For in vitro diagnostic use only. VITROS® Chemistry Products Calibrator Kit 3 is used to calibrate VITROS® 250/350/5,1 FS and 4600 Chemistry Systems and the VITROS 5600 Integrated System for the quantitative measurement of ALT, ALKP, AMYL, AST, CK, GGT, LDH and LIPA.

Device Description

VITROS® Calibrator Kit 3 contains three levels of calibrators: Calibrator 1, 2, and 3. The calibrators are lyophilized, multi-analyte products prepared from processed bovine serum to which enzymes, electrolytes, stabilizers, and preservatives have been added. VITROS Chemistry Products Calibrator Kit 3 contains four vials each of lyophilized calibrator 1, 2, and 3 and four vials each of calibrator diluent 1, 2, and 3.

AI/ML Overview

This document describes the VITROS Chemistry Products Calibrator Kit 3, a multi-analyte calibrator. The submission focuses on modifications to the calibrator kit, specifically the addition of nominal values and traceability information for Lactate Dehydrogenase (LDH) to the IFCC/L->P method, and the removal of value-assignment information for Acid Phosphatase (ACP).

Here's the breakdown of the acceptance criteria and study information:

1. Acceptance Criteria and Reported Device Performance

The core of this submission is demonstrating substantial equivalence to a predicate device (VITROS Chemistry Products Calibrator Kit 3, K001679). Unlike a diagnostic or screening algorithm with specific performance metrics like sensitivity and specificity, this device is a calibrator, meaning its performance is tied to its ability to accurately assign values and maintain stability for subsequent diagnostic tests.

The document does not present a single table of "acceptance criteria" and "reported device performance" in the typical sense of a diagnostic assay's accuracy metrics. Instead, the acceptance is based on establishing Substantial Equivalence to the predicate device and meeting stability and traceability requirements.

Implicit Acceptance Criteria and Reported Performance:

Acceptance Criteria Category	Specific Criteria (Implicit)	Reported Device Performance (as described in the document)
Device Intent/Functionality	New device must have the same intended use as the predicate.	Intended Use: "For in vitro diagnostic use only. VITROS® Chemistry Products Calibrator Kit 3 is used to calibrate VITROS® 250/350/5,1 FS and 4600 Chemistry Systems and the VITROS 5600 Integrated System for the quantitative measurement of ALT, ALKP, AMYL, AST, CK, GGT, LDH and LIPA." (Matches predicate, except for ACP removal)
Measured Analytes (Value Assigned)	Must measure the same analytes as the predicate (with intended modifications).	Measured Analytes: ALT, ALKP, AMYL, AST, CK, GGT, LDH, LIPA. (Matches predicate, ACP removed as stated in modifications)
Form and Source	Form of the calibrator and source of analytes should be consistent with the predicate.	Form: Lyophilized. Analyte Source: ALT: Porcine Heart, ALKP: Porcine Kidney, AMYL: Porcine Pancreas, AST: Porcine Heart, CK: Porcine Heart, GGT: Porcine Kidney, LDH: Chicken Heart, LIPA: Porcine Pancreas. (Matches predicate)
Number of Levels	Number of calibrator levels should be consistent.	Number of Levels: Three. (Matches predicate)
Target Concentrations (for shared analytes)	Target concentrations for analytes (excluding LDH due to change) should be consistent with the predicate.	Target Concentrations (U/L): ALT: 20, 250, 900; ALKP: 20, 150, 1450; AMYL: 35, 360, 1000; AST: 11, 243, 775; CK: 40, 700, 1650; GGT: 25, 125, 1360; LIPA: 30, 200, 1950. (Matches predicate for these analytes)
Stability	The device must meet established stability criteria for shelf-life and reconstituted product.	Stability: "Real-time stability studies for shelf-life and open-vial claims have been conducted and acceptance criteria were met. VITROS Chemistry Products Calibrator Kit 3 is to be stored frozen at less than or equal to -18℃ for 24 months or until the expiration date printed on each carton. Real-time stability studies for shelf-life are on-going. The final shelf life claims will be based on the completed real-time study results. Reconstituted products should be used immediately or stored refrigerated at 2-8°C for less than or equal to 24 hours." (Acceptance criteria met, ongoing study for final claims)
Traceability (LDH specific)	The modified device's LDH values must be traceable to the specified reference method.	Traceability (LDH): "Values assigned to the VITROS Chemistry Products Calibrator Kit 3 for lactate dehydrogenase LDHI Slides are traceable to the IFCC recommended reference method as described in IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase." (Traceability to IFCC/L->P/37 °C established)
Nominal Calibrator Values (LDH specific)	New nominal values for LDH, corresponding to the new traceability, must be provided and validated.	Nominal Calibrator Value LDH (U/L): Calibrator Vial 1: 90; Calibrator Vial 2: 320; Calibrator Vial 3: 800. (New values provided and implicit to be accurate based on traceability)
Overall Substantial Equivalence	The modified device must be substantially equivalent to the predicate device, demonstrating that the changes do not raise new questions of safety or effectiveness.	Conclusion: "Based on the testing and the comparisons with the predicate device, the VITROS Calibrator Kit 3 (Modified) is substantially equivalent to the VITROS Calibrator Kit 3 cleared under K001679." (Overall acceptance criterion met)

Summary of Differences from Predicate (and how they meet criteria):

Target Concentrations (U/L) for LDH: New Device (LDH: 90, 320, 800) vs. Predicate Device (LDH: 225, 800, 2000). This change is justified by the updated traceability method.
Traceability for LDH: New Device (Buhl method and IFCC method) vs. Predicate Device (Buhl method). The addition of IFCC method traceability is an improvement and aligns the calibrator with a recognized standard.

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

The document does not explicitly state a "test set" and its sample size in a manner typical for diagnostic device validation (e.g., a cohort of patient samples). The studies performed for this calibrator focus on stability testing and traceability/value assignment.

Stability Studies: "Real-time stability studies for shelf-life and open-vial claims have been conducted..." No specific sample size (number of calibrator kits or vials) is given, nor is the data provenance by country. These are generally prospective studies done in-house by the manufacturer.
Traceability and Value Assignment: "...using a panel of human samples as an intermediate Working Calibrator."
- Sample Size for "panel of human samples": Not specified.
- Data Provenance: The "panel of human samples" implies human-derived samples, but specific country of origin or whether they were retrospective/prospective is not mentioned. This is typically internal validation data.

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

N/A. This is a calibrator, not a diagnostic device that interprets clinical output requiring expert review for ground truth.

For the traceability and value assignment, the reference methods (e.g., IFCC recommended reference method) are the "ground truth" for the calibrator values themselves, rather than clinical experts establishing a ground truth for a test set. This process relies on scientific and metrological standards for enzyme activity measurement.

4. Adjudication Method for the Test Set

N/A. Not applicable for a calibrator device.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

N/A. This is a calibrator, not a diagnostic device involving human readers or interpretation of cases.

6. Standalone Performance Study (Algorithm Only)

N/A. This is a physical calibrator product, not a software algorithm. Its "performance" is its ability to accurately transfer values and maintain stability. The "algorithm" for value assignment is described as analogous to the Broughton and Eldjarn method, which is a statistical and analytical process for value transfer.

7. Type of Ground Truth Used

For Calibrator Values: The ground truth for the assigned values of the analytes, particularly LDH, is established by internationally recognized reference methods/procedures. For LDH, it is the "IFCC recommended reference method as described in IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase." Other analytes also have their traceability linked to established reference methods (e.g., IFCC, PG5, NCCLS, pH Stat).
For Stability: The ground truth is experimental measurement against predefined stability specifications/acceptance criteria.

8. Sample Size for the Training Set

N/A. This is a calibrator, not an AI/ML algorithm that is "trained" on data. The "training" for a calibrator (if an analogy must be made) is the process of its manufacturing and initial value assignment according to established scientific methods.

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

N/A, for the reasons mentioned above. However, the document does describe how the values are assigned:

"The process by which Supplementary Assigned Values (SAV) are assigned to VITROS Chemistry Products Calibrator Kit 3 is analogous to the value transfer process described by Broughton and Eldjarn... The major difference is that instead of transferring values from one serum pool to another, reference method values are transferred to product calibrator fluids, using a panel of human samples as an intermediate Working Calibrator."

This implies a multi-step process involving:

Reference method measurement (the ultimate ground truth).
Transferring these values to human samples (the "panel of human samples").
Using these human samples as an "intermediate Working Calibrator" to assign values to the final product calibrator fluids.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

May 20, 2016

ORTHO-CLINICAL DIAGNOSTICS, INC. MARLENE HANNA SENIOR REGULATORY AFFAIRS MANAGER 100 INDIGO CREEK DRIVE ROCHESTER, NY 14626-5101

Re: K161140

Trade/Device Name: VITROS Chemistry Products Calibrator Kit 3 Regulation Number: 21 CFR 862.1150 Regulation Name: Calibrator, multi-analyte mixture Regulatory Class: II Product Code: JIX Dated: April 21, 2016 Received: April 22, 2016

Dear Marlene Hanna:

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 approval 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, listing 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 either 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 may 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 your 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 (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

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), 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/Resourcesfor You/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/Safety/ReportaProblem/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 vours.

Katherine Serrano -S

: Court

For : 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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Indications for Use

510(k) Number (if known) K161140

Device Name

VITROS® Chemistry Products Calibrator Kit 3

Indications for Use (Describe)

For in vitro diagnostic use only. VITROS® Chemistry Products Calibrator Kit 3 is used to calibrate VITROS 250/350/5,1 FS and 4600 Chemistry Systems and the VITROS 5600 Integrated System for the quantitative measurement of ALT, ALKP, AMYL, AST, CK, GGT, LDH, and LIPA.

Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)	Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary of Safety and Effectiveness for the

VITROS® Chemistry Calibrator Kit 3

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

1. 510(k) Number: K161140

2. Applicant:

Contact:	Marlene A. Hanna, RACSr. Regulatory Affairs Manager
Address:	Ortho Clinical Diagnostics, Inc.100 Indigo Creek DriveRochester, NY 14506
Phone:	(585) 453-4041(585) 453-3368 (Facsimile)

1. Date: April 21, 2016

4. Proprietary and Established Names:

VITROS® Chemistry Products Calibrator Kit 3

5. Regulatory Information:

Regulation section: 21 CFR §862.1150, calibrator, multi-analyte mixture Classification: Class II Product Code: JIX Panel: Clinical Chemistry

6. Purpose of the 510(k) Submission:

The VITROS® Chemistry Products Calibrator Kit 3 is being modified by addition of nominal values and information to support traceability of lactate dehydrogenase (LDH) to the IFCC/L->P method and removal of value-assignment information for acid phosphatase (ACP). The VITROS ACP assay is no longer commercially available. There are no changes made to the other analytes (ALT, ALKP, AMYL, AST, CK, GGT and LIPA) the calibrator kit is used with.

7. Predicate Device:

Device Name: VITROS® Chemistry Products Calibrator Kit 3 510(k) Number: K001679 Manufacturer: Ortho-Clinical Diagnostics, Inc.

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8. Intended Use:

See Indications for Use

9. Indications for Use:

Special Conditions for Use Statement(s): For prescription use only.

10. Device Description:

11. Test Principle:

VITROS® Chemistry Products Calibrator Kit 3 is intended for in vitro diagnostic use in the calibration of ALT, ALKP, AMYL, AST, CK, GGT, LDH, and LIPA on VITROS® Chemistry and Integrated Systems.

12. Substantial Equivalence Information:

VITROS® Chemistry Products Calibrator Kit 3 Predicate device name: Predicate K number: K001679 Comparison with Predicate: Please see Table 1 below for Similarities and differences for the VITROS Calibrator Kit 3.

SIMILARITIES
Item	New Device	Predicate Device
Intended Use	For in vitro diagnostic use only.VITROS® Chemistry ProductsCalibrator Kit 3 is used to calibrateVITROS® 250/350/5,1 FS and 4600Chemistry Systems and the VITROS5600 Integrated System for thequantitative measurement of ALT,ALKP, AMYL, AST, CK, GGT,LDH and LIPA.	Same
SIMILARITIES
Item	New Device	Predicate Device
MeasuredAnalytes (Value assigned)	Alanine Aminotransferase (ALT)Alkaline Phosphatase (ALKP)Amylase (AMYL)Aspartate Aminotransferase (AST)Creatine Kinase (CK)Gamma Glutamyltransferase (GGT)Lactate Dehydrogenase (LDH)Lipase (LIPA)	Same
Form	Lyophilized	Same
Analyte Source	ALT: Porcine HeartALKP: Porcine KidneyAMYL: Porcine PancreasAST: Porcine HeartCK: Porcine HeartGGT: Porcine KidneyLDH: Chicken HeartLIPA: Porcine Pancreas	Same
Number of Levels	Three	Same
TargetConcentrations(U/L)	ALT: 20, 250, 900ALKP: 20, 150, 1450AMYL: 35, 360, 1000AST: 11, 243, 775CK: 40, 700, 1650GGT: 25, 125, 1360LIPA: 30, 200, 1950	Same
Stability	Unopened: Frozen: ≤ -18 °C (< 0F):for 24 monthsReconstituted (Refrigerated): 2- 8°C(36-46°F): < 24 hours	Same

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DIFFERENCES
Item	New Device	Predicate Device
TargetConcentrations(U/L) for LDH	LDH: 225, 800, 2000LDH: 90, 320, 800	LDH: 225, 800, 2000
Traceability forLDH	Buhl method andIFCC method	Buhl method

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13. Standard/Guidance Document Reference

The following recognized standard and guidance documents were used:

CEN 13640 Stability Testing of In Vitro Diagnostic Reagents .
Guidance for Industry Abbreviated 510(k) Submissions for In Vitro ● Diagnostic Calibrators

14. Performance Characteristics

The following studies are not applicable for the purpose of this submission:

Precision/Reproducibility .
Linearity/Assay Reportable Range ●
Detection limit ●
Method and Matrix Comparison Studies ●
Analytical Specificity ●
Assay cut-off ●
Expected Values/Reference Interval ●

Summary of Stability:

Real-time stability studies for shelf-life and open-vial claims have been conducted and acceptance criteria were met. VITROS Chemistry Products Calibrator Kit 3 is to be stored frozen at less than or equal to -18℃ for 24 months or until the expiration date printed on each carton. Real-time stability studies for shelf-life are on- going. The final shelf life claims will be based on the completed real-time study results. Reconstituted products should be used immediately or stored refrigerated at 2-8°C for less than or equal to 24 hours.

Summary of Traceability and Value Assignment

Values assigned to the VITROS Chemistry Products Calibrator Kit 3 for lactate dehydrogenase LDHI Slides are traceable to the IFCC recommended reference method as described in IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase .1

The process by which Supplementary Assigned Values (SAV) are assigned to VITROS Chemistry Products Calibrator Kit 3 is analogous to the value transfer process described by Broughton and Eldjarn (P.M.G. Broughton and L. Eldjarn, Methods of assigning accurate values to reference serum, Part 1. The use of reference laboratories and consensus values, with an evaluation of a procedure transferring values from one reference serum to another, Ann. Clin. Biochem. 22: 625-634, 1985). The major difference is that instead of transferring values from one serum pool to another, reference method values are transferred to product calibrator fluids, using a panel of human samples as an intermediate Working Calibrator.

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Product	Analyte	Traceability
VITROS®CalibratorKit 3	ALT	IFCC/NRSCL RS4-A/37 °C
	ALKP	IFCC/37 °C
	AMYL	PG5/37 °C
	AST	IFCC/NRSCL RS2-A/37 °C
	CK	IFCC/NRSCL RS14-P/37 °C
	GGT	IFCC/NRSCL RS17-P/37 °C
	LDH	NCCLS/P->L/37 °C
	LDHI	IFCC/L->P/37 °C
	LIPA	pH Stat

The assigned values of the VITROS Calibrator Kit 3 are traceable as listed in the following table:

Refer to the below table for representative target concentrations for LDH in VITROS Calibrator Kit 3.

VITROS CalibratorKit 3	Nominal Calibrator ValueLDH (U/L)
Calibrator Vial 1	90
Calibrator Vial 2	320
Calibrator Vial 3	800

16. Conclusions

Based on the testing and the comparisons with the predicate device, the VITROS Calibrator Kit 3 (Modified) is substantially equivalent to the VITROS Calibrator Kit 3 cleared under K001679.

Regulation Number and Section

§ 862.1150 Calibrator.

(a)
Identification. A calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens. (See also § 862.2 in this part.)(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.