Threshold Requirements for Administrative and Technical Review
• Electromagnetic Compatibility for Medical Devices and Accessories: Testing, Documentation, and Labeling Requirements

Related references and norms 📂

• IEC 601-1: Medical electrical equipment, Part 1: General Requirements for Safety
• IEC 529: Classification of Degrees of Protection Provided by Enclosures
• ISO 10993-1: Biological evaluation of medical devices
• CISPR 11: Limits and Methods of Measurement of Radio-Interference Characteristics
• IEC 68: Environmental Testing

---

Original guidance

• Premarket Notification Requirements for Aerosol Delivery Devices: Nebulizers, Metered Dose Inhalers, Spacers and Actuators
• HTML
• Issue date: 1993-09-30
• Last changed date: 2020-03-17
• Status: FINAL
• Official FDA topics: Medical Devices, Premarket
• ReguVirta ID: 5e5a2edb6562aefea4d9931d24497794