K Number
K133652
Date Cleared
2014-04-28

(152 days)

Product Code
Regulation Number
862.1310
Reference & Predicate Devices
Predicate For
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

The GSP Neonatal Total Galactose kit is intended for the quantitative determination of total galactose (galactose and galactose-1-phosphate) concentrations in blood specimens dried on filter paper as an aid in screening newborns for galactosemia using the GSP® instrument.

Device Description

The GSP Neonatal Total Galactose kit contains sufficient reagents to perform 1152 assays. The GSP Neonatal Total Galactose test system measures total galactose, i.e. both galactose and galactose-1-phosphate, using a fluorescent galactose oxidase method. The fluorescence is measured using an excitation wavelength of 505 nm and an emission wavelength of 580 nm. The kit contains Neonatal Total Galactose Assay Reagent 1, Neonatal Total Galactose Assay Reagent 2, Neonatal Total Galactose Assay Buffer, Neonatal Total Galactose Assay Reconstitution Solution, and Neonatal Extraction Solution. Calibrators and Controls are also included.

AI/ML Overview

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance CriteriaReported Device Performance
Precision (Total Variation)Ranged from 9.3% to 14.1% CV.
Limit of Blank (LoB)0.34 mg/dL
Limit of Detection (LoD)0.97 mg/dL
Limit of Quantitation (LoQ)1.15 mg/dL (defined as the lowest concentration with a total CV equal to or less than 20%).
LinearityDemonstrated linear performance throughout the measuring range (from 1.15 mg/dL to 50 mg/dL).
RecoveryAverage recovery of 109% for galactose, 117% for galactose-1-phosphate, and 103% for both combined from three contrived dried blood spot samples.
Interference- Acetaminophen: Concentrations above 2.75 mg/dL caused a significant decrease (>15%) in measured total galactose. Maximum tested (5.5 mg/dL) caused a decrease of ~20-22%.- Conjugated Bilirubin: Concentrations above 16.6 mg/dL caused a significant decrease (>15%) in measured total galactose. At 24.9 mg/dL and above, the decrease was 100% at some total galactose concentrations.- Intralipid: Concentrations above 250 mg/dL (at 5 and 10 mg/dL total galactose) or 375 mg/dL (at 15 mg/dL total galactose) caused a significant increase (>15%) in measured total galactose. Maximum tested (1500 mg/dL) caused an increase of ~52-77%.- Hemoglobin (with Bilirubin): Hemoglobin levels at 198 g/L and above in combination with an elevated bilirubin level of 15 mg/dL caused a significant increase (>15%) in measured total galactose at certain total galactose concentrations. For example, at 5 mg/dL total galactose, 198 g/L Hb led to a 26.3% increase.- Non-Interfering Substances: Unconjugated bilirubin (20 mg/dL), ß-Nicotinamide adenine dinucleotide (100 µmol/L), Glutathione (3 mmol/L), Human Serum Albumin (30 mg/mL), Ascorbate (6 mg/dL), D-glucose (1000 mg/dL), D-mannose (100 mg/dL), D-fructose (18 mg/dL), Ampicillin (152 µmol/L), and Lithium heparin (0.375 mg/ml), and Hematocrit levels from 30% to 66% (102-230 g/L Hemoglobin) were found not to interfere.
Screening Performance vs. Predicate (95th percentile)Overall percent agreement = 96.0%Positive percent agreement = 63.6%Negative percent agreement = 97.9%
Screening Performance vs. Predicate (99th percentile)Overall percent agreement = 98.8%Positive percent agreement = 53.3%Negative percent agreement = 99.4%

2. Sample Size Used for the Test Set and Data Provenance

  • Sample Size for Precision Study: 7 samples, with 216 total measurements per sample (4 replicates per sample, in 27 runs over 21 days using 3 kit lots and 3 GSP instruments).
  • Sample Size for LoD: 216 determinations of 4 low-level samples.
  • Sample Size for LoB: 150 blank samples.
  • Sample Size for Recovery: 3 contrived dried blood spot samples.
  • Sample Size for Interference Studies: Not explicitly stated for each concentration, but involved various concentrations of interfering substances at three total galactose concentrations (5, 10, and 15 mg/dL).
  • Sample Size for Internal Method Comparison: 141 routine screening and spiked blood spot specimens.
  • Sample Size for Screening Performance Study: 2320 samples (6 confirmed positive samples and 2314 routine samples).
  • Data Provenance: The screening performance study was conducted at "one newborn screening laboratory in the United States." Other non-clinical studies (precision, linearity, LoB/LoD/LoQ, recovery, interference) appear to be internal laboratory studies without specific geographic provenance mentioned, but presumably also conducted in the US or Finland (Wallac Oy headquarters). The studies were retrospective, using banked samples and contrived samples.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not mention the use of experts to establish ground truth for the test set. For the screening performance study, "6 confirmed positive samples" are mentioned, implying prior clinical diagnosis as the ground truth. The qualifications of who confirmed these positive cases or how the "routine samples" were classified as normal are not specified.

4. Adjudication Method for the Test Set

Not applicable. The document does not describe any expert adjudication process for the test set. Ground truth for confirmed positive samples likely came from clinical diagnosis.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This device is an in-vitro diagnostic test kit (laboratory assay) for quantitative determination, not an imaging device or AI-assisted diagnostic tool that would involve human readers interpreting results in a MRMC study.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This refers to the performance of the assay itself. The entire submission details the standalone performance of the GSP Neonatal Total Galactose kit (assay only) without human-in-the-loop interpretation beyond standard laboratory procedures and reporting. The "GSP® instrument" is automated, as stated in the comparison chart ("GSP instrument, automated").

7. The Type of Ground Truth Used

  • For Analytical Performance (Precision, LoB, LoD, LoQ, Linearity, Recovery, Interference): Ground truth was established by preparing samples with known concentrations of total galactose or specific interfering substances. For example, for recovery, the "recovery of galactose, galactose-1-phosphate, and both combined was determined from three contrived dried blood spot samples," meaning these samples were prepared with known amounts.
  • For Screening Performance Study: The ground truth for the 6 positive samples was "confirmed positive." This implies a clinical diagnosis of galactosemia, likely through follow-up diagnostic testing. The other 2314 samples are referred to as "routine samples" and classified as "normal" in the context of screening performance, likely based on either their negative predicate device result or their actual clinical status. The document also compares the new device's results against the predicate device's results as a reference for "Manual result."

8. The Sample Size for the Training Set

Not applicable in the conventional sense of machine learning training sets. This is a chemical assay, not an AI/ML device that requires a distinct training set for model development. The development and optimization of the assay would involve various experiments, but these are not referred to as "training sets" in this context.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no "training set" in the context of an AI/ML model for this chemical assay. The development of the calibrators and controls (which are prepared with known concentrations of galactose and galactose-1-phosphate) serves an analogous function in ensuring accuracy and consistency of the assay.

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510(k) Summary

This 510(k) Summary information is supplied in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510 (k) number is K133652

Date: April 28, 2014

Submitted by:

Wallac Oy, a subsidiary of PerkinElmer Inc. 940 Winter Street Waltham, MA 02451

Wallac Oy Mustionkatu 6 Turku Finland 20750

Submission Contact Person: Primary: Jeanette Schier-Pugsley Director, Regulatory and Clinical Affairs 781-663-6025 Tel: Fax: 781-663-5969 Trade Name: GSP Neonatal Total Galactose kit (3309-001U) Common Name: Galactose test system Regulation: 21 CFR 862.1310 Classification Name: Galactose test system Classification: I, Reserved Panel: 75 Clinical Chemistry Product Code: . JIA Predicate device: Neonatal Total Galactose kit [K071649]; Wallac Ove

Device Description:

The GSP Neonatal Total Galactose kit contains sufficient reagents to perform 1152 assays. The GSP Neonatal Total Galactose test system measures total galactose, i.e. both galactose and galactose-1-phosphate, using a fluorescent galactose oxidase method. The fluorescence is measured using an excitation wavelength of 505 nm and an emission wavelength of 580 nm.

The kit contains the following components:

APR 2 8 2014

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Calibrators have been prepared from human red blood cells enriched with galactose, and with ProClin 300 as preservative. The hematocrit value is 50 - 55 % to correspond to a hematocrit of a newborn. The calibrators have been calibrated against primary calibrators gravimetrically prepared using a U.S. Pharmacopeia Reference Standard Preparation for galactose.

Controls have been prepared from human blood enriched with galactose and galactose-1phosphate, and with ProClin 300 as preservative. Prior to dispensing the blood onto the filter paper, the hematocrit value of blood used in the controls preparation is adjusted to 50 - 55 % to correspond to a hematocrit of a newborn. The low control is approximately 4.0 mg/dL and the high control approximately 12 mg/dL.

All human source materials used in the preparation of kit components were tested and found to be non-reactive for the presence of HBsAg, anti-HIV 1 and 2, and HCV by FDA approved methods.

Neonatal Total Galactose Assay Reagent 1 - 3 lyophilized vials Neonatal Total Galactose Assay Reagent 2 - 3 lyophilized vials Neonatal Total Galactose Assay Buffer - 3 bottles, 40 ml Neonatal Total Galactose Assay Reconstitution Solution - 1 bottle, 20 ml Neonatal Extraction Solution - 1 bottle, 60 ml

Intended Use:

The GSP Neonatal Total Galactose kit is intended for the quantitative determination of total galactose (galactose and galactose-1-phosphate) concentrations in blood specimens dried on filter paper as an aid in screening newborns for galactosemia using the GSP® instrument.

Comparison Chart:

Comparison of the GSP Neonatal Total Galactose device with its predicate:

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GSP Neonatal Total Galactose kit
CharacteristicsProposed DevicePredicate (K071649)
IntendedUse/Indications forUseThe GSP Neonatal TotalGalactose kit is intended for thequantitative determination of totalgalactose (galactose andgalactose-1-phosphate)concentrations in blood specimensdried on filter paper as an aid inscreening newborns forgalactosemia using the GSP®instrument.This kit is intended for thequantitative determination of totalgalactose (galactoseand galactose-1-phosphate)concentrations in blood specimensdried on filterpaper as an aid in screeningnewborns for galactosemia.
Test MethodologyEnzymatic assaySame
Detection MethodFluorescence - measured at 505nm and 580 nm wavelengthsFluorescence - measured at 340 nmand 405 nm wavelengths
InstrumentPlatformGSP instrument, automated(K090846)Fluorometer, manual
Sample TypeDried blood spotSame
Reportable Range1.15 - 50 mg/dL1.3 - 40 mg/dL
Lower Limits ofMeasureLoB = 0.34 mg/dLLoD = 0.97 mg/dLLoQ = 1.15 mg/dLLoB = 0.7 mg/dLLoD = 1.3 mg/dL
CalibratorsA - 0.5 mg/dLB – 2.5 mg/dLC - 5.0 mg/dLD - 10.0 mg/dLE - 20 mg/dLF - 50 mg/dLA - 0 mg/dLB - 1.5 mg/dLC – 4.0 mg/dLD - 9.0 mg/dLE - 18 mg/dLF -- 40 mg/dL

Summary of Non-Clinical Studies:

The variation of the GSP Neonatal Total Galactose assay was determined using dried blood spot samples, 3 kit lots, and 3 GSP instruments. The study was performed in 27 runs over 21 days, each run consisting of 2 plates with 4 replicates per sample. Total number of measurements was 216 per each of seven samples. Total variation ranged from 9.3 to 14.1 %CV.

The Limit of Blank (LoB) for total galactose is 0.34 mg/dL, defined as the 95th percentile of a distribution of blank samples (n = 150). The Limit of Detection (LoD) is 0.97 mg/dL based on 216 determinations of 4 low level samples. The Limit of Quantitation (LoQ) is 1.15 mg/dL, defined as the lowest concentration with a total CV equal to or less than 20%.

For the GSP Neonatal Total Galactose kit, the assay has been demonstrated to be linear throughout the measuring range (from 1.15 mg/dL to 50 mg/dL).

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The recovery of galactose, galactose-1-phosphate, and both combined was determined from three contrived dried blood spot samples with an average recovery of 109%. 117% and 103%. respectively.

The potentially interfering substances were added to whole blood with three total galactose concentrations (5, 10, and 15 mg/dL). A bias exceeding ±15% is considered a significant interference. Acetaminophen and conjugated bilirubin were found to interfere with the assay by decreasing the measured total galactose concentration (see the tables below). Acetaminophen concentrations above 2.75 mg/dL and conjugated bilirubin concentrations above 16.6 mg/dL may cause a false negative screening result for a specimen with measured total galactose concentration close to the cut-off value.

Total Galactoseconc. (mg/dL)AcetaminophenConcentration testedmg/dLPercent change inmeasured galactose(%)Significantchange
51.38-9.6No
2.75-9.3No
4.13-20.6Yes
5.5-22.4Yes
101.38-7.1No
2.75-11.8No
4.13-20.4Yes
5.5-21.9Yes
151.38-7.5No
2.75-11.6No
4.13-20.5Yes
5.5-21.8Yes
Total Galactoseconc. (mg/dL)Conjugated bilirubinConcentration testedmg/dLPercent change inmeasured galactose(%)Significantchange
58.3-6.0No
16.6-10.3No
24.9-100Yes
33.2-100Yes
108.3-1.6No
16.6-2.7No
24.9-16.3Yes
33.2-99.9Yes
158.35.9No
16.69.3No
24.94.4No
33.2-25.6Yes

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Intralipid ' was found to not interfere up to added concentrations of 250 mg/dL at 5 and 10 mg/dL total galactose; and up to 375 mg/dl at 15 mg/dl total galactose. When present above these amounts Intralipid may cause a false positive screening result for a specimen with measured total galactose concentration close to the cut-off value.

Total Galactoseconc. (mg/dL)IntralipidConcentration testedmg/dLPercent change inmeasured galactose (%)Significantchange
51256No
25010No
37523Yes
50033Yes
75037Yes
113054Yes
150077Yes
1012515No
25013No
37519Yes
50019Yes
75030Yes
113040Yes
150052Yes
151254No
25013No
37515No
50024Yes
75022Yes
113022Yes
150029Yes

In addition, hemoglobin in combination with elevated bilirubin concentration of 15 mg/dL was found to interfere with the assay by increasing the measured total galactose concentration (see the table below). Therefore, hemoglobin level at 198 g/L and above in combination with elevated bilirubin level may cause a false positive screening result for a specimen with measured total galactose concentration close to the cut-off value .

Total Galactoseconc. (mg/dL)HemoglobinConcentration testedg/L at Bilirubin level15 mg/dLPercent change inmeasured galactose (%)Significantchange
5102-0.8No
519826.3Yes
52175.1No

Intralipid is a registered trademark of Fresenius Kabi AB.

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102304.0No
1022.2No
19819.3Yes
217-11.0No
2307.1No
15*1023.5No
1985.8No
23022.0Yes
  • Due to insufficient blood volume during sample preparation, a hemoglobin sample at 217 g/L could not be prepared at 15 mg/dL total galactose.

Hematocrit levels from 30% to 66% (Hemoglobin levels 102-230 g/L) were found not to interfere at total galactose concentrations of 5, 10 and 15 mg/dL.

The following substances were tested and found to not interfere with the measurement of total galactose for the concentration noted; Unconjugated bilirubin (20 mg/dL), ß-Nicotinamide adenine dinucleotide (100 umol/L), Glutathione (3 mmol/L), Human Serum Albumin (30 mg/mL), Ascorbate (6 mg/dL), D-glucose (1000 mg/dL), D-mannose (100 mg/dL), D-fructose (18 mg/dL), Ampicillin (152 umol/L), and Lithium heparin (0.375 mg/ml).

Summary of Internal Method Comparison and Screening Performance Studies:

The 3309-001U GSP Neonatal Total Galactose kit (y) was compared internally with the 3029-0010 Neonatal Total Galactose kit (x) using routine screening and spiked blood spot specimens. duplicate measurements, in the range of 1.3-40 mg/dL (72-2220 umol/L) in the 3029-0010 kit, the range in the 3309-001U kit being 1.15-50 mg/dL (64-2775 umol/L. The correlation from weighted Deming regression was found to be: mg/dL: y= 1.16x - 0.49; 95% CJ: slope (1.07; 1.26), intercept (-0.73; -0.25) (n=141).

The GSP Neonatal Total Galactose test system was designed with an adjusted calibration (shift of approximately 20%) to better align performance with CDC Newborn Screening Quality Assurance Program control material. Therefore current Neonatal Total Galactose users will observe an increased recovery with the GSP Neonatal Total Galactose when running the same samples on both test systems.

In a study conducted at one newborn screening laboratory in the United States, the screening performance of the new and predicate device was evaluated with a total of 2320 samples (6 confirmed positive samples and 2314 routine samples). The screening performance is shown below based on 95.0 and 99.0 percentile values.

GSP resultManualresultTotalPositiveNormal
++82676
+-45045
-+47047
--214602146
Total232062314

Screening performance of GSP Neonatal Total Galactose test system (95.0 percentile).

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Overall percent agreement = (82+ 2146) / 2320* 100% = 96.0 % Positive percent agreement = (82/129) * 100% = 63.6 % Negative percent agreement = (2146/ 2191) * 100% = 97.9%

Screening performance of GSP Neonatal Total Galactose test system (99.0 percentile).
ManualI GSP result !TotalDacitivaNormsl
GSP resultresultTotalPositiveNormal
++16റ്10
+14014
+14C14
227602276
Total232062314
Overall percent agreement = (16+ 2276) / 2320* 100% = 98.8%
Positive percent agreement = (16/30) * 100% = 53.3 %

Negative percent agreement = (2276/ 2290) * 100% = 99.4%

Substantial Equivalency:

The proposed device and predicate device utilize similar enzymatic pathway and design shown to produce equivalent screening performance in a clinical setting. Both devices are intended for use in for the quantitative determination of total galactose and galactose and galactose-1-phosphate) concentrations in blood specimens dried on filter paper as an aid in screening newborns for galactosemia

Conclusion:

The GSP Neonatal Total Galactose test system demonstrates analytical and screening performance that supports its substantial equivalency with the predicate device, the Neonatal Total Galactose test system (K071649).

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Image /page/7/Picture/0 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three tail feathers, representing the department's mission to protect the health of all Americans and provide essential human services. The eagle is positioned to the right of the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA", which is arranged in a circular fashion around the logo.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G69 Silver Spring, MD 20993-0002

April 28, 2014

WALLAC OY. A SUBSIDIARY OF PERKIN ELMER. INC. C/O JEANETTE SCHIER-PUGSLEY DIRECTOR OF REGULATORY AFFAIRS 940 WINTER STREET WALTHAM MA 02451

Rc: K133652

Trade/Device Name: GSP Neonatal Total Galactose Kit Regulation Number: 21 CFR 862.1310 Regulation Name: Galactose test system Regulatory Class: 1. Reserved Product Code: JIA Dated: April 14, 2014 Received: April 15, 2014

Dear Ms. Jeanette Schier-Pugslev:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28. 1976. the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require annroval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. Iisting of devices. good manufacturing practice. labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into cither class II (Special Controls) or class III (PMA). it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations. Title 21. Parts 800 to 898. In addition, FDA mav publish further announcements concerning your device in the Federal Register.

Please be advised that FDA s issuance of a substantial equivalence determination does not mean that FDA has made a determination that vour device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements. including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting of medical device-related adverse events) (21 CFR 803): good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820): and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act): 21 CFR 1000-1050.

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Page 2-Ms. Schier-Pugsley

ff you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resources/orYou/Industry/default.htm. Also. please note the regulation entitled. "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/SafetyReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Courtney H. Lias -S

Courtney H. Lias. Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

510(k) Number (if known) K133652

Device Name

GSP Neonatal Total Galactose kit

Indications for Use (Describe)

The GSP Neonatal Total Galactose kit is intended for the quantitation of total galactose (galactose and galactose-1-phosphate) concentrations in blood specimens dried on filter paper as an aid in screening newborns for galactosemia using the GSP® instrument.

Type of Use (Select one or both, as applicable)

2 Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

PLEASE DO NOT WRITE BELOW THIS LINE -- CONTINUE ON A SEPARATE PAGE IF NEEDED.

FOR FDA USE ONLY

Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

Yung W. Chan -S

This section applies only to requirements of the Paperwork Reduction Act of 1995.

*DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW."

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

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"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

§ 862.1310 Galactose test system.

(a)
Identification. A galactose test system is a device intended to measure galactose in blood and urine. Galactose measurements are used in the diagnosis and treatment of the hereditary disease galactosemia (a disorder of galactose metabolism) in infants.(b)
Classification. Class I.