Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges, Lumipulse G B•R•A•H•M•S PCT Calibrators set

K172713 · Fujirebio Diagnostics,Inc. · PRI · Dec 10, 2017 · Microbiology

Device Facts

• Record ID: K172713
• Device Name: Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges, Lumipulse G B•R•A•H•M•S PCT Calibrators set
• Applicant: Fujirebio Diagnostics,Inc.
• Product Code: PRI · Microbiology
• Decision Date: Dec 10, 2017
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3215
• Device Class: Class 2

Intended Use

The Lumipulse G B•R•A•H•M•S PCT is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of PCT (procalcitonin) in human serum and plasma (sodium heparin, lithium heparin, sodium citrate or dipotassium EDTA) on the LUMIPULSE G System. Used in conjunction with other laboratory findings and clinical assessments, Lumipulse G B.R.A.H.M.S PCT is intended for use as an: · Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock. · Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time. · Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) – in an inpatient setting or an emergency department. · Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Device Story

Lumipulse G B.R.A.H.M.S. PCT is an automated CLEIA assay for quantitative measurement of procalcitonin (PCT) in human serum/plasma. Used on the LUMIPULSE G1200 System; utilizes two-step sandwich immunoassay. Input: patient serum/plasma sample. Process: PCT binds to anti-PCT/anti-calcitonin monoclonal antibody-coated particles; unbound material washed; ALP-labeled anti-katacalcin antibody binds to immunocomplexes; substrate added; luminescence generated proportional to PCT concentration. Output: quantitative PCT concentration (ng/mL). Used in clinical/hospital laboratories by trained personnel. Results aid clinicians in sepsis risk assessment, mortality risk stratification, and antibiotic stewardship (initiation/discontinuation) for sepsis and lower respiratory tract infections. Benefits include standardized, automated PCT measurement to support critical care decision-making.

Clinical Evidence

No clinical prospective/retrospective trials performed. Evidence consists of analytical performance studies (precision, linearity, LoD/LoQ, interference, cross-reactivity) and a method comparison study (n=223) against the predicate device. Method comparison showed high correlation (r=0.9846) and acceptable bias at clinical decision points. Reference interval study (n=213) established 95th percentile at 0.045 ng/mL.

Technological Characteristics

CLEIA-based two-step sandwich immunoassay. Reagents: anti-PCT/anti-calcitonin monoclonal antibody-coated particles, alkaline phosphatase-labeled anti-katacalcin antibody. Energy source: LUMIPULSE G1200 System. Connectivity: Standalone instrument; web-based calculator for clinical decision support. Sterilization: Not applicable (reagents). Software: Automated analysis on LUMIPULSE G1200; web-based PCT change calculator.

Indications for Use

Indicated for critically ill patients on first day of ICU admission for risk assessment of progression to severe sepsis/septic shock; patients with severe sepsis/septic shock in ICU or ED/wards for 28-day all-cause mortality risk assessment; patients with suspected/confirmed lower respiratory tract infections (CAP, acute bronchitis, AECOPD) in inpatient/ED settings for antibiotic therapy decision-making; and patients with suspected/confirmed sepsis for antibiotic discontinuation decision-making.

Regulatory Classification

Identification

A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.

Special Controls

A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis must comply with the following special controls:

*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended. (2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection. (3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability. (4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information: (i) Results must demonstrate adequate device performance relative to a well-accepted comparator. (ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population. (iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses. (5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics ( *e.g.,* age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument. (7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples ( *e.g.,* collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.

Predicate Devices

• B•R•A•H•M•S PCT sensitive KRYPTOR® (K171338)

Submission Summary (Full Text)

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December 10, 2017

Fujirebio Diagnostics, Inc. Stacey Dolan Manager, Regulatory Affairs 201 Great Valley Parkway Malvern, Pennsylvania 19355

Re: K172713

Trade/Device Name: Lumipulse G B.R.A.H.M.S.PCT Immunoreaction Cartridges, Lumipulse G B•R•A•H•M•S PCT Calibrators set Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: Class II Product Code: PRI, PMT, NTM Dated: September 7, 2017 Received: September 8, 2017

Dear Stacey Dolan:

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 Part

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801 and Part 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.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Kristian M. Roth - S
For:

Uwe Scherf, Ph.D. Director Division of Microbiology 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) K172713

#### Device Name

Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges Lumipulse G B•R•A•H•M•S PCT Calibrators set

#### Indications for Use (Describe) Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges:

The Lumipulse G B•R•A•H•M•S PCT is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of PCT (procalcitonin) in human serum and plasma (sodium heparin, sodium citrate or dipotassium EDTA) on the LUMIPULSE G System.

Used in conjunction with other laboratory findings and clinical assessments, Lumipulse G B.R.A.H.M.S PCT is intended for use as an:

· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.

· Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the

emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.

· Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic

obstructive pulmonary disease (AECOPD) – in an inpatient setting or an emergency department.

· Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Lumipulse G B.R.A.H.M.S PCT Calibrators set

Lumipulse G B R A H M S PCT Calibrators set is for in vitro diagnostic use in the calibration of Lumipulse G B.R.A.H.M.S.PCT on the LUMIPULSE G System.

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

| <span style="font-size: 10pt;"> <input checked="true" type="checkbox"/> Prescription Use (Part 21 CFR 801 Subpart D) </span> |
|----------------------------------------------------------------------------------------------------------------------------------|
| <span style="font-size: 10pt;"> <input type="checkbox"/> Over-The-Counter Use (21 CFR 801 Subpart C) </span> |

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#### Section 5 510(k) SUMMARY

Lumipulse® G PCT

Date: December 6, 2017

A. 510(k) Number: K172713

B. Purpose of Submission: New device

C. Measurand:

Procalcitonin

# D. Type of Test:

Quantitative assay, automated chemiluminescent enzyme immunoassay (CLEIA)

#### E. Applicant:

- Submitter: Fujirebio Diagnostics, Inc. 201 Great Valley Parkway Malvern, PA 19355
- Contact Person: Stacey Dolan Manager, Regulatory Affairs Phone: [phone] Fax: [phone] Email: [e-mail]

#### F. Proprietary and Established Names:

Lumipulse® G B•R•A•H•M•S PCT

#### G. Regulatory Information:

- Regulation section: 1. 21 CFR § 866.3215
- 2. Classification: Class II
- 3. Product codes: PRI, NTM, PMT
- 4. Panel: 83, Microbiology

# H. Intended Use:

- 1. Intended Use:

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#### Lumipulse G B .R .A .H .M .S PCT Immunoreaction Cartridges

The Lumipulse G B+R+A+H+M+S PCT is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of PCT (procalcitonin) in human serum and plasma (sodium heparin, lithium heparin, sodium citrate or dipotassium EDTA) on the LUMIPULSE G System.

Used in conjunction with other laboratory findings and clinical assessments, Lumipulse G B•R•A•H•M•S PCT is intended for use as an:

- Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.
- . Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
- . Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
- Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

#### Lumipulse G B•R•A•H•M•S PCT Calibrators Set

Lumipulse G B+R+A•H•M•S PCT Calibrators set are for in vitro diagnostic use in the calibration of LUMIPULSE G B+R•A•H•M•S PCT on the LUMIPULSE G System.

- 2. Indications for use: Same as Intended Use.
- 3. Special conditions for use statement(s): Prescription use only.
- 4. Special instrument requirements: LUMIPULSE G1200 System

#### -Device Description:

Lumipulse G B+R•A•H•M•S PCT is an assay system, including a set of immunoassay reagents, for the quantitative measurement of PCT in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G1200 System.

Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges: | IRC 235058. The Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges consists of 3 x 14 tests. Each kit contains the following:

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1.) Antibody-Coated Particle Solution

(Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-PCT monoclonal antibody (mouse) and anti-calcitonin monoclonal antibody (mouse) coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: sodium azide.

2.) Enzyme-Labeled Antibody Solution

(Liquid, 350 µL/Immunoreaction Cartridge)

Contains 0.25 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-katacalcin monoclonal antibody (mouse), protein stabilizers (bovine, calf and mouse) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

#### Lumipulse G B+R+A+H+M+S PCT Calibrators set |CAL SET 234150, Lyophilized, 2 x 2 Concentrations

Each calibrator kit contains one bottle each of Calibrators 1 - 2, and Reconstituting Solution. The calibrator kit is packaged separately.

CAL 1

0 ng/mL PCT calibrator (2 x 0.5 mL/vial)

CAL 2 100 ng/mL PCT calibrator (2 x 0.5 mL/vial)

Contains procalcitonin in 0.15 M sodium chloride in Tris buffer with protein stabilizer (bovine). Preservative: ProClin 300.

RS Reconstituting Solution: Liquid, 1 x 10 mL Preservative: sodium azide.

These calibrators are lyophilized and have to be prepared by adding exactly 0.5 mL of Reconstituting Solution to each Iyophilized calibrator.

#### J. Substantial Equivalence:

- 1. Predicate device name(s): B•R•A•H•M•S PCT sensitive KRYPTOR®
- 2. Predicate 510(k) number(s): k171338
- Comparison with predicate: 3.

| B•R•A•H•M•S PCT sensitive KRYPTOR® | | |
|------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Similarities and Differences | | |
| | Lumipulse® G<br>B•R•A•H•M•S PCT (Proposed<br>Device) | B•R•A•H•M•S PCT sensitive<br>KRYPTOR®<br>(Predicate Device)<br>K171338 |
| Device Type | <i>In vitro</i> diagnostic | Same |
| Classification | Class II | Same |
| Similarities and Differences | | |
| | Lumipulse® G<br>B·R·A·H·M·S PCT (Proposed<br>Device) | B·R·A·H·M·S PCT sensitive<br>KRYPTOR®<br>(Predicate Device)<br>K171338 |
| Analyte | Procalcitonin | Same |
| Regulation Number | 21CFR § 866.3215; Device to<br>detect and measure non-<br>microbial analyte(s) in human<br>clinical specimens to aid in<br>assessment of patients with<br>suspected sepsis | Same |
| Product Usage | Clinical and Hospital laboratories | Same |
| Principle of Operation | Automated Quantitative<br>Chemiluminscent Enzyme<br>Immunoassay (CLEIA) | Time-Resolved Amplified<br>Cryptate Emission (TRACE) |
| Specimen Collection<br>Method | Routine Phlebotomy Techniques | Same |
| Intended Use | The Lumipulse G B•R•A•H•M•S<br>PCT is a Chemiluminescent<br>Enzyme Immunoassay (CLEIA)<br>for the quantitative determination<br>of PCT (procalcitonin) in human<br>serum and plasma (sodium<br>heparin, lithium heparin, sodium<br>citrate or dipotassium EDTA) on<br>the LUMIPULSE G System.<br>Used in conjunction with other<br>laboratory findings and clinical<br>assessments, Lumipulse G<br>B•R•A•H•M•S PCT is intended for<br>use as an:<br>• Aid in the risk assessment<br>of critically ill patients on<br>their first day of intensive<br>care unit (ICU) admission<br>for progression to severe<br>sepsis and septic shock.<br>• Aid in assessing the<br>cumulative 28-day risk of<br>all-cause mortality for<br>patients diagnosed with<br>severe sepsis or septic<br>shock in the ICU or when | The B-R·A·H·M·S<br>PCT sensitive<br>KRYPTOR® is an<br>immunofluorescent<br>assay using Time-<br>Resolved Amplified<br>Cryptate Emission<br>(TRACE) technology<br>to determine the<br>concentration of PCT<br>(procalcitonin) in<br>human serum and<br>EDTA or heparin<br>plasma.<br>The B-R·A·H·M·S<br>PCT sensitive<br>KRYPTOR® is<br>intended to be<br>performed on the<br>B-R·A·H·M·S<br>KRYPTOR® analyzer<br>family.<br>Used in conjunction<br>with other laboratory<br>findings and clinical<br>assessments,<br>B·R·A·H·M·S PCT<br>sensitive KRYPTOR® |
| Similarities and Differences | | |
| | Lumipulse® G<br>B·R·A·H·M·S PCT (Proposed<br>Device) | B·R·A·H·M·S PCT sensitive<br>KRYPTOR®<br>(Predicate Device)<br>K171338 |
| | department or other<br>medical wards prior to ICU<br>admission, using a change<br>in PCT level over time.<br><br>• Aid in decision making on<br>antibiotic therapy for<br>patients with suspected or<br>confirmed lower<br>respiratory tract infections<br>(LRTI) – defined as<br>community acquired<br>pneumonia (CAP), acute<br>bronchitis, and acute<br>exacerbation of chronic<br>obstructive pulmonary<br>disease (AECOPD) – in an<br>inpatient setting or an<br>emergency department.<br><br>• Aid in decision making on<br>antibiotic discontinuation<br>for patients with suspected<br>or confirmed sepsis. | is intended for use as<br>follows:<br><br>• to aid in the risk<br>assessment of<br>critically ill patients<br>on their first day of<br>ICU admission for<br>progression to severe<br>sepsis and septic<br>shock,<br><br>• to determine the<br>change in PCT level<br>over time as an aid in<br>assessing the cumulative<br>28-day<br>risk of all-cause<br>mortality for patients<br>diagnosed with<br>severe sepsis or<br>septic shock in the<br>ICU or when<br>obtained in the<br>emergency<br>department or other<br>medical wards prior<br>to ICU admission,<br><br>• to aid in decision<br>making on antibiotic<br>therapy, for<br>inpatients or patients<br>in the emergency<br>department with<br>suspected or<br>confirmed lower<br>respiratory tract<br>infections (LRTI) –<br>defined as<br>community-acquired<br>pneumonia (CAP),<br>acute bronchitis, and<br>acute exacerbation<br>of chronic |
| Similarities and Differences | | |
| | Lumipulse® G<br>B-R・A・H・M・S PCT (Proposed<br>Device) | B-R・A・H・M・S PCT sensitive<br>KRYPTOR®<br>(Predicate Device)<br>K171338 |
| | | obstructive<br>pulmonary disease<br>(AECOPD), |
| | | • to aid in decision<br>making on antibiotic<br>discontinuation for<br>patients with<br>suspected or<br>confirmed sepsis. |
| Instrument System | LUMIPULSE G System | The BRAHMS KRYPTOR<br>analyzer |
| Assay Type | Two-step sandwich<br>immunoassay based on<br>chemiluminescent<br>technology | Immunofluorescent assay |
| Type of Specimen | Human serum and plasma<br>(sodium heparin, lithium heparin,<br>sodium citrate or dipotassium<br>EDTA) | Human serum and plasma<br>(EDTA, heparin) |
| Assay Range | 0.020 - 100 ng/mL | 0.02-5000ng/mL |
| Sample Volume | 60 μl | 50μl |

# Comparison between the Lumipulse® G B-R-A-H-M-S PCT and

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Image /page/6/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic to the left of the company name. The graphic is a blue and white design. The text "FUJIREBIO" is in a bold, blue sans-serif font, with the registered trademark symbol next to "BIO". Below that, "Diagnostics, Inc." is in a smaller, less bold font.

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Image /page/7/Picture/1 description: The image contains the logo for FUJIREBIO Diagnostics, Inc. The logo features a stylized graphic on the left, consisting of blue and green shapes that resemble a water droplet. To the right of the graphic, the text "FUJIREBIO" is displayed in a bold, blue sans-serif font. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, lighter font.

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Image /page/8/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic on the left, consisting of blue and green shapes. To the right of the graphic is the company name, "FUJIREBIO," in a bold, blue sans-serif font, with the registered trademark symbol next to it. Below the company name is the text "Diagnostics, Inc." in a smaller, lighter blue font.

#### K. Standard/Guidance Document Referenced (if applicable):

- CLSI EP5-A3 - Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
- CLSI EP7-A2 - Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition
- CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical . Laboratory; Approved Guideline-Third Edition
- CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement . Procedures; Approved Guideline Second Edition
- CLSI EP6-A - Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline
- . CLSI EP9-A3 – Measurement Procedure Comparison and Bias Estimation Using Patient Samples; approved Guideline - Third Edition
- CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents: Approved Guideline ●
- Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover ● Human Specimens that are Not Individually Identifiable - Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff
- Test Principle: Guidance for Industry and Food and Drug Administration Staff - eCopy Program for Medical Device Submissions (December 31, 2012)

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- . Guidance for Industry and Food and Drug Administration Staff - Refuse to Accept Policy for 510(k)s (August 4, 2015)
#### L. Test Principle:

Lumipulse G B.R.A.H.M.S PCT is an assay system, including a set of immunoassay reagents, for the quantitative measurement of PCT in specimens based on CLEIA technology by a twostep sandwich immunoassay method on the LUMIPULSE G1200 System.

PCT in specimens specifically binds to anti-PCT monoclonal antibody (mouse) and anti-calcitonin monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP: calf)-labeled anti-katacalcin monoclonal antibody (mouse) specifically binds to PCT of the immunocomplexes on the particles, and additional immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Substrate Solution is added and mixed with the particles. AMPPD contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles. Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of PCT.

#### M. Performance Characteristics

Data were generated using the LUMIPULSE G1200 System.

- 1. Analytical performance:
- a. Precision/Reproducibility:

#### 20 Day

The results of the 20-day precision calculations for Lumipulse G B.R.A.H.M.S PCT performed at FDI are shown below:

- Lot A ICs/Lot A Calibrators for Control Levels 1-3 and Panels 1-6 .
- . Lot D ICs/Lot D Calibrators for Panels 7 and 8

The analyses determined the total precision for the Lumipulse G B•R•A•H•M•S PCT assay to be ≤ 4.7%. The total precision of the Lumipulse G B•R•A•H•M•S PCT for the eight (8) panels ranged from 1.8% to 3.1%. The total precision of the Lumipulse G B+R+A+H+M+S PCT for the three (3) controls ranged from 3.3% to 4.7%. The precision of all controls and panels for the 20-day Precision Study met the acceptance criteria of a CV ≤ 10%.

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Image /page/10/Picture/1 description: The image is a logo for Fujirebio Diagnostics, Inc. The logo consists of a blue and white abstract shape on the left, followed by the company name in blue, and the word "Diagnostics, Inc." in a smaller, darker font below the company name. The abstract shape appears to be a stylized representation of a water droplet or a similar fluid, possibly alluding to the company's work in diagnostics.

#### Summary for FDI 20-day Precision (n=80 for each sample) for Lot A (Controls and Panels 1-6) and Lot D (Panels 7 and 8)

| Sample | Mean (ng/mL) | Within-Run (Repeatability) | | Between Run | | | | Within-Laboratory (Total) | |
|-----------------|--------------|----------------------------|------|-------------|------|-------|------|---------------------------|------|
| | | SD | %CV | Between-Day | | SD | %CV | SD | %CV |
| Control Level 1 | 0.662 | 0.010 | 1.6% | 0.026 | 3.9% | 0.014 | 2.1% | 0.031 | 4.7% |
| Control Level 2 | 3.911 | 0.045 | 1.2% | 0.129 | 3.3% | 0.026 | 0.7% | 0.139 | 3.6% |
| Control Level 3 | 14.978 | 0.163 | 1.1% | 0.393 | 2.6% | 0.245 | 1.6% | 0.490 | 3.3% |
| Panel 1 | 0.300 | 0.005 | 1.6% | 0.004 | 1.5% | 0.003 | 1.0% | 0.007 | 2.4% |
| Panel 2 | 2.219 | 0.032 | 1.5% | 0.016 | 0.7% | 0.027 | 1.2% | 0.045 | 2.0% |
| Panel 3 | 12.323 | 0.129 | 1.0% | 0.144 | 1.2% | 0.098 | 0.8% | 0.217 | 1.8% |
| Panel 4 | 36.217 | 0.379 | 1.0% | 0.308 | 0.8% | 0.445 | 1.2% | 0.661 | 1.8% |
| Panel 5 | 54.132 | 0.596 | 1.1% | 0.529 | 1.0% | 0.642 | 1.2% | 1.024 | 1.9% |
| Panel 6 | 80.361 | 1.265 | 1.6% | 0.879 | 1.1% | 0.632 | 0.8% | 1.666 | 2.1% |
| Panel 7 | 0.112 | 0.002 | 2.0% | 0.002 | 2.2% | 0.001 | 1.1% | 0.004 | 3.1% |
| Panel 8 | 0.534 | 0.010 | 1.9% | 0.008 | 1.5% | 0.003 | 0.6% | 0.013 | 2.5% |

# Lot-To-Lot Reproducibility for Combined Data

The precision analyses for the combined lot-to-lot analysis for Lots A, B and C determined the total precision for Lumipulse G PCT to be ≤ 5.3% in this study. The total precision for Lumipulse G B+R•A•H•M•S PCT to be ≤ 3.0% for the six (6) panels. The total precision for Lumipulse G PCT to be ≤ 5.3% for the three (3) controls. The total precision of Lumipulse G B+R+A+H+M+S PCT ranged from 1.8% to 5.3%. The between-lot precision for Lumipulse G B•R•A•H•M•S PCT was ≤ 6.5%.

The precision of controls and panels for the lot-to-lot reproducibility met the targeted acceptance criteria of a CV ≤ 10%.

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Image /page/11/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic element on the left, consisting of blue and white shapes. To the right of the graphic is the company name, "FUJIREBIO" in large, blue, sans-serif font, with the registered trademark symbol. Below the company name is the text "Diagnostics, Inc." in a smaller, sans-serif font, also in blue.

#### Summary of the Lot-to-Lot Reproducibility for the Combined Data for Lots A, B and C (n=120 for each sample)

| | | Between<br>Lots | | Between<br>Day | | Between<br>Run | | Within Runs<br>(Repeatabilit<br>y) | | Within-<br>Laboratory<br>(Total) | |
|--------------------|----------------|-----------------|------|----------------|------|----------------|------|------------------------------------|------|----------------------------------|------|
| Sample | Mean<br>(ng/L) | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Control Level<br>1 | 0.634 | 0.030 | 4.7% | 0.013 | 2.0% | 0.030 | 4.7% | 0.009 | 1.4% | 0.033 | 5.3% |
| Control Level<br>2 | 3.816 | 0.137 | 3.6% | 0.016 | 0.4% | 0.127 | 3.3% | 0.055 | 1.4% | 0.139 | 3.7% |
| Control Level<br>3 | 14.875 | 0.313 | 2.1% | 0.141 | 0.9% | 0.434 | 2.9% | 0.164 | 1.1% | 0.487 | 3.3% |
| Panel 1 | 0.290 | 0.012 | 4.3% | 0.004 | 1.3% | 0.006 | 2.0% | 0.005 | 1.8% | 0.009 | 3.0% |
| Panel 2 | 2.163 | 0.075 | 3.4% | 0.021 | 1.0% | 0.038 | 1.8% | 0.026 | 1.2% | 0.048 | 2.2% |
| Panel 3 | 12.332 | 0.320 | 2.6% | 0.221 | 1.8% | 0.133 | 1.1% | 0.122 | 1.0% | 0.280 | 2.3% |
| Panel 4 | 38.147 | 2.280 | 6.0% | 0.363 | 1.0% | 0.467 | 1.2% | 0.367 | 1.0% | 0.701 | 1.8% |
| Panel 5 | 57.114 | 3.392 | 5.9% | 0.856 | 1.5% | 0.625 | 1.1% | 0.674 | 1.2% | 1.248 | 2.2% |
| Panel 6 | 86.233 | 5.585 | 6.5% | 1.018 | 1.2% | 1.138 | 1.3% | 1.489 | 1.7% | 2.141 | 2.5% |

# Site to Site Reproducibility for Combined Data

The precision analyses for the combined site-to-site analysis for Lots A determined the total precision for Lumipulse G B+R•A•H•M•S PCT to be ≤ 4.9% in this study. The total precision for Lumipulse G B+R+A+H+M+S PCT to be ≤ 4.8% for the six (6) panels. The total precision for Lumipulse G PCT to be ≤ 4.9% for the three (3) controls. The total precision of Lumipulse G B+R•A•H•M•S PCT ranged from 2.9% to 4.9%. The betweensite precision for Lumipulse G B+R•A•H•M•S PCT was ≤ 4.7%.

The precision of the controls and panels for the site-to-site reproducibility met the targeted acceptance criteria of a CV ≤10%.

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Image /page/12/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized blue and white graphic on the left, resembling a water droplet or a stylized flower. To the right of the graphic, the text "FUJIREBIO" is displayed in a bold, blue sans-serif font, with the registered trademark symbol next to it. Below "FUJIREBIO", the text "Diagnostics, Inc." is written in a smaller, lighter blue font.

#### Summary of the Site-to-Site Reproducibility for the Combined Data for Lot A (n=120 for each panel)

| | | Between<br>Sites | | Between<br>Days | | Between<br>Runs | | Within Runs<br>(Repeatability) | | Reproducibility<br>(Total) | |
|-----------------|-----------------|------------------|------|-----------------|------|-----------------|------|--------------------------------|------|----------------------------|------|
| Sample | Mean<br>(ng/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Control Level 1 | 0.647 | 0.019 | 2.9% | 0.023 | 3.5% | 0.020 | 3.0% | 0.012 | 1.8% | 0.032 | 4.9% |
| Control Level 2 | 3.872 | 0.077 | 2.0% | 0.109 | 2.8% | 0.096 | 2.5% | 0.054 | 1.4% | 0.149 | 3.8% |
| Control Level 3 | 15.062 | 0.085 | 0.6% | 0.337 | 2.2% | 0.312 | 2.1% | 0.166 | 1.1% | 0.481 | 3.2% |
| Panel 1 | 0.291 | 0.008 | 2.8% | 0.008 | 2.7% | 0.010 | 3.6% | 0.005 | 1.9% | 0.014 | 4.8% |
| Panel 2 | 2.170 | 0.033 | 1.5% | 0.049 | 2.3% | 0.061 | 2.8% | 0.032 | 1.5% | 0.075 | 3.5% |
| Panel 3 | 12.297 | 0.375 | 3.0% | 0.222 | 1.8% | 0.417 | 3.4% | 0.170 | 1.4% | 0.485 | 3.9% |
| Panel 4 | 37.074 | 1.303 | 3.5% | 0.586 | 1.6% | 1.182 | 3.2% | 0.361 | 1.0% | 1.354 | 3.6% |
| Panel 5 | 55.428 | 2.043 | 3.7% | 1.144 | 2.1% | 1.385 | 2.5% | 0.613 | 1.1% | 1.846 | 3.3% |
| Panel 6 | 82.850 | 3.868 | 4.7% | 1.006 | 1.2% | 1.719 | 2.1% | 1.285 | 1.6% | 2.365 | 2.9% |

# b. Linearity/assay reportable range:

Lumipulse G B+R+A+H•M•S PCT on the LUMIPULSE G1200 System demonstrated linearity in a study consistent with the guidelines in the CLSI Protocol EP6-A.9) High and low sample pools were created using patient serum samples that contained naturally expressed PCT. The linearity was found in the range of 0.010 ng/mL to 104.260 ng/mL. Lumipulse G B+R+A+H•M•S PCT correlated with expected concentrations according to the linear regression formula:

# o y= 0.008734 + 0.856577; R-squared: 0.9979

High dose effect is a phenomenon whereby very high level specimens may read within the dynamic range of the assay. For Lumipulse G B+R+A+H•M•S PCT on the LUMIPULSE G1200 System, no high dose effect was observed for samples containing approximately 12,000 ng/mL of PCT.

#### c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Calibration of the Lumipulse G B·R·A·H·M·S PCT is traceable to in-house reference calibrators, whose values have been assigned to correlate to Thermo Fisher Scientific Inc.'s B-R-A-H-M-S PCT sensitive Kryptor.

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Image /page/13/Picture/1 description: The image contains the logo for "FUJIREBIO Diagnostics, Inc." The logo consists of a stylized graphic on the left, featuring blue and white shapes, followed by the company name in blue text. The word "FUJIREBIO" is in a larger, bolder font, while "Diagnostics, Inc." is in a smaller font below it.

Cal Set Contains Cal 1 and Cal 2 (2 x 0.5 mL/vial) and Reconstituting Solution (1 x 10 mL). Preservative: ProClin 300. The calibrators are at the following concentrations:

| Calibrator Level | PCT Concentration (ng/mL) |
|------------------|---------------------------|
| CAL 1 | 0 |
| CAL 2 | 100 |

Master calibration data are recorded in a two-dimensional bar code on the Lumipulse G B+R+A+H+M+S PCT Immunoreaction Cartridge case. The calibration curve is created based on the recorded master calibration data and measured calibration data. The PCT concentration of a specimen is automatically calculated from the calibration curve. The result of the calculation is reported in ng/mL.

#### Shelf life

The shelf life for Lumipulse G B+R+A+H•M•S PCT Immunoreaction Cartridges and the Lumipulse G B.R.A.H.M.S PCT Calibrators is 6 months at 2-10°C.

#### On board the LUMIPULSE G1200

The Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges are sealed unit dose stored at 2-10°C. To reduce risk for any misuse, the package insert states The Lumipulse G B•R•A•H•M•S PCT Cartridges can be stored on-board the LUMIPULSE G System for a maximum of 30 days.

The package insert recommends calibrator curve storage on the LUMIPULSE G1200 for a maximum of 30 days.

#### Transport Conditions

Lumipulse G B R . A . H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B•R•A•H•M•S PCT Calibrators are shipped at 2-10°C.

Materials will be shipped to the end user using an insulated container and a predetermined configuration of gel (cold and/or frozen) packs to maintain the product for up to 72 hours when stored at ambient temperature.

- d. Detection limit:
The Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) of Lumipulse G B+R•A•H•M•S PCT on the LUMIPULSE G1200 System is ≤0.0114 ng/mL.

#### 1)LoB and LoD

The LoB for Lumipulse G B+R+A+H+M+S PCT was 0.0095 ng/mL. The LoD for Lumipulse G PCT on the LUMIPULSE G1200 System was 0.0114 ng/mL, determined consistent with the guidelines in the CLSI Protocol EP17-A2, Seven low level specimens were tested over 3 days using two LUMIULSE G1200 Systems and two Lumipulse G PCT lots giving 120 determinations per panel.

2)LoQ

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Image /page/14/Picture/1 description: The image contains the logo for FUJIREBIO Diagnostics, Inc. The logo features a stylized graphic element on the left, consisting of blue and white shapes. To the right of the graphic is the company name, "FUJIREBIO" in a bold, blue sans-serif font, with the word "Diagnostics, Inc." appearing in a smaller, black font below it.

The LoQ for Lumipulse G B.R.A.H+M+S PCT on the LUMIPULSE G1200 System was 0.0114 ng/mL, determined consistent with the guidelines in the CLSI Protocol EP17-A2.

A modeling analysis was conducted to evaluate the LOQ and for each lower cut-off (i.e., 0.10 ng/mL and 0.25 ng/mL). The Max % Total Error, % bias and %CV were calculated, see below.

TE ≤ 11.4% at 0.25 ng/mL (with a % bias ≤ -5.7% and a precision CV ≤ 2.8%)

TE ≤ 14.1% at 0.10 ng/mL (with a % bias ≤ -9.2% and a precision CV ≤ 2.5%)

e. Analytical specificity:

Lumipulse G B+R•A•H•M•S PCT on the LUMIPULSE G1200 System demonstrated an average interference of ≤10% (for each compound) in a study consistent with the guidelines in the CLSI Protocol EP7-A2 Human serum specimen pools with procalcitonin concentrations of approximately 0.25 and 2.0 ng/mL were supplemented with potentially interfering compounds. The following compounds were tested using Lumipulse G B•R•A•H•M•S PCT and found not to interfere with the assay.

| Endogenous Interferences | Test Concentration |
|-----------------------------------------|--------------------|
| Free Bilirubin (unconjugated) | 50 mg/dL |
| Conjugated Bilirubin | 50 mg/dL |
| Hemoglobin | 400 mg/dL |
| Total Protein (Human Serum Albumin) | 12 g/dL |
| Triglycerides (Intralipid 20% Emulsion) | 2500 mg/dL |
| Immunoglobulin G (IgG) | 5 g/dL |
| Biotin | 19.7 mg/dL |
| Human Anti-Mouse Antibodies (HAMA) | 1,000 ng/mL |
| Rheumatoid Factor (RF) | 1,000 IU/mL |

| Therapeutic Drug<br>Interferences | Test Concentration (mg/dL) |
|-----------------------------------|----------------------------|
| Acetaminophen | 20.01 |
| Acetylsalicylic Acid | 65.22 |
| 1% Ethanol | 789.00 |
| Azithromycin | 2.00 |
| Caffeine | 6.00 |
| Celecoxib | 24.00 |
| Cetirizine HCI | 0.55 |
| Dextromethorphan | 0.10 |
| Dobutamine | 1.13 |
| Dopamine | 13.00 |
| Doxycycline | 5.00 |
| Epinephrine | 0.18 |
| Furosemide | 2.00 |
| Heparin | 8000.00 |
| Ibuprofen | 50.03 |
| Imipenem | 118.00 |
| Levofloxacin | 2.93 |

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Image /page/15/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic on the left, consisting of blue and white shapes, possi…