Guidance for Industry and for FDA Reviewers
`
`Guidance Document for Premarket
`Notification Submissions for Nitric Oxide
`Delivery Apparatus, Nitric Oxide Analyzer
`and Nitrogen Dioxide Analyzer
`
` Document Issued on: January 24, 2000
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Devices and Radiological Health
`
` Anesthesiology, Respiratory, and Defibrillator Devices Group
` Division of Cardiovascular, Respiratory, and Neurological Devices
`Office of Device Evaluation
`
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`

`
`Preface
`
`Public Comment
`
`For 90 days following the date of publication in the Federal Register of the notice announcing the
`availability of this guidance, comments and suggestions regarding this document should be submitted
`to Docket No. 99D-5297, Dockets Management Branch, Division of Management Systems and
`Policy, Office of Human Resources and Management Services, Food and Drug Administration,
`5630 Fishers Lane, (HFA-305), Room 1061, Rockville, MD 20852.. Such comments will be
`considered when determining whether to amend the current guidance.
`
`After 90 days following the date of publication in the Federal Register of the notice announcing the
`availability of this guidance comments and suggestions may be submitted at any time for Agency
`consideration to: Michael Bazaral, M.D., Ph.D., Center for Devices and Radiological Health
`(HFZ-450), Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850.
`Comments may not be acted upon by the Agency until the document is next revised or updated.
`For questions regarding the use or interpretation of this guidance contact Michael Bazaral, M.D.,
`Ph.D. at 301-443-8609.
`
`Additional Copies
`
`World Wide Web/CDRH/home page at http://www.fda.gov/cdrh/ode/1157.pdf or CDRH Facts
`on Demand at 1-800-899-0381 or 301-827-0111, specify number 1157 when prompted for the
`document shelf number.
`
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`Table of Contents
`
`1.
`INTRODUCTION...................................................................................................................................................................1
`1.1
`PURPOSE..........................................................................................................................................................................1
`1.2
`BACKGROUND ..................................................................................................................................................................1
`1.3
`SCOPE .............................................................................................................................................................................. 1
`2. DEVICE DESCRIPTION .....................................................................................................................................................3
`2.1
`NITRIC OXIDE ADMINISTRATION APPARATUS............................................................................................................. 3
`NITRIC OXIDE GAS ANALYZER......................................................................................................................................3
`2.2
`NITROGEN DIOXIDE GAS ANALYZER............................................................................................................................ 4
`2.3
`3. SPECIFIC CRITERIA AND TESTING............................................................................................................................5
`3.1
`NITRIC OXIDE DELIVERY APPARATUS ......................................................................................................................... 5
`3.1.1
`Loss of nitric oxide therapy and incorrect nitric oxide concentration...................................................5
`3.1.2
`Insufficient or excess ventilation or oxygenation.......................................................................................8
`3.1.3
`Excessive nitrogen dioxide administration...................................................................................................9
`3.1.4
`Potential for catastrophic release of nitric oxide .....................................................................................10
`3.1.5
`Adulteration of the nitric oxide.......................................................................................................................11
`3.1.6
`Electrical hazards .............................................................................................................................................11
`3.1.7
`Adverse effects on other electronic devices.............................................................................................11
`3.1.8
`Release of nitric oxide and release and generation of nitrogen dioxide............................................11
`NITRIC OXIDE ANALYZER.............................................................................................................................................12
`3.2
`3.2.1
`Nitric Oxide measurement error....................................................................................................................12
`3.2.2
`Electrical hazards .............................................................................................................................................14
`3.2.3
`Adverse effects on other electronic devices.............................................................................................14
`NITROGEN DIOXIDE ANALYZER...................................................................................................................................14
`3.3
`3.3.1
`Nitrogen Dioxide measurement error...........................................................................................................15
`3.3.2
`Electrical hazards .............................................................................................................................................17
`3.3.3
`Adverse effects on other electronic devices.............................................................................................17
`
`4. GENERAL CRITERIA AND TESTING..........................................................................................................................18
`GENERAL CRITERIA ......................................................................................................................................................18
`4.1
`GENERAL TEST METHODS...........................................................................................................................................18
`4.2
`5. ELECTRICAL SAFETY.....................................................................................................................................................20
`5.1
`PERFORMANCE CRITERIA ............................................................................................................................................20
`5.1.1
`Battery power......................................................................................................................................................20
`5.1.2
`Electrical power indicators..............................................................................................................................20
`5.1.3
`Overcurrent protection .....................................................................................................................................21
`5.1.4
`Dielectric withstand...........................................................................................................................................21
`5.1.5
`AC power grounding and polarity..................................................................................................................21
`5.1.6
`Leakage current.................................................................................................................................................21
`5.1.7
`Auxiliary output...................................................................................................................................................22
`TEST METHODS.............................................................................................................................................................22
`5.2
`5.2.1
`Battery power......................................................................................................................................................22
`5.2.2
`Electrical power indicators..............................................................................................................................23
`5.2.3
`Overcurrent protection .....................................................................................................................................23
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`5.2.4
`5.2.5
`5.2.6
`5.2.7
`
`Dielectric withstand...........................................................................................................................................24
`AC power grounding and polarity..................................................................................................................24
`Leakage current.................................................................................................................................................24
`Auxiliary output...................................................................................................................................................24
`
`6. ELECTROMAGNETIC COMPATIBILITY....................................................................................................................25
`PERFORMANCE CRITERIA ............................................................................................................................................25
`6.1
`6.1.1
`Emissions............................................................................................................................................................25
`6.1.1.1
` Radiated and conducted electromagnetic energy.............................................................................. 25
`6.1.1.2
` Magnetic fields........................................................................................................................................... 25
`6.1.2
`Immunity..............................................................................................................................................................25
`6.1.2.1
` Electrostatic discharge ............................................................................................................................ 26
`6.1.2.2
` Radiated electromagnetic fields ............................................................................................................ 26
`6.1.2.3
` AC voltage fluctuations, transients, and surges ................................................................................. 26
`6.1.2.4
` Conducted electromagnetic energy...................................................................................................... 27
`6.1.2.5
` Magnetic fields........................................................................................................................................... 28
`6.1.2.6
` Quasi-static electric fields ....................................................................................................................... 28
`TEST METHODS.............................................................................................................................................................28
`6.2
`6.2.1
`Emissions............................................................................................................................................................28
`6.2.1.1
` Radiated and conducted electromagnetic energy.............................................................................. 28
`6.2.1.2
` Magnetic fields........................................................................................................................................... 29
`6.2.2
`Immunity..............................................................................................................................................................29
`6.2.2.1
` Electrostatic discharge ............................................................................................................................ 29
`6.2.2.2
` Radiated electromagnetic fields ............................................................................................................ 30
`6.2.2.3
` AC voltage fluctuations, transients, and surges ................................................................................. 33
`6.2.2.4
` Conducted electromagnetic energy...................................................................................................... 35
`6.2.2.5
` Magnetic fields........................................................................................................................................... 36
`6.2.2.6
` Quasi-static electric fields ....................................................................................................................... 36
`7. PERFORMANCE SPECIFICATIONS, ENVIRONMENTAL AND MECHANICAL SAFETY.........................38
`7.1
`PERFORMANCE CRITERIA ............................................................................................................................................38
`7.1.1
`Controls protection............................................................................................................................................38
`7.1.2
`Connector protective incompatibility...........................................................................................................38
`7.1.3
`Mechanical safety.............................................................................................................................................38
`7.1.4
`Mechanical vibration and shock resistance..............................................................................................39
`7.1.5
`Fluid spill resistance........................................................................................................................................39
`7.1.6
`High and low temperature and humidity......................................................................................................39
`7.1.7
`Surface temperature.........................................................................................................................................39
`7.1.8
`Toxic materials...................................................................................................................................................40
`7.1.9
`Strangulation.......................................................................................................................................................40
`7.1.10 Determination of Endurance..........................................................................................................................40
`7.1.11 Material Compatibility.......................................................................................................................................40
`7.1.12 Medical Gas Cylinder Connections ..............................................................................................................40
`TEST METHODS.............................................................................................................................................................40
`7.2
`7.2.1
`Controls protection............................................................................................................................................40
`7.2.2
`Connector protective incompatibility...........................................................................................................40
`7.2.3
`Mechanical safety.............................................................................................................................................41
`7.2.4
`Mechanical vibration and shock resistance..............................................................................................41
`7.2.5
`Fluid spill resistance........................................................................................................................................41
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`High and low temperature and humidity......................................................................................................41
`7.2.6
`Surface temperature.........................................................................................................................................42
`7.2.7
`Toxic materials...................................................................................................................................................42
`7.2.8
`Strangulation.......................................................................................................................................................42
`7.2.9
`7.2.10 Determination of Endurance..........................................................................................................................42
`7.2.11 Material Compatibility.......................................................................................................................................42
`
`8. HARDWARE DOCUMENTATION..................................................................................................................................43
`
`9. SOFTWARE DOCUMENTATION..................................................................................................................................44
`
`10.
`LABELING........................................................................................................................................................................45
`10.1 IDENTIFICATION OF MEDICAL GAS CYLINDERS AND CONNECTIONS ...................................................................... 45
`10.2 INSTRUCTIONS FOR USE...............................................................................................................................................45
`10.2.1
`Intended Use......................................................................................................................................................45
`10.2.2 Validated Ventilators ........................................................................................................................................45
`10.2.3
`Installation Instructions ...................................................................................................................................46
`
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`
`Guidance1 Document for Premarket
`Notification Submissions for Nitric Oxide
`Delivery Apparatus, Nitric Oxide Analyzer
`and Nitrogen Dioxide Analyzer
`
`SECTION 1. Introduction
`
`1.1
`
`Purpose.
`
`The purpose of this document is to facilitate the preparation and the review of premarket
`submissions for nitric oxide delivery apparatus, nitric oxide analyzers, and nitrogen dioxide
`analyzers.
`
`1.2
`
`Background
`
`On September 23, 1996, Ohmeda Inc. submitted a petition under section 513(f)(2) of the
`Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360c(f)(2)), requesting that the
`devices included in the Ohmeda I-NOvent Delivery System intended for administration of
`inhaled nitric oxide, be reclassified from class III into class II. The system includes three
`devices which may be separately manufactured; a nitric oxide administration apparatus, a
`nitric oxide gas analyzer, and a nitrogen dioxide gas analyzer. This guidance document is
`proposed as a special control for these devices.
`
`This guidance document describes a means by which nitric oxide delivery and analyzing
`devices and nitrogen dioxide analyzing devices for use during the administration of nitric
`oxide may comply with the requirement of special controls for Class II devices.
`Designation of this guidance document as a special control means that manufacturers
`attempting to establish that their device is substantially equivalent to a predicate device
`should demonstrate that the proposed device complies with either the specific
`recommendations of this guidance or some alternate control that provides equivalent
`assurances of safety and effectiveness.
`
`1.3
`
`Scope
`
`This guidance document identifies information that should be included in premarket
`notifications for the Nitric Oxide Delivery Apparatus, the Nitric Oxide Analyzers, and the
`
`1 This guidance document represents the agency’s current thinking on this
`subject. It does not create or confer any rights for or on any person and does
`not operate to bind FDA or the public. An alternative approach may be used if
`such approach satisfies the applicable statute, regulations, or both.
`
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`
`Nitrogen Dioxide Analyzers.
`
`A description of certain information typically provided in a premarket notification such as
`comparative performance evaluations, table of comparison, device description, discussion
`of similarities and difference, biocompatibility is not included in this guidance. Such
`information is common for all premarket notifications and is discussed in current guidances
`and manuals, including the Draft Guidance for Premarket Notification Submissions, and
`the Premarket Notification [510(k)] Manual. Both of these are available from the Division of
`Small Manufacturers Assistance (DSMA).
`
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`
`SECTION 2. Device Description
`
`A complete Nitric Oxide Delivery System includes three component medical devices; a
`nitric oxide administration apparatus, a nitric oxide gas analyzer, and a nitrogen dioxide
`gas analyzer. Each of the three components of a generic nitric oxide administration system
`may be manufactured and distributed separately; for that reason this guidance document
`addresses the three component devices individually.
`
`2.1
`
`Nitric Oxide Administration Apparatus
`
`The nitric oxide administration apparatus (product code MRN) is a device used to add
`nitric oxide to gases that are to be breathed by a patient. The nitric oxide administration
`apparatus is to be used in conjunction with a ventilator or other breathing gas
`administration system. The concentration of nitric oxide is maintained approximately
`constant during the inspiratory flow regardless of the variation in flow rate within the
`inspiratory portion of the respiratory cycle. The concentration of inspired nitric oxide can
`be set, typically in the range of 0 to 80 parts per million (ppm). The administration
`apparatus includes a pressure regulator and connectors with fittings which are specific for
`nitric oxide gas cylinders, typically containing 400 or 800 ppm nitric oxide in nitrogen. The
`nitric oxide administration apparatus design should minimize the time that nitric oxide is
`mixed with oxygen (dwell time), and thus minimize the concentration of nitrogen dioxide in
`the gas breathed by the patient (nitrogen dioxide is a toxic reaction product which forms in
`a chemical reaction of nitric oxide with oxygen).
`
`The administration device should include provisions for a nitric oxide gas concentration
`gas analyzer with alarms, a nitrogen dioxide gas analyzer with an alarm, and an oxygen
`analyzer with alarms. Suitable gas analysis devices should be identified in the labeling for
`the nitric oxide gas administration device.
`
`The delivery system should include or indicate a nitric oxide administration apparatus for
`use as a "backup" system (product code MRO) for administration of nitric oxide when the
`main administration apparatus cannot be used.
`
`2.2
`
`Nitric Oxide Gas Analyzer
`
`A nitric oxide gas analyzer (product code MRP) is a device intended to measure the
`concentration of nitric oxide in respiratory gas mixtures during administration of nitric oxide.
` The gas should be sampled from the inspiratory limb of the patient circuit. The nitric oxide
`gas analyzer usually includes provisions for setting upper and lower measured nitric oxide
`concentrations at which an alarm will be activated.
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`2.3
`
`Nitrogen Dioxide Gas Analyzer
`
`A nitrogen dioxide gas analyzer (product code MRQ) is a device intended to measure the
`concentration of nitrogen dioxide in respiratory gas mixtures during administration of nitric
`oxide. The gas is sampled from the inspiratory limb of the patient circuit. The nitrogen
`dioxide gas analyzer usually includes provisions for setting an upper measured nitrogen
`dioxide concentration, with an alarm to be activated when the measured concentration
`exceeds the set value.
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`SECTION 3.
`
`Specific Criteria and Testing
`
`A nitric oxide administration system has each of these three components; a nitric oxide
`delivery apparatus, a nitric oxide analyzer, and a nitrogen dioxide analyzer. The
`components may be manufactured and distributed separately; for that reason this section
`of the guidance document addresses the three component devices individually.
`
`3.1
`
`Nitric Oxide Delivery Apparatus
`
`The design and testing of the nitric oxide delivery apparatus should take into consideration
`the risks associated with the device. Risks for the nitric oxide delivery apparatus and the
`applicable controls are discussed in the follow subsections.
`
`3.1.1
`
`Loss of nitric oxide therapy and incorrect nitric oxide concentration. Loss of
`nitric oxide therapy may result in acute respiratory failure or acute pulmonary
`hypertension. Incorrect low nitric oxide concentration may result in ineffective
`treatment, while incorrect high nitric oxide concentration may result in excess
`side effects, and generation and administration of excess nitrogen dioxide.
`
`The controls for this risk consist of the following elements:
`
`a.
`
`b.
`
`c.
`
`If the device is the primary nitric oxide delivery system, the device should
`include a reserve (backup) nitric oxide delivery system. Alternatively,
`labeling may specify a marketed reserve (backup) nitric oxide delivery
`system. The back-up system will minimize the risk of loss of NO therapy
`resulting from failure of the primary NO administration apparatus.
`
`The administration device should include provision for nitric oxide gas
`analysis with alarms. The breathing circuit location for sampling should
`sample gas which is representative of the inspired gas. Labeling should
`specify a suitable nitric oxide gas analyzer. The specified nitric oxide
`analyzer should include an alarm with settable upper and lower nitric
`oxide concentration limits. The inclusion of nitric oxide gas analysis with
`alarms will minimize the risk result from loss of nitric oxide therapy or
`incorrect therapy, by alerting the practitioner of the need to correct a
`malfunction.
`
`The device should include a cylinder pressure gauge. Information provide
`by the cylinder pressure will permit verification of an adequate reserve of
`compressed nitric oxide in nitrogen and permit planning for replacement
`of near-empty cylinders without loss of therapy.
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`d.
`
`e.
`
`f.
`
`The device should include provision for attachment of two nitric oxide
`cylinders which can be used alternately via a manifold, or other means to
`assure a continuous supply of nitric oxide for normal operation of a
`primary administration system during replacement of cylinders. This
`provision will minimize the risk of loss of nitric oxide therapy.
`
`A primary nitric oxide administration device and the gas analysis devices
`should have battery backup power if the administration device or the gas
`analysis devices require main electrical power, and if the device is
`labeled for use with a ventilator having a battery backup power supply, or
`a ventilator capable of operation without main electrical power. Backup
`power should be demonstrated to have the duration of the ventilators
`listed for use with the device, or for at least 20 minutes. Backup power
`will minimize the risk of loss of nitric oxide therapy during transient power
`failure. If the devices are intended for use only with a ventilator having no
`backup power supply, then the manual backup nitric oxide administration
`device may be used, and no battery backup power for the nitric oxide
`administration system is needed.
`
`If a nitric oxide administration device is intended for use only as a backup
`or reserve system, then the device should be labeled for use only as a
`backup to a primary system, and only for use with a specified manual
`ventilator or a non-powered breathing circuit. The manual ventilator or
`non-powered breathing circuit should be specified. The device should be
`tested under simulated conditions of use to verify accuracy and the
`delivery of near-constant concentrations of NO within the respiratory
`cycle. Nitric oxide administration devices labeled for use as backup
`devices should not require main electrical power during use. The labeling
`for the backup device need not specify compatible gas analysis devices.
` If the backup system provides only a fixed concentration of NO then the
`manual should note that the system should be used only during periods
`when the primary system has failed or cannot be used for other
`unanticipated reasons, unless the patient is known to have no adverse
`effects at the concentration provided by the backup system. The labeling
`should also note that if a patient is thought to require a concentration
`different than provided by the backup system, then a separate system
`capable of providing the required concentration should be available. A
`backup system which provides a set single concentration will reduce the
`risks resulting from failure of the primary system, since for most patients
`inhaled nitric oxide will be effective over a wide range of concentrations,
`
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`g.
`
`h.
`
`and the primary system should fail only infrequently. Although the risks
`may in principle be further minimized by the use of an adjustable
`concentration system, the use of an adjustable system may introduce
`additional hazards of complexity. Thus the use either of a fixed
`concentration system or an adjustable backup system, within the device
`labeling recommendations, can sufficiently limit the risk resulting from
`possible failure of the primary administration system.
`
`For either backup or primary nitric oxide administration devices the mean
`nitric oxide concentration in the inspired gas should be reasonably
`constant in the circumstances of intended use. Testing should be
`performed in simulated use to determine the accuracy with which the
`device can maintain the mean nitric oxide concentration when the mean
`inspired concentration is sampled while the device is delivering
`representative respiratory flow patterns. Testing should evaluate the
`stability of the concentration produced, and the repeatability of the
`settings. Inspired concentrations within 20% of the set concentration of
`nitric oxide will be considered sufficiently accurate, since currently
`available data typically demonstrates that within a study, the effect of nitric
`oxide is similar over a range of concentrations. The testing will establish
`that the device is capable of providing sufficient accuracy, and thus will
`control the risk of incorrect delivered concentration of nitric oxide.
`Results of testing should be included in the labeling as specifications to
`allow selection of suitable devices.
`
`The device should provide nitric oxide concentrations at the patient
`connection which are well-defined at all times within the duration of each
`breath, and which correspond to available data regarding safety. Testing
`should be done under conditions of intended use to determine the
`delivered concentration at the patient connection, using a test system
`having an adequate response time. Sufficient accuracy within a breath
`cannot be defined on the basis of current data. However the currently
`available data (NINOS and Ohmeda) were developed using devices
`which provide reasonably constant concentrations within breaths.
`Transient concentrations as high as 150% of the mean concentration and
`as low as 0.0 ppm would be considered reasonably safe if the total
`duration of these transient concentrations did not exceed 10% of the
`volumetric duration of the breath. Testing may be done using a tracer gas
`in place of nitric oxide if adequate response times cannot be achieved for
`analysis of nitric oxide concentrations. Representative test result
`tracings should be included in the device labeling. Conformance to the
`
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`
`accuracy range stated above will control the risk of incorrect NO
`concentration, within the stated limit. Also, inclusion of the test results in
`the labeling will permit the practitioner to select devices on the basis of
`delivered concentration profile within the respiratory cycle.
`
`Gas-specific connectors with integral check valve which allow connection
`only to fittings (Compressed Gas Association 626 fitting) for
`pharmaceutical grade ni