Predicate Devices

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Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a device based on mid-infrared spectroscopy and standard analytical methods for measuring milk composition. There is no mention of AI or ML in the device description, intended use, or performance studies. The performance studies focus on traditional analytical validation metrics.

Therapeutic

No
The device measures components in human milk to aid in nutritional management, but it does not directly treat or prevent any condition.

Diagnostic

Yes

The device quantitatively measures the concentration of fat, carbohydrate, and protein in human milk, and provides calculated values for total solids and energy. These measurements are used "to aid in the nutritional management of newborns," which is a diagnostic purpose.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the Miris Human Milk Analyzer (HMA) includes hardware components such as a mid-infrared spectroscopy system, a mainboard, CPU board, display, touch button, fan, case, and consumables. This indicates it is a hardware device with integrated software, not a software-only medical device.

IVD (In Vitro Diagnostic)

Based on the provided information, the Miris Human Milk Analyzer (HMA) is an IVD (In Vitro Diagnostic) device.

Here's why:

Intended Use: The device is intended to "quantitatively measure the concentration of fat, carbohydrate, and protein in human milk." This measurement is performed on a biological sample (human milk) outside of the body.
Purpose: The measurements are used "in conjunction with other clinical assessments, may be used to aid in the nutritional management of newborns, including preterm, and infants." This indicates a diagnostic or aid-to-diagnosis purpose related to patient health.
Setting: It is intended for use "in healthcare by trained healthcare personnel at clinical laboratories." This is a typical setting for IVD devices.
Device Description: The description details a system for analyzing a biological sample (milk) using a specific technology (mid-infrared spectroscopy) to obtain quantitative results.

The key characteristics of an IVD device are that it is used to examine specimens derived from the human body to provide information for the diagnosis, prevention, monitoring, treatment, or alleviation of disease or injury. The Miris HMA fits this description by analyzing human milk to provide information that aids in the nutritional management of infants, which is directly related to their health and well-being.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Miris Human Milk Analyzer (HMA) quantitatively measures the concentration of fat, carbohydrate, and protein in human milk. The Miris HMA also provides calculated values for total solids and energy. These measurements, in conjunction with other clinical assessments, may be used to aid in the nutritional management of newborns, including preterm, and infants. This device is intended for use in healthcare by trained healthcare personnel at clinical laboratories.

Product codes (comma separated list FDA assigned to the subject device)

QEI

Device Description

The Miris Human Milk Analyzer (HMA) is a system for the quantitative measurement of fat, protein, and total carbohydrate content in human milk. The measurements of fat, protein and carbohydrate are also used in calculating the total solids and the energy content of human milk samples. The HMA unit includes a mid-infrared (mid-IR) spectroscopy system and a user interface. The user is guided by the interactive interface, via the screen, through the measurement process by use of the six-button controlled menu system. Milk samples (3 mL) are injected into the measuring unit (cuvette) via the instrument inlet using a syringe, with excess sample and waste exiting via the outlet.

The HMA device is comprised of a sample cuvette, hardware consisting of a mainboard and central processing unit (CPU) board, a display, touch button, fan, case, and consumables. The hardware consists of a mainboard with a CPU-board, detector board, and emitter board.

Consumables:

Miris Check (provided) - This is a solution to be used during start up to check zero-level transmission.
Miris Calibration Control Kit (provided) ●
Miris Cleaner (provided) ●
Syringes (provided)
Distilled or deionized water (not provided)

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

newborns, including preterm, and infants

Intended User / Care Setting

healthcare by trained healthcare personnel at clinical laboratories. For central laboratory use. Not for point-of-care use.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Precision/Reproducibility: A precision study was conducted per CLSI EP05-A3 guideline. At site 1, 3 milk samples were tested using one device over 20 different days, with duplicate measurements per run and 2 runs per day, totaling 80 measurements per sample. Additional precision studies were conducted at sites 2 and 3, where milk samples were analyzed using one device over 5 days with triplicate measurements per run and 2 runs per day, totaling 30 measurements per sample.

Linearity/Assay Reportable Range: Linearity studies were conducted per CLSI EP06-A guideline. A minimum of 12 samples of known relative concentration (covering the range for each analyte) were prepared. Observed values were plotted against expected values, and linear regression analysis was performed.

Fat: R2 = 0.9972, Slope = 1.0119, Intercept = -0.0724 (claimed range: 0.6-4.0 g/100mL)
Crude Protein: R2 = 0.9964, Slope = 0.9925, Intercept = 0.0364 (claimed range: 0.8-3.0 g/100mL)
True Protein: R2 = 0.9967, Slope = 0.9811, Intercept = 0.0647 (claimed range: 0.6-2.4 g/100mL)
Carbohydrates: R2 = 0.9854, Slope = 0.9457, Intercept = 0.5095 (claimed range: 6.6-8.7 g/100mL)

Calibration stability: A real-time calibration stability study was performed with five (5) Miris Human Milk Analyzers. Human milk samples were analyzed each day on each analyzer for up to weeks. Results demonstrate calibration is stable for up to weeks.

Detection Limit: LoB, LoD, and LoQ were established using a 5-day study protocol per CLSI EP17-A2 guideline.

LoB: evaluated with 3 replicate measurements on 4 blank samples per day across 5 days (60 total measurements).
LoD and LoQ: evaluated with 7 milk samples (low fat, low protein, low carbohydrate) tested in triplicates across 5 days using 1 instrument and 1 operator (105 replicates per variable).
- LoB (g/100mL): Fat 0.06, Crude protein 0.06, True protein 0.05, Carbohydrate 0.04
- LoD (g/100mL): Fat 0.11, Crude protein 0.25, True protein 0.20, Carbohydrate 0.35
- LoQ (g/100mL): Fat 0.41, Crude protein 0.42, True protein 0.34, Carbohydrate 3.00

Analytical Specificity (Interference Studies): Conducted following CLSI EP07-A2 guideline by spiking 2 milk sample pools with two concentrations of each interferent substance. Each sample was analyzed on 2 devices during one analytical run, with 2 replicates per device. Significant interference was defined as a difference >0.10 g/100 mL for fat, crude protein, and true protein and >0.15 g/100mL for carbohydrates. A table of maximum concentrations that showed no interference is provided. Certain substances (Citalopram, Sertraline, Ampicillin, Vancomycin, Clindamycin, Cephalexin, Pseudoephedrine) were found to interfere with fat measurements (negative or positive bias), and one substance (Propoxyphene) with protein measurements (positive bias). Hemoglobin contamination also results in positive bias on protein measurements.

Method Comparison with reference method: An accuracy study was performed to determine the bias of the Miris HMA against validated comparative chemical methods. A total of 112 native human milk samples were tested in duplicate on 1 HMA device over 5 days.

Fat (N=80): R2 = 0.99, Slope = 1.11, Intercept = -0.11 (Conc. tested 0.6-4.0 g/100mL)
Crude Protein (N=112): R2 = 0.96, Slope = 1.19, Intercept = -0.33 (Conc. tested 0.9-3.5 g/100mL)
True Protein (N=112): R2 = 0.96, Slope = 1.19, Intercept = -0.27 (Conc. tested 0.7-2.8 g/100mL)
Carbohydrates (N=106): R2 = 0.85, Slope = 0.90, Intercept = 0.62 (Conc. tested 6.6-8.7 g/100mL)
Total Solids (N=112): R2 = 0.96, Slope = 0.97, Intercept = 0.32 (Conc. tested 9.8-15.6 g/100mL)
A method comparison study also evaluated the bias between estimated energy values from Miris HMA and a validated bomb calorimetric method.

Carryover: Studies performed determined acceptable levels of carryover for water to milk and milk to water.

Electrical Safety and Electromagnetic Compatibility (EMC): Complies with IEC 60601-1-2, IEC 61010-2 standards for safety and IEC 61326-1 for EMC.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Not Found. Precision and accuracy metrics (SD, %CV, R2, Slope, Intercept, Bias) are provided.

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Not Found

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 862.1493 Breast milk macronutrients test system.

(a)
Identification. A breast milk macronutrients test system is a device intended to quantitatively measure fat, protein, and total carbohydrate content in human breast milk. These measurements, in conjunction with other clinical assessments, may be used to aid in the nutritional management of infants.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include the following:
(i) An appropriate traceability plan, as determined by FDA, to minimize the risk of drift in the breast milk macronutrient test system results over time.
(ii) Data that demonstrate appropriate precision, as determined by FDA, of the breast milk macronutrients test system. Precision studies must include assessment of a minimum of three breast milk specimens containing different concentrations (low, medium, and high levels) of fat, carbohydrates, and protein. Precision data must include breast milk specimen measurements that are collected at a minimum of three laboratory sites.
(iii) Data that demonstrate appropriate measurement accuracy, as determined by FDA, of fat, carbohydrates, and protein in breast milk. Measurement accuracy data must include breast milk specimen measurements that are collected at a minimum of one laboratory site.
(iv) Data from studies appropriate, as determined by FDA, to demonstrate that the device is free from significant interference from substances that could be present in human milk, including hemoglobin, and medications that are used by breastfeeding subjects.
(2) The labeling required under § 809.10 of this chapter must include a limiting statement indicating that the results should be used only as an aid in the nutritional management of infants and not as the sole basis for making nutrition decisions.

Summary

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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR The Miris Human Milk Analyzer

DECISION SUMMARY

A. DEN Number:

DEN180007

B. Purpose for Submission:

De Novo request for evaluation of automatic class III designation of the Miris Human Milk Analyzer

C. Measurand:

Fat, carbohydrates, and proteins in breast milk

D. Type of Test:

Quantitative, mid-infrared spectroscopy

E. Applicant:

Miris AB

F. Proprietary and Established Names:

Miris Human Milk Analyzer (HMA)

G. Regulatory Information:

1. Regulation section:
  21 CFR 862.1493 Breast Milk Macronutrients Test System
1. Classification:
  Class II (Special Controls)

3. Product code(s):

QEI

1

4. Panel:

Clinical Chemistry (75)

H. Indications for Use:

1. Indications for Use:

The Miris Human Milk Analyzer (HMA) quantitatively measures the concentration of fat, carbohydrate, and protein in human milk. The Miris HMA also provides calculated values for total solids and energy. These measurements, in conjunction with other clinical assessments, may be used to aid in the nutritional management of newborns, including preterm, and infants. This device is intended for use in healthcare by trained healthcare personnel at clinical laboratories.

2. Special conditions for use statement(s):

For prescription use only.

For central laboratory use. Not for point-of-care use.

The Miris Human Milk Analyzer (HMA) is not the sole basis for nutritional management of the newborn. Use of the Miris HMA device is intended as part of an overall treatment plan and nutritional measures for newborns. The Miris HMA is an aid to the healthcare providers' standard of care assessment of nutritional management of newborns through monitoring of weight gain and growth.

Do not use the HMA with fortified human milk or infant formula.

Clinicians should follow clinical practice guidelines and standard of care when supplementing or fortifying human breast milk.

1. Special instrument requirements:
  Miris Human Milk Analyzer

I. Device Description:

The Miris Human Milk Analyzer (HMA) is a system for the quantitative measurement of fat, protein, and total carbohydrate content in human milk. The measurements of fat, protein and carbohydrate are also used in calculating the total solids and the energy content of human milk samples. The HMA unit includes a mid-infrared (mid-IR) spectroscopy system and a user interface. The user is guided by the interactive interface, via the screen, through the measurement process by use of the six-button controlled menu system. Milk samples (3 mL) are injected into the measuring unit (cuvette) via the instrument inlet using a syringe, with excess sample and waste exiting via the outlet.

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The HMA device is comprised of a sample cuvette, hardware consisting of a mainboard and central processing unit (CPU) board, a display, touch button, fan, case, and consumables. The hardware consists of a mainboard with a CPU-board, detector board, and emitter board.

Consumables:

. Miris Check (provided) - This is a solution to be used during start up to check zero-level transmission.
Miris Calibration Control Kit (provided) ●
Miris Cleaner (provided) ●
· Syringes (provided)
· Distilled or deionized water (not provided)

J. Standard/Guidance Document Referenced (if applicable):

CLSI EP05-A3 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Third Edition, October 2014.

CLSI EP06-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline, April 2003.

CLSI EP07-A2 Interference Testing in Clinical Chemistry; Approved Guideline - Second edition, November 2005.

CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - second edition, June 2012.

CLSI EP25-A Evaluation of Stability of In vitro Diagnostic Reagents: Approved Guideline, September 2009.

ISO 14971:2012 Medical devices - Application of Risk Management to Medical Devices, August 2012.

IEC 60601-1-2:2007 Medical Electrical Equipment - Part 1- 2: General Requirements for Basic Safety and Essential Performance - Collateral standard: Electromagnetic Compatibility - Requirements and Tests, March 2007.

EN/IEC 61010-1:2001 Safety Requirements for Electrical Equipment for Measurement, Control, and Laboratory Use - Part 1: General Requirements, February 2001.

K. Test Principle:

The Miris Human Milk Analyzer (HMA) detector contains four waveband filters, where three are used for detection of the macronutrients and one is a reference filter. The wavebands used for the macronutrients are specific for the functional carbonyl groups

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(5.7 µm) for fat determination, amide groups (6.5 µm) for protein determination, and hydroxyl groups (9.6 um) for carbohydrate determination. The fourth waveband is a reference filter to correct, according Lambert-Beer's law, for variations in the optical path length in the liquid phase in the gap between the calcium fluoride windows. For determination of each component, the quantity of radiation absorbed by the functional groups is used, and estimations are made by reference to the amount of infrared radiation absorbed by water at the same waveband. The reference waveband is used to adjust for the background absorbance that is not derived from the presence of functional groups.

At a measurement, the HMA software application processes the transmission data via an internal calibration and presents values for fat, crude protein, true protein, and total carbohydrate concentrations (g/100 mL milk), and also calculated values for total solids (g/100 mL milk) and energy (kcal/100 mL milk), on the instrument display.

L. Performance Characteristics:

1. Analytical performance:

a. Precision/Reproducibility
The precision of the Miris Human Milk Analyzer was evaluated in accordance to the CLSI EP05-A3 guideline. A precision study was conducted at site 1, by testing a minimum of 3 milk samples using one device over 20 different days, with duplicate measurements per run and 2 runs per day for a total of 80 measurements per sample. Additional precision studies were conducted at sites 2 and 3, where milk samples were analyzed using one device over 5 days with triplicate measurements per run and 2 runs per day for a total of 30 measurements per sample. The results of the precision studies are summarized below:

Fat - Site 1

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|---------|--------|---------|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | (b)(4) | (b) (4) | | | | 0.1302 | 17.6875 | 0.1374 | 18.6570 |
| 3 | | | | | | 0.1443 | 7.6878 | 0.1450 | 7.7209 |
| 4 | | | | | | 0.0433 | 1.3526 | 0.0609 | 1.9028 |
| 5* | | | | | | 0.0494 | 1.3409 | 0.0649 | 1.7636 |

*N=78, the number

in one run and no results were obtained.

e 5 was unintentionally not tested

Fat	1	Site 2

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 0.71 | (b)(4) | | | | | | | |
| 3 | 1.91 | | | | | | | | |
| 4 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |

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Fat - Site 3

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | (b)(4) | | | | | | | | |
| 3 | | | | | | | | | |
| 4 | | | | | | | | | |
| 5 | | | | | | | | | |

Crude Protein - Site 1

Sample	Mean (g/100mL)	Between Day	Between Run		Total
		(b) (4)	SD	%CV	SD	%CV
3	0.80		0.0433	5.3874	0.0542	6.7395
5*	(b) (4)		0.0160	1.5382	0.0501	4.8132
4	1.29		0.0274	2.1148	0.0389	3.0038
1	2.77		0.2710	9.7807	0.2710	9.7807

*N=78, the number o

one run and no results were obtained.

5 was unintentionally not tested in

Crude Protein - Site 2

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 3 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 4 | | | | | | | | | |

Crude Protein - Site 3

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 3 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 4 | | | | | | | | | |

True Protein - Site 1

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|----|------------|----|-------------|----|-------|--|
| | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |
| 3 | (b)(4) | | | | | | | | |
| 5* | | | | | | | | | |
| 4 | | | | | | | | | |
| 1 | | | | | | | | | |

*N=78, the number of results is reduced because sample 5 was unintentionally not tested in one run and no results were obtained.

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True Protein - Site 2

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 3 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 4 | | | | | | | | | |
| 1 | | | | | | | | | |

True Protein - Site 3

| | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| Sample | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 3 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 4 | | | | | | | | | |
| 1 | | | | | | | | | |

Carbohydrates - Site 1

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| 4 | (b)(4) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 5* | | | | | | | | | |

*N=78, the number of results is reduced because sample 5 was unintentionally not tested in one run and no results were obtained.

Carbohydrates - Site 2

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 4 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 1 | | | | | | | | | |

Carbohydrates - Site 3

| Sample | Mean
(g/100mL) | Between Day | | Within Run | | Between Run | | Total | |
|--------|-------------------|-------------|-----|------------|-----|-------------|-----|-------|-----|
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 4 | (b)(4) | | | | | | | | |
| 5 | | | | | | | | | |
| 1 | | | | | | | | | |

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b. Linearity/assav reportable range:

The linearity studies were conducted in accordance to CLSI EP06-A guideline. A minimum of 12 samples of known relative concentration (covering the range for the specific analyte) were prepared. The observed values were plotted against the expected values and linear regression analysis was performed. The results are provided in the table below.

| Analyte | Concentration
tested (g/100mL) | R2 | Slope | Intercept |
|---------------|-----------------------------------|--------|--------|-----------|
| Fat | 0.4-4.8 | 0.9972 | 1.0119 | -0.0724 |
| Crude Protein | 0.40 - 3.8 | 0.9964 | 0.9925 | 0.0364 |
| True Protein | 0.3-3.1 | 0.9967 | 0.9811 | 0.0647 |
| Carbohydrates | 6.1 - 8.9 | 0.9854 | 0.9457 | 0.5095 |

The results of the linearity study support the following claimed measuring ranges:

| Analyte | Claimed range
(g/100mL) |
|---------------|----------------------------|
| Fat | 0.6-4.0 |
| Crude Protein | 0.8-3.0 |
| True Protein | 0.6-2.4 |
| Carbohydrates | 6.6-8.7 |

c. Traceability, Stability, Expected Values (controls, calibrators, or methods):
The Miris Human Milk Analyzer is traceable to certified reference materials and validated chemical methods. The validation of these chemical methods was reviewed and found to be acceptable. The applicant submitted a detailed traceability assurance plan which was reviewed and found to be acceptable.

Calibration stability:

A real-time calibration stability study was performed with five (5) Miris Human Milk Analyzers. A total of (b) (4)human milk samples were analyzed each day on each analyzer, ""days per week for up to""" weeks. The results demonstrate calibration is
stable for up to "" weeks. The instrument should be re-calibrated by the manufacturer before the ""-week period if a transmission change of 10% or more for any filter is detected during the start-up process and after a major instrument servicing.

d. Detection Limit:
Limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) of the Miris HMA was established using a 5-day study protocol per CLSI EP17-A2 guideline.

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To evaluate the LoB. 3 replicate measurements were made on 4 blank samples per day across 5 days, on a single instrument for a total of 60 measurements. LoB was calculated using a non-parametric data analysis.

For the LoD and LoO determination. 7 milk samples with low fat levels and 7 samples with low protein and carbohydrate levels were tested in triplicates across 5 days using 1 instrument and 1 operator. A total of 105 replicates per variable were obtained. LoD was calculated as LoD =LoB+(b) (4)SD pooled, and LoQ was defined as the lowest amount of analyte that met a pre-determined total error (TE) of 0.10 g/100 mL for fat, crude protein, and true protein and >0.15 g/100mL for carbohydrates.

The compounds and the highest concentration that don't interfere are listed in the table below:

| Interference | Maximum concentration tested that
showed no interference (mg/L) |
|-------------------------------|--------------------------------------------------------------------|
| Acetaminophen | 45 |
| Ibuprofen | 1.2 |
| Aspirin | 15 |
| Oxycodone | 0.60 |
| Paroxetine | 0.15 |
| Gentamicin | 0.6 |
| Cefazolin | 3 |
| Diphenhydramine | 0.3 |
| Loratadine | 0.90 |
| Phenytoin | 3 |
| Carbamazepine | 7.5 |
| Hydrochlorothiazide | 0.60 |
| Propranolol | 0.090 |
| Metoprolol | 0.450 |
| Progestin only contraceptives | 0.00075 |

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| Interference | Maximum concentration tested that
showed no interference (mg/L) |
|--------------|--------------------------------------------------------------------|
| (b)(4) | |
| Prednisolone | 0.750 |
| Domperidone | 0.015 |
| Morphine | 0.150 |
| Fluoxetine | 0.300 |
| Methyldopa | 3 |
| Caffeine | 15 |
| Bronopol | 0.10% |

The following substances were found to interfere and the sponsor states in the labeling that milk that may contain any of the drugs listed below should not be analyzed with the Miris HMA:

| Interfering
Substance | Concentration tested
that caused
interference (mg/dL) | Affected analytes |
|--------------------------|-------------------------------------------------------------|-------------------------------------------------------|
| Citalopram | (b) (4) | Results in a negative bias on fat
measurements |
| Sertraline | | Results in a negative bias on fat
measurements |
| Ampicillin | | Results in a negative bias on fat
measurements |
| Vancomycin | | Results in a positive bias on fat
measurements |
| Clindamycin | | Results in a negative bias on fat
measurements |
| Cephalexin | | Results in a negative bias on fat
measurements |
| Pseudoephedrine | | Results in a negative bias on fat
measurements |
| (b)(4) | | Result in a positive bias on protein
measurements. |

The sponsor includes the following limitation in the labeling:

"Human milk may be contaminated with hemoglobin, from whole blood. This will result in a positive bias on protein measurements. If the milk is visibly pink, presumed from blood contamination, macronutrient analysis by HMA is not recommended."

f. Assay Cut-off:

Not applicable.

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2. Comparison Studies:

a. Method Comparison with reference method:

The sponsor performed an accuracy study to determine the bias of the Miris Human Milk Analyzer (HMA) against validated comparative chemical methods. A total of 112 native human milk samples were tested in duplicate on 1 HMA device over 5 days. Regression analysis and bias estimations were based on first replicate results. The comparative method included the same 112 samples analyzed in triplicate. The mean of the triplicates results was used as the comparative values.

The results of the method comparison are summarized in the table below.

| Analyte | N | Concentration
tested (g/100mL) | R2 | Slope | Intercept |
|---------------|-----|-----------------------------------|------|-------|-----------|
| Fat | 80 | 0.6-4.0 | 0.99 | 1.11 | -0.11 |
| Crude Protein | 112 | 0.9-3.5 | 0.96 | 1.19 | -0.33 |
| True Protein | 112 | 0.7-2.8 | 0.96 | 1.19 | -0.27 |
| Carbohydrates | 106 | 6.6 - 8.7 | 0.85 | 0.90 | 0.62 |
| Total Solids* | 112 | 9.8- 15.6 | 0.96 | 0.97 | 0.32 |

calculated results from HMA compared to a validated chemical method.

The bias at low, medium, and high levels of each analyte was calculated. The results are presented in the table below.

| Analyte | N | Range
(g/100mL) | Concentration
(g/100mL) | Bias
(g/100mL) | 95% CI |
|---------------|-----|--------------------|----------------------------|-------------------|--------|
| Fat | 80 | 0.6- 4.0 | (b) (4) | | |
| Crude Protein | 112 | 0.9- 3.5 | | | |
| True Protein | 112 | 0.7- 2.8 | | | |
| Carbohydrates | 106 | 6.6-8.7 | | | |

In addition, the sponsor conducted a method comparison study to evaluate the bias between the estimated energy values from Miris HMA method compared to a validated bomb calorimetric method. A total of (010) native human milk samples were analyzed on the Miris HMA and the validated bomb calorimetric method. Data analysis and bias was estimated from the first replicate results obtained from the Miris HMA and triplicate means were used for the comparative method. The results of the regression analysis were:

10

(b) (4)

Bias of the energy results was estimated at three concentrations; the results are summarized below:

Energy (kcal/100mL)	Bias (kcal/100mL)	95% CI
45	(b) (4)
70
110

b. Matrix comparison:
Not Applicable. The device is intended for use with human breast milk only.
1. Clinical Studies:
  Not Applicable.
1. Clinical cut-off:
  Not applicable.
1. Expected values/Reference range:
  The composition of human milk is highly variable and affected by multiple factors such as diurnal variation, longitudinal changes associated with postpartum duration, time since last feed, volume of milk consumed at the prior feed, time during feed, and maternal physiological let down. The sponsor included in the labeling the breast milk composition variation in macronutrients in human milk which is based on meta-analysis results reported in the literature. The following tables are not intended to be used as expected values for milk supplementation.

Meta-analysis results of the macronutrient composition of term (37-42 weeks of gestation) human milk 11

| Time After
Delivery | Fat
(g/100 mL) | | Crude Protein
(g/100 mL) | | True Protein
(g/100mL) | | Lactose
(g/100mL) | | Oligo-
saccharides
(g/100mL) | | Energy
(kcal/100mL) | |
|------------------------|-------------------|-----|-----------------------------|-----|---------------------------|-----|----------------------|-----|------------------------------------|-----|------------------------|----|
| | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD |
| Day 1-3 | 1.8 | 0.7 | 2.0 | 0.6 | 2.0 | 0.9 | 5.6 | 0.6 | 1.6 | 0.2 | 54 | 8 |
| Day 4-7 | 2.6 | 0.8 | 2.0 | 0.5 | 1.6 | 0.3 | 6.0 | 1.0 | 1.9 | 0.4 | 66 | 9 |
| Week 2 | 3.0 | 0.9 | 1.8 | 0.4 | 1.3 | 0.2 | 6.2 | 0.6 | 1.9 | 0.4 | 66 | 9 |
| Week 3-4 | 3.4 | 0.8 | 1.5 | 0.3 | 1.1 | 0.2 | 6.7 | 0.7 | 1.6 | 0.3 | 66 | 8 |
| Week 5-6 | 3.6 | 1.1 | 1.1 | 0.2 | 1.0 | 0.1 | 6.1 | 1.0 | 1.4 | 0.3 | 63 | 7 |
| Week 7-9 | 3.4 | 0.8 | 1.3 | 0.2 | 0.9 | 0.1 | 6.5 | 0.5 | 1.3 | 0.3 | 63 | 7 |
| Week 10-12 | 3.4 | 0.9 | 1.2 | 0.2 | 1.0 | 0.1 | 6.7 | 0.7 | - | 0.7 | 63 | 8 |

11

| Time After
Delivery | Fat
(g/100 mL) | | Crude Protein
(g/100 mL) | | True Protein
(g/100mL) | | Lactose
(g/100mL) | | Oligo-
saccharides
(g/100mL) | | Energy
(kcal/100mL) | |
|----------------------------|-------------------|----|-----------------------------|----|---------------------------|----|----------------------|----|------------------------------------|----|------------------------|----|
| | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD |
| Colostrum
(day1-3) | 1.8 | | | | 2.0 | | 5.6 | | | | 54 | |
| Mature milk
(week 5-12) | 3.4 | | | | 1.0 | | 6.5 | | | | 63 | |

Meta-analysis results of the macronutrient composition of preterm (