ADVIA CENTAUR TNI-ULTRA MASTER CURVE MATERIAL (MCM), ADVIA CENTAUR DIGOXIN MASTER CURVE MATERIAL (MCM) by Siemens Healthcare Diagnostics Inc.

The ADVIA Centaur® TnI-Ultra® Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur TnI-Ultra assay.
The ADVIA Centaur® Digoxin Master Curve Material is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur Digoxin assay.

Device Description

ADVIA Centaur® TnI-Ultra® Master Curve Material is an in vitro diagnostic product containing various levels of bovine cardiac troponin I in a goat serum matrix with preservatives. Each set contains five lyophilized levels (MCM1-5); with a reconstituted volume of 1.0 ml each. MCM1 contains no analyte. The Tnl-Ultra MCMs assigned values are lot-specific of target values 0.00, 1.00, 3.50, 14.0 and 40.0 ng/mL.
ADVIA Centaur® Digoxin Master Curve Materials is an in vitro diagnostic product containing various levels of digoxin in defibrinated human plasma with sodium azide (0.1% after reconstitution) and preservatives. Each set contains six lyophilized levels (MCM1-6); with a reconstituted volume of 1.0 mL each. MCM1 contains no analyte. The Digoxin MCMs assigned values are lot specific of target values 0.0, 0.50, 1.00, 2.00, 3.00, 5.50 ng/mL.

AI/ML Overview

The provided text describes two separate devices: ADVIA Centaur® TnI-Ultra® Master Curve Material (MCM) and ADVIA Centaur® Digoxin Master Curve Material (MCM). Both are quality control materials. I will detail the acceptance criteria and study information for each device independently.

ADVIA Centaur® TnI-Ultra® Master Curve Material (MCM)

1. Table of Acceptance Criteria and Reported Device Performance

Study Type	Acceptance Criteria	Reported Device Performance (Supports Claims)
Stability: Real Time/Shelf Life (Unopened)	- MCM1: Dose recovery ≤ 0.02 dose - MCM2-5: % dose recovery within 85% to 115% calculated to Day 0 - No adverse trends	Acceptance criteria were met up to the 10 months time point, supporting a shelf-life claim of 9 months.
Stability: In Use (Open Vial) @ 2-8°C (Reconstituted)	- MCM1: Dose recovery ≤ 0.02 dose (versus freshly reconstituted -80°C stored MCM1 average dose) - MCM2-5: % dose recovery within 85% to 115% (versus freshly reconstituted -80°C stored MCM2-5 average dose)	Acceptance criteria were met up to the 9 hour time point, supporting an open vial claim of 8 hours when stored at 2-8°C.
Stability: In Use (Open Vial) @ -20°C (Reconstituted)	- MCM1: Dose recovery ≤ 0.02 dose (versus freshly reconstituted -80°C stored MCM1 average dose) - MCM2-5: % dose recovery within 85% to 115% (versus freshly reconstituted -80°C stored MCM2-5 average dose)	Acceptance criteria were met up to the 63 days time point, supporting an open vial (reconstituted) claim stored at -20°C for 60 days.
Stability: On-Board	- MCM1: Dose recovery < 0.02 dose - MCM2-5: % dose recovery within 85% to 115% calculated to Time=0	Acceptance criteria were met up to 5 hours, supporting an on-board stability claim for 4 hours.
Value Assignment (New Lot Release)	- New MCM doses must fall within the final value assignment specification for TnI-Ultra MCMs. - Mean MCM doses of the new TnI-Ultra MCM lot manufactured must fall within the release range specifications (which are 5% tighter than customer ranges). - MCM1 range is claimed as "<" less than 3X the limit of sensitivity (≤0.018 ng/mL) of the ADVIA Centaur TnI-Ultra assay.	The document states that "The new MCM doses must fall within the final value assignment specification for TnI-Ultra MCMs" and "The mean MCM doses of the new TnI-Ultra MCM lot manufactured must fall within the release range specifications," implying these criteria are met for manufactured lots. An example lot-specific assigned value and range table is provided, demonstrating how these values would be presented and indicating successful assignment for a sample lot. MCM1 is assigned 0.0 dose and the range is < 0.018 ng/mL, meeting the <3X limit of sensitivity claim.

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

Real Time/Shelf Life (Unopened): Samples were tested at T=0, 3 months, and 10 months. The number of replicates per time point is not explicitly stated, but the study "supports a shelf-life claim of 9 months." Data provenance is assumed to be internal laboratory data, prospective (as it's a real-time study). No country of origin is specified beyond general Siemens Healthcare Diagnostics Inc. information.
In Use (Open Vial) @ 2-8°C (Reconstituted): Each level tested in 5 replicates per level at T=0, 2, 4, 6, 8, 9, 24, and 25 hours.
In Use (Open Vial) @ -20°C (Reconstituted): Each level tested in 5 replicates per level at Day=0, 14, 28, 35, 45, 60, and 63 days.
On-Board Stability: Each level tested at T=0, 2, 4, and 5 hours. The number of replicates per level is not explicitly stated.
Value Assignment:
- MCM1: 5 replicates on two separate runs.
- MCM2-MCM5: 20 replicates in total (one run, four sample cups run in 5 replicates).
- Performance Verification Run: 6 replicates of each MCM level.

Data provenance for all these studies is internal Siemens laboratory data, prospective in nature as they are performance characteristic studies for the device.

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

Not applicable. This device is a quality control material intended for verification of calibration and reportable range for an assay. Its performance is assessed against defined analytical criteria, not against clinical expert interpretations of patient data. The "ground truth" here is the result from reference calibrators and defined analytical specifications, not expert consensus on patient conditions.

4. Adjudication Method for the Test Set

Not applicable, as no expert adjudication of clinical cases is involved. Performance is based on predefined analytical acceptance criteria compared to measured values.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This type of study is not relevant for a quality control material.

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

Yes, the performance studies described are essentially "standalone" in that they evaluate the analytical performance of the Master Curve Material itself, independent of human interpretation of clinical outcomes. The device is a reagent, and its performance is measured directly by an automated system (ADVIA Centaur system).

7. The Type of Ground Truth Used

The ground truth used for performance evaluation is based on:

Pre-defined analytical specifications and acceptance criteria for dose recovery and stability.
Comparison against T=0 dose recovery results for stability studies.
Comparison against freshly reconstituted -80°C stored MCM average dose results for "in use" stability.
Traceability to NIST SRM 2921 and highly purified internal materials for value assignment.
The "target for MCM1 is assigned a 0.0 dose" without a statistical method, and its range is less than 3 times the limit of sensitivity.

8. The Sample Size for the Training Set

Not applicable. This device is a quality control material and does not involve an "algorithm" in the sense of machine learning that requires a training set. The "training" for such a product would be its manufacturing and validation process to meet specifications.

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

Not applicable, as there is no training set for this type of device.

ADVIA Centaur® Digoxin Master Curve Material (MCM)

1. Table of Acceptance Criteria and Reported Device Performance

Study Type	Acceptance Criteria	Reported Device Performance (Supports Claims)
Stability: Real Time/Shelf Life (Unopened)	- MCM1: Dose recovery ≤ 0.10 dose - MCM2: % dose recovery within 82% to 118% - MCM3-6: % dose recovery within 85% to 115% calculated to Day 0 - No adverse trends	Acceptance criteria were met up to the 33 months' time point, supporting a shelf-life claim of 32 months.
Stability: In Use (Open Vial) @ 2-8°C (Reconstituted)	- MCM1: Dose recovery ≤ 0.10 dose (versus -80°C stored MCM1 average dose) - MCM2: % dose recovery within 82% to 118% (versus -80°C stored MCM2 average dose) - MCM3-6: % dose recovery within 85% to 115% (versus -80°C MCMs 3-6 average dose)	Acceptance criteria were met up to the 29 days' time point, supporting an open vial claim of 28 days when stored at 2-8°C.
Stability: On-Board	- MCM1: Dose recovery ≤ 0.10 dose - MCM2: % dose recovery within 82% to 118% - MCM3-6: % dose recovery within 85% to 115% calculated to T=0	Acceptance criteria were met up to 5 hours, supporting an on-board stability claim for 4 hours.
Value Assignment (New Lot Release)	- New MCM doses must fall within the final value assignment specification for Digoxin MCMs. - Mean MCM doses of the new Digoxin MCM lot manufactured must fall within the release range specifications (which are 5% tighter than customer range specifications). - MCM1 range is claimed as "<" less than 3X the limit of sensitivity (≤ 0.1 ng/mL) of the ADVIA Centaur Digoxin assay.	The document states that "The new MCM doses must fall within the final value assignment specification for Digoxin MCMs" and "The mean MCM doses of the new Digoxin MCM lot manufactured must fall within the release range specifications," implying these criteria are met for manufactured lots. An example lot-specific assigned value and range table is provided, demonstrating how these values would be presented and indicating successful assignment for a sample lot. MCM1 is assigned 0.0 dose and the range is < 0.300 ng/mL, meeting the <3X limit of sensitivity claim.

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

Real Time/Shelf Life (Unopened): Samples were tested at T=0, 12 months, 18 months, and 33 months. The number of replicates per time point is not explicitly stated. Data provenance is assumed to be internal laboratory data, prospective.
In Use (Open Vial) @ 2-8°C (Reconstituted): Each level tested in 5 replicates per level at T=0, 7, 14, 21, 28, and 29 days.
On-Board Stability: Each level tested at T=0, 2, 4, and 5 hours. The number of replicates per level is not explicitly stated.
Value Assignment:
- MCM1: 5 replicates on two separate runs.
- MCM2-MCM6: 20 replicates in total (one run, four sample cups run in 5 replicates).
- Performance Verification Run: 6 replicates of each MCM level.

Data provenance for all these studies is internal Siemens laboratory data, prospective in nature.

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

Not applicable. This device is a quality control material, and its performance is assessed against defined analytical criteria, not against clinical expert interpretations of patient data. The "ground truth" here is the result from reference calibrators and defined analytical specifications.

4. Adjudication Method for the Test Set

Not applicable, as no expert adjudication of clinical cases is involved. Performance is based on predefined analytical acceptance criteria compared to measured values.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This type of study is not relevant for a quality control material.

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

7. The Type of Ground Truth Used

The ground truth used for performance evaluation is based on:

Pre-defined analytical specifications and acceptance criteria for dose recovery and stability.
Comparison against T=0 dose recovery results for stability studies.
Comparison against -80°C stored MCM average dose results for "in use" stability.
Traceability to USP (United States Pharmacopeia) Digoxin stock and USP internal material for value assignment.
The "target for MCM1 is assigned a 0.0 dose" without a statistical method, and its range is less than 3 times the limit of sensitivity.

8. The Sample Size for the Training Set

Not applicable. This device is a quality control material and does not involve an "algorithm" in the sense of machine learning that requires a training set.

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

Not applicable, as there is no training set for this type of device.

Summary

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(Bundled) Abbreviated 510(k) Premarket Notification

ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

Section 006: 510(k) Summary

510(k) Summary

Introduction: According to the requirements of 21 CFR 807.92, the following information provides sufficient details to understand the basis for determination of substantial equivalence.

K140267 The assigned 510(k) Number:

1. Applicant Information
- Mailing Address:

Contact Person:

Phone Number: Fax Number: E-mail Address: Date Prepared:

1. Device Name Proprietary Name: Measurand: Type of Test:
  Regulation Section: Classification: Products Code:

Panel:

1. Predicate Device Name Predicate 510(k) No:
1. Device Description:

Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue Tarrytown, NY 10591 USA

Fatima Pacheco Regulatory Clinical Affairs Specialist (914) 524-2450 (914) 524-3579 fatima.pacheco@siemens.com January 29, 2014

ADVIA Centaur® TnI-Ultra® Master Curve Material Quality Control materials for ADVIA Centaur TnI-Ultra assay Master Curve Material (MCM) for ADVIA Centaur TnI-Ultra assav 21 CFR 862.1660. Quality Control Material Class I Reserved JJX - Single (Specified) Analyte Controls (Assayed and Unassaved)

Clinical Chemistry (75)

Elecsys Troponin I CalCheck 5 k 100594

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® Tinl-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

5. Intended Use:Indication for Use:	See Indications for Use Statement below:The ADVIA Centaur TnI-Ultra Master Curve Material is forin vitro diagnostic use in the verification of calibration andreportable range of the ADVIA Centaur TnI-Ultra assay.
Special Conditions forUse Statement(s):	For prescription use only
Special InstrumentRequirements:	ADVIA Centaur ® SystemsA description of the ADVIA Centaur system is documentedin K971418. Subsequent modifications to the instrument havebeen reviewed and cleared in K032525 and K041133
6. Technological Characteristicsand Substantial EquivalenceComparison with Predicate:	A comparison of the device features, intended use, and otherinformation demonstrates that the ADVIA Centaur TnI-UltraMCM is substantially equivalent to the predicate device assummarized in Table 1.

of target values 0.00, 1.00, 3.50, 14.0 and 40.0 ng/mL

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

SIMILARITIES
	Candidate Device	Predicate Device
Item	ADVIA Centaur Tnl-Ultra MCM	Elecsys Troponin I CalCheck 5
IntendedUse	The ADVIA Centaur Tnl-UltraMaster Curve Material is for in vitrodiagnostic use in the verification ofcalibration and reportable range of theADVIA Centaur Tnl-Ultra assay.	The Elecsys Troponin I CalCheck 5 isan assayed control for use incalibration verification and for use inthe verification of the assay rangeestablished by the Elecsys Troponin Ireagent on the indicated Elecsys andcobas e immunoassay analyzers.
Analyte	Troponin I	Same
Form	Lyophilized	Same
Use	Multiple Use	Same
Levels	5	Same
Storage	2–8°C	Same
DIFFERENCES
Matrix	Goat Serum	Human Serum
Stability	Unopened - Stable when storedunopened at 2-8°C until the expirationdate on the vial label.Opened (Reconstituted) - Stablewhen stored at 2-8°C for 8 hours; oron-board for 4 hours; or when stored	Unopened - Stable at 2-8°C up to theexpiration date printed on the bottlelabels.Reconstituted - Stable for 4 hours at20-25°C.

Table I: Substantial Equivalence Comparison

7. Standard/Guidance Document References

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
- Guidance for Industry and FDA Staff Assayed and Unassayed Quality Control . Material

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

8. Test Principle

The MCMs are specifically intended for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur assays for use on the ADVIA Centaur systems. Customers use MCMs for bi-annual calibration verification checks of the assav range and linearity in order to meet the requirements of hospital accreditation bodies.

9. Performance Characteristics

9.1 Analytical performance:

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

. Precision/Reproducibility
Linearity/Assay Reportable Range .
Detection limit .
Analytical Specificity .
Assay cul-off ◆
Method Comparison Studies ●
Clinical Studies (Sensitivity, Specificity, and cut-off) .

9.2 Non-Clinical Performance Testing

9.2.1 Stability Studies

Stability studies were conducted to support the shelf life unopened and reconstituted material for the ADVIA Centaur TnI-Ultra MCMs to ensure that it maintains optimal product performance throughout the established shelf-life. The data supports the stability claims detailed in the ADVIA Centaur Thl-Ultra MCM Instructions for Use.

The following stability studies were performed for ADVIA Centaur Thi-Ultra MCM:

. Real Time/Shelf Life (unopened)
. In Use (open vial) storage at 2-8℃ (reconstituted)
. In Use (open vial) storage at -20℃ (reconstituted)
. On-Board

Real time shelf-life studies (unopened): Test Tnl-Ultra MCMs were stored unopened at 2-8°C and tested at T=0 and at the following time points: 3 months, and 10 months. Shelf life claims are based upon real time stability carried out one month after the duration claimed. Real time shelf-life stability studies of MCMs were determined by comparison of dose recoveries to the T=0 dose recovery results. Acceptance criteria for the real-time stability study were met up to the 10 months time point, which supports a shelf-life claim of 9 months. Unopened storage shelf-life is indicated by expiration date on the vial label.

In use open vial (reconstituted) stored at 2-8℃: Test Tnl-Ultra MCMs were reconstituted, each level pooled, aliquotted and stored at 2-8°C, tested in 5 replicates per level at T=0, 2, 4, 6, 8, 9, 24 and 25 hours. Acceptance criteria for the open vial (reconstituted) stability study were met up to the 9 hour time point, which supports the open vial claim of 8 hours when stored at 2-8°C.

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® Tol-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

In use open vial (reconstituted) stored at -20°C: Test TnI-Ultra MCMs were reconstituted, each level pooled, aliquotted and stored at -20°C. tested in 5 replicates per level at Day=0, 14, 28, 35,45. 60 and 63days. Acceptance criteria for the open vial (reconstituted) stability study were met up to the 63days time point, which supports the open vial (reconstituted) claim stored -20℃ for 60 days.

On-board Stability: Test TnI-Ultra MCMs were reconstituted, each level pooled. aliquotted into sample cups and stored on the ADVIA Centaur system and measured at time point T= 0, 2, 4 and 5 hours. Acceptance criteria for the on-board stability study were met up to 5 hours, which supports the on-board stability claim for 4 hours.

Stability Acceptance Criteria

The stability specifications acceptance criteria for the ADVIA Cenatur Tnl-Ultra MCM are as follows:

· Real Time/Shelf life (Unopened): The dose recovery for MCM1 must be ≤ 0.02 dose and for MCM2-5, the % dose recovery must be within 85 to 115% calculated to Day 0 and/or no adverse trends.
· In Use (Open Vial) storage at 2-8°C (reconstituted): The dose recovery for MCM1 versus freshly reconstituted -80°C stored MCM1 average dose must be ≤ 0.02 dose and for MCM 2-5 versus freshly reconstituted -80℃ stored MCM2-5 average dose, the % dose recovery must be within 85 to 115%.
· In Use (Open Vial) storage at -20°C (reconstituted): The dose recovery for MCM1 versus freshly reconstituted -80°C stored MCM1 average dose must be ≤ 0.02 dose and for MCM 2-5 versus freshly reconstituted -80℃ stored MCM2-5 the average % dose recovery must be within 85 to 115%.
· On-Board: The dose recovery for MCM1 must be < 0,02 dose and for MCM2-5 the % dose recovery must be within 85 to 115% calculated to Time=0.

Value Assignment 9.2.2

The ADVIA Centaur TnI-Ultra MCMs are value assigned using assigned reference calibrators and MCMs. The assigned reference calibrators are prepared using bovine troponin I antigen stock and are traceable to highly purified internal material. The MCMs are manufactured using qualified materials and measurement procedures,

For each new TnI-Ultra MCM lot manufactured, MCM1 is run in 5 replicates on two separate runs using one reagent kit lot. A nested testing run protocol is used for MCM2-MCM5 value assignment. This consists of running alternating samples of the reference and new MCM level in the same run. MCM2-MCM5 were tested on 20 replicates in total, comprised of one run and four sample cups run in 5 replicates on one system and one reagent kit lot. This protocol is designed to remove system and run variation. The new MCM doses must fall within the final value assignment specification for TnI-Ultra MCMs. A performance verification run consisting of 6 replicates of each MCM level is run using one instrument, one reagent kit lot and Bio-Rad Cardiac controls. The mean MCM doses of the new Tnl-Ultra MCM lot manufactured must fall within the release range specifications. The release ranges are 5% tighter than the customer ranges.

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(Bundled) Abbreviated 510(k) Premarket Notification

ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM) The target for MCM1 is assigned a 0.0 dose. There is no statistical method used to

assign the 0.0 dose. MCM1range is claimed as "< " less than 3X the limit of sensitivity (≤0.018 ng/mL) of the ADVIA Centaur Tni-Ultra assay.

9.2.3 Expected Values

The expected values are the lot-specific assigned values obtained at value assignment and the lot-specific assigned ranges are the lot-specific customer ranges established per % interval as below.

MCM Level	% Interval
MCM1	N/A
MCM2	20%
MCM3	20%
MCM4	20%
MCM5	20%

Lot-specific assigned values and ranges are provided in the ADVIA Centaur TinI-Ultra MCM lot-specific value sheet example as below in Table 2.

MCM level	Target Values(ng/mL)	Assigned Values(ng/mL)	Range(ng/mL)
MCM1	0	0.00	< 0.018
MCM2	1.00	0.612	0.490-0.734
MCM3	3.50	3.24	2.59-3.89
MCM4	14.0	12.2	9.76-14.6
MCM5	40.0	32.5	> 26.0
Assay Range	0.006-50 ng/mL

Table 2: Example Lot-specific Assigned Values and Ranges for Tnl-Ultra MCM

9.2.4 Traceability

The ADVIA Centaur TnI-Ultra assay is traceable to NIST SRM 2921. The ADVIA Centaur Til-Ultra assay is standardized to an internal standard manufactured using highly purified material. Assigned values for callbrators and MCMs are traceable to this standardization. The Tnl-Ultra MCMs are manufactured using qualified materials and measurement procedures.

10. Proposed Labeling

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

11. Conclusion

The ADVIA Centaur ThI-Ultra Master Curve Material (MCM) is substantially cquivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the currently marketed Elecsys Troponin I CalCheck 5. Based on the testing completed and the comparisons with predicate device, the ADVIA Centaur Tinl-Ultra Maser Curve Material does not raise any new questions on safety and effectivencss and the results support a determination of substantial equivalence.

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KI40267

(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

510(k) Summary

Introduction: According to the requirements of 21 CFR 807.92, the following information provides sufficient details to understand the basis for determination of substantial equivalence.

K140267 The assigned 510(k) Number: _

1. Applicant Information
Mailing Address:	Siemens Healthcare Diagnostics Inc.
	511 Benedict Avenue
	Tarrytown, NY 10591 USA
Contact Person:	Fatima Pacheco
	Regulatory Clinical Affairs Specialist
Phone Number:	(914) 524-2450
Fax Number:	(914) 524-3579
E-mail Address:	fatima.pacheco@siemens.com
Date Prepared:	January 29, 2014
2. Device Name
Proprietary Name:	ADVIA Centaur® Digoxin Master Curve Material
Measurand:	Quality Control materials for ADVIA Centaur Digoxin assay
Type of Test:	Master Curve Material (MCM) for ADVIA Centaur Digoxinassay
Regulation Section:	21 CFR 862.1660, Quality Control Material
Classification:	Class I Reserved
Products Code:	JJX - Single (Specified) Analyte Controls (Assayed andUnassayed)
Panel:	Clinical Chemistry (75)
3. Predicate Device Name	Elecsys Dogixin CalCheck 5
Predicate 510(k) No:	K102044
4. Device Description:	ADVIA Centaur® Digoxin Master Curve Materials is anin vitro diagnostic product containing various levels of digoxinin defibrinated human plasma with sodium azide (0.1% afterreconstitution) and preservatives. Each set contains sixlyophilized levels (MCM1-6); with a reconstituted volume of1.0 mL each. MCM1 contains no analyte. The Digoxin MCMsassigned values are lot specific of target values 0.0, 0.50,1.00, 2.00, 3.00, 5.50 ng/mL.
	CAUTION! POTENTIAL BIOHAZARD: Contains humansource material. While each human serum or plasma donor uni

Section 006, Page 7 of 12

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM) used in the manufacture of this product was tested by FDAapproved methods and found nonreactive for hepatitis B surface antigen (HBsAg), antibody to hepatitis C (HCV), and antibody to HIV-1/2, all products manufactured using human source material should be handled as potentially infectious. Because no test method can offer complete assurance that hepatitis B or C viruses. HIV, or other infectious agents are absent, these products should be handled according to established good laboratory practices. 5. Intended Use: See Indications for Use Statement below: The ADVIA Centaur® Digoxin Master Curve Material is for Indication for Use: in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur Digoxin assay. Special Conditions for For prescription use only Use Statement(s): ADVIA Centaur® Systems Special Instrument Requirements: A description of the ADVIA Centaur system is documented in K971418. Subsequent modifications to the instrument have been reviewed and cleared in K032525 and K041133. 6. Technological Characteristics A comparison of the device features, intended use, and other and Substantial Equivalence information demonstrates that the ADVIA Centaur Digoxin Comparison with Predicate: MCM is substantially equivalent to the predicate device as summarized in Table 1.

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® Tol-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

SIMILARITIES
	Candidate Device	Predicate Device
Item	ADVIA Centaur Digoxin MCM	Elecsys Digoxin CalCheck 5
IntendedUse	The ADVIA Centaur Digoxin MCM is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur Digoxin assay.	The Elecsys Digoxin CalCheck 5 is an assayed control for use in calibration verification and for use in the verification of the assay range established by the Elecsys Digoxin reagent on the indicated Elecsys and cobas e immunoassay analyzers.
Analyte	Digoxin	Same
Use	Multiple Use	Same
Storage	2-8°C	Same
DIFFERENCES
Form	Lyophilized	Liquid
Matrix	Defibrinated human plasma	Bovine Serum
Levels	6	5
Stability	Unopened - Stable when stored unopened at 2-8°C until the expiration date on the vial label.Opened (Reconstituted) - Stable when stored at 2-8°C for 28 days; or on-board for 4 hours.	Unopened - Stable at 2-8°C up to the expiration date printed on the bottle labels.Opened - Stable for 5 hours at 20-25°C.

Table 1: Substantial Equivalence Comparison

7. Standard/Guidance Document References

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
. Guidance for Industry and FDA Staff - Assayed and Unassayed Quality Control Material

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

8. Test Principle

The MCMs are specifically intended for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur assays for use on the ADVIA Centaur systems. Customers use MCMs for bi-annual calibration verification checks of the assay range and linearity in order to meet the requirements of hospital accreditation bodies.

9. Performance Characteristics

9.1 Analytical performance:

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

. Precision/Reproducibility
Linearity/Assay Reportable Range .
Detection limit .
Analytical Specificity .
Assay cut-off ●
. Method Comparison Studies
Clinical Studies (Sensitivity, Specificity, and cut-off) .

9.2 Non-Clinical Performance Testing

9.2.1 Stability Studies

The stability studies were conducted to support the shelf life (unopened) and opened reconstituted material for the ADVIA Centaur Digoxin MCMs. The data supports the stability claims detailed in the ADVIA Centaur Digoxin MCM Instructions for Use.

The following stability studies were performed for ADVIA Centaur Digoxin MCM:

Real Time/Shelf Life (unopened) .
. In Use (open vial) storage at 2-8℃ (reconstituted)
. On-Board Stability

Real time shelf-life studies (unopened): Test Digoxin MCMs were stored unopened at 2-8°C and tested at T=0 and at the following time points: 12 months, 18 months, and 33 months. Shelf life claims are based upon real time stability carried out one month after the duration claimed. Real time shelf-life stability studies of MCMs were determined by comparison of dose recoveries to the T=0 dose recovery results. Acceptance criteria for the real-time stability study were met up to the 33 months' time point, which supports a shelf-life claim of 32 months. Unopened storage shelf-life is indicated by expiration date on the vial label.

In use open vial (reconstituted)_stored an 2-8℃: Test Digoxin MCMs were reconstituted, each level pooled, aliquotted and stored at 2-8°C. tested in 5 replicates per level at T=0, 7, 14, 21, 28 and 29 davs. Acceptance criteria for the open vial (reconstituted) stability study were met up to the 29 days' time point, which supports the open vial claim of 28 davs when stored at 2-8℃.

On-board Stability: Test Digoxin MCMs were reconstituted, each level pooled, aliquotted into sample cups and stored on the ADVIA Centaur system and

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(Bundled) Abbreviated 510(k) Premarket Notification ADVIA Centaur® Til-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

measured at time point T= 0, 2, 4 and 5 hours. Acceptance criteria for the onboard stability study were met up to 5 hours, which supports the on-board stability claim for 4 hours.

Stability Acceptance Criteria

The stability specifications acceptance criteria for the ADVIA Centaur Digoxin MCM are as follows:

. Real Time/Shelf life (Unopened): The dose recovery for MCM1 must be ≤ 0.10 dose, for MCM2 the % dose recovery must be within 82 to 118% and for MCM3-6 the % dose recovery must be within 85 to 115% calculated to Day 0 and/or no adverse trends.
In Use (Open Vial) storage at 2-8°C (reconstituted): The dose recovery for . MCM1 versus -80°C stored MCM1 average dose must be ≤0.10 dose, for
. MCM2 versus -80°C stored MCM2 average dose the % dose recovery must be within 82 to 118% and for MCM 3-6 versus -80°C MCMs 3-6 average dose the % dose recovery must be within 85 to 115%.
On-Board Stability: The dose recovery for MCM1 must be ≤ 0.10 dose, for . MCM2 the % dose recovery must be within 82 to 118% and for MCM3-6 the % dose recovery must be within 85 to 115% calculated to T=0.

9.2.2 Value Assignment

The ADVIA Centaur Digoxin MCMs are value assigned using assigned reference calibrators and MCMs. The assigned reference calibrators are prepared using USP (United States Pharmacopeia) Digoxin stock and are traccable to USP internal material. The MCMs are manufactured using qualified materials and measurement procedures.

For each new Digoxin MCM lot manufactured, MCM1 is run in 5 replicates on two separate runs using one reagent kit lot. A nested testing rum protocol is used for MCM2-MCM6 value assignment. This consists of running alternating samples of the reference and new MCM level in the same run, MCM2-MCM6 were tested on 20 replicates in total, comprised of one run and four sample cups run in 5 replicates on one system and one reagent kit lot. This protocol is designed to remove system and run variation. The new MCM doses must fall within the final value assignment specification for Digoxin MCMs. A performance verification run consisting of 6 replicates of each MCM level is run using one instrument, one reagent kit lot and Bio-Rad controls. The mean MCM doses of the new Digoxin MCM lot manufactured must fall within the release range specifications. The release ranges are 5% tighter than the customer range specifications.

The target for MCM1 is assigned a 0.0 dose. There is no statistical method used to assign the 0.0 dose. MCM1 range is claimed as "<" less than 3X the limit of sensitivity (≤ 0.1 ng/mL) of the ADVIA Centaur Digoxin assay. MCM6 is targeted greater than the assav range, customers need to dilute with MCM1 to meet the reportable range of the assay.

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(Bundled) Abbreviated 510(k) Premarket Notification

ADVIA Centaur® TnI-Ultra® and ADVIA Centaur® Digoxin Master Curve Material (MCM)

9.2.3 Expected Values

The expected values are the lot-specific assigned values obtained at value assignment and the lot-specific assigned ranges are the lot-specific customer ranges established per % interval as below.

MCM Level	% Interval
MCM1	N/A
MCM2	40%
MCM3	20%
MCM4	20%
MCM5	20%
MCM6	20%

Lot-specific assigned values and ranges are provided in the ADVIA Centaur Digoxin MCM lot-specific value sheet example as below in Table 2.

MCM level	Target Values(ng/mL)	Assigned Values(ng/mL)	Range(ng/mL)
MCM1	0.00	0.032	< 0.300
MCM2	0.500	0.574	0.344-0.804
MCM3	1.00	1.12	0.896-1.34
MCM4	2.00	2.14	1.71-2.57
MCM5	3.00	3.14	2.51-3.77
MCM6	5.50	5.53	> 4.42
Assay Range	0.1-5.0 ng/mL

Tuble 2: Example Lot-specific Assigned Values and Ranges for Digoxin MCM

9.2.4 Traceability

The ADVIA Centaur Digoxin assay is standardized to an internal standard manufactured using USP (United States Pharmacopeia) material. Assigned values for calibrators and MCMs are traceable to this standardization.

1 (). Proposed Labeling

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

11. Conclusion

The ADVIA Centaur Digoxin Master Curve Material (MCM) is substantially equivalent to other products in commercial distribution intended for similar use. Most notably, it is substantially equivalent to the currently marketed Elecsys Digoxin CalCheck 5. Based on the testing completed and the comparisons with predicate device, the ADVIA Centaur Digoxin Maser Curve Material does not raise any new questions on safety and effectiveness and the results support a determination of substantial equivalence.

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Image /page/12/Picture/0 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized eagle with three stripes forming its wing, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES. USA" arranged in a circular fashion around the eagle. The eagle is facing to the right. The logo is in black and white.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002 March 10, 2014

SIEMENS HEALTHCARE DIAGNOSTICS INC. FATIMA PACHECO REGULATORY CLINICAL AFFAIRS SPECIALIST 511 BENEDICT AVENUE TARRYTOWN NY 10591-5097

Re: K140267

Trade/Device Name: ADVIA Centaur TnI-Ultra® Master Curve Material (MCM), ADVIA Centaur® Digoxin Master Curve Material (MCM)

Regulation Number: 21 CFR 862.1660 Regulation Name: Quality control material Regulatory Class: I, reserved Product Code: JJX Dated: February 04, 2014 Received: February 7, 2014

Dear Ms. Pacheco:

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

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Page 2-Ms. Pacheco

,上一篇

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance 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. 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 Small Manufacturers, International and Consumer Assistance 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

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

Indications for Use

510(k) Number (if known)

K140267

Device Name

ADVIA Centaur® TnI-Ultra® Master Curve Material (MCM)

Indications for Use (Describe)

The ADVIA Centaur® Thi-Ultra® Master Curve Material is for in the verification of calibration and reportable range of the ADVIA Centaur TnI-Ultra assay.

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

🇿 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)

. .

Ruth A. Chesler -S

FORM FDA 3881 (1/14)

Section 005, Page 1 of 4

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. 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:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"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."

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration .. .

Indications for Use

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

510(k) Number (if known)

K140267

Device Name

ADVIA Centaur® Digoxin Master Curve Material (MCM)

Indications for Use (Describe)

The ADVIA Centaur@ Digoxin Master Curve Material is for in the verification of calibration and reportable range of the ADVIA Centaur Digoxin assay.

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

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)

Ruth A. Chesler -S

FORM FDA 3881 (1/14)

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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."

Department of Health and Human Services Food and Drug Administration Office of Chiaf Information Officer Paperwork Reduction Act (PRA) Staff PRAStam@da.hhs.gov

"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."

. .....

Regulation Number and Section

§ 862.1660 Quality control material (assayed and unassayed).

(a)
Identification. A quality control material (assayed and unassayed) for clinical chemistry is a device intended for medical purposes for use in a test system to estimate test precision and to detect systematic analytical deviations that may arise from reagent or analytical instrument variation. A quality control material (assayed and unassayed) may be used for proficiency testing in interlaboratory surveys. This generic type of device includes controls (assayed and unassayed) for blood gases, electrolytes, enzymes, multianalytes (all kinds), single (specified) analytes, or urinalysis controls.(b)
Classification. Class I (general controls). Except when intended for use in donor screening tests, quality control materials (assayed and unassayed) are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.