Elecsys CYFRA 21-1

cobas e 411
11820966119 11820966500 100 cobas e 601
cobas e 602

English
System information
For cobas e 411 analyzer: test number 370 Test principle
For cobas e 601 and cobas e 602 analyzers: Application Code Sandwich principle. Total duration of assay: 18 minutes.
Number 063 ▪ 1st incubation: 20 µL of sample, a biotinylated monoclonal
Please note cytokeratin 19‑specific antibody, and a monoclonal
cytokeratin 19‑specific antibody labeled with a ruthenium complexa) form
The measured CYFRA 21‑1 value of a patient’s sample can vary a sandwich complex.
depending on the testing procedure used. The laboratory finding must ▪ 2nd incubation: After addition of streptavidin-coated microparticles, the
therefore always contain a statement on the CYFRA 21‑1 assay method complex becomes bound to the solid phase via interaction of biotin and
used. CYFRA 21‑1 values determined on patient samples by different streptavidin.
testing procedures cannot be directly compared with one another and ▪ The reaction mixture is aspirated into the measuring cell where the
could be the cause of erroneous medical interpretations. If there is a microparticles are magnetically captured onto the surface of the
change in the CYFRA 21‑1 assay procedure used while monitoring electrode. Unbound substances are then removed with
ProCell/ProCell M. Application of a voltage to the electrode then induces
therapy, then the CYFRA 21‑1 values obtained upon changing over to the chemiluminescent emission which is measured by a photomultiplier.
new procedure must be confirmed by parallel measurements with both
methods. ▪ Results are determined via a calibration curve which is instrument-
specifically generated by 2‑point calibration and a master curve provided
Intended use via the reagent barcode or e‑barcode.
Immunoassay for the in vitro quantitative determination of fragments of a) Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy) )
cytokeratin 19 in human serum and plasma. Reagents - working solutions
The reagent rackpack is labeled as CYFRA.
The assay is to be used as an aid in monitoring disease progression
during the course of disease and treatment in lung cancer patients. Serial M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL:
testing for patient CYFRA 21-1 assay values should be used in
conjunction with other clinical methods used for monitoring lung cancer. Streptavidin-coated microparticles 0.72 mg/mL; preservative.
R1 Anti-cytokeratin 19‑Ab~biotin (gray cap), 1 bottle, 10 mL:
The electrochemiluminescence immunoassay “ECLIA” is intended for use
on Elecsys and cobas e immunoassay analyzers. Biotinylated monoclonal anti‑cytokeratin 19 antibody (KS 19.1;
mouse) 1.5 mg/L, phosphate buffer 100 mmol/L, pH 7.2; preservative.
Note: Please note that the catalogue number appearing on the package R2 Anti-cytokeratin 19‑Ab~Ru(bpy) (black cap), 1 bottle, 10 mL:
insert retains only the first 8 digits of the licensed 11-digit Catalogue Monoclonal anti‑cytokeratin 19 antibody (BM 19.21; mouse) labeled
Number: 11820966122 for the Elecsys CYFRA 21-1 assay. The last 3
digits -122 have been replaced by -119 for logistic purposes with ruthenium complex 2 mg/L; phosphate buffer 100 mmol/L,
pH 7.2; preservative.
Summary Precautions and warnings
Cytokeratins are structural proteins forming the subunits of epithelial For in vitro diagnostic use.
intermediary filaments. Twenty different cytokeratins have so far been Exercise the normal precautions required for handling all laboratory
identified, CYFRA 21‑1 which is a fragment of cytokeratin 19, being the reagents.
most prominent one. Intact cytokeratin polypeptides are poorly soluble, but Disposal of all waste material should be in accordance with local guidelines.
soluble fragments like CYFRA 21‑1, are frequently released into the blood Safety data sheet available for professional user on request.
of cancer patients and can be detected in serum.1 Although being
expressed in different organs, its major occurrence is in the lung. This kit contains components classified as follows in accordance with the
CYFRA 21‑1 can be considered as the biomarker of choice for non-small Regulation (EC) No. 1272/2008:
cell lung cancer (primarily for squamous cell and large cell carcinoma 2-methyl-2H-isothiazol-3-one hydrochloride
subtypes).2,3,4,5,6 In adenocarcinoma of the lung, a combination of
CYFRA 21‑1 and Carcinoembryonic antigen (CEA) has been found to be EUH 208 May produce an allergic reaction.
the most useful.7,8 Product safety labeling follows EU GHS guidance.
The main indication for CYFRA 21‑1 is monitoring the course of NSCLC.9 Avoid foam formation in all reagents and sample types (specimens,
Successful therapy is accompanied by a rapid decrease of serum levels to calibrators and controls).
the normal range.9,10
Increased CYFRA 21‑1 levels have also been described in non-malignant Reagent handling
diseases (i.e. pneumonia, sepsis)11,12,13 and renal dysfunction.14 Therefore The reagents in the kit have been assembled into a ready‑for‑use unit that
evaluation of renal function (i.e. by measuring serum creatinine levels) cannot be separated.
should be considered in cases of high CYFRA 21‑1 levels that are not All information required for correct operation is read in from the respective
consistent with the diagnostic and clinical characteristics of the patient. reagent barcodes.
With the use of two specific monoclonal antibodies (KS 19.1 and Storage and stability
BM 19.21), the Elecsys CYFRA 21‑1 assay measures a fragment of
cytokeratin 19 having a molecular weight of approximately 30000 Da.15 Store at 2‑8 °C.
Do not freeze.

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Elecsys CYFRA 21-1
Store the Elecsys reagent kit upright in order to ensure complete ▪ 03023141001, PC/CC‑Cups, 12 cups to prewarm ProCell M and
availability of the microparticles during automatic mixing prior to use. CleanCell M before use
Stability: ▪ 03005712190, ProbeWash M, 12 x 70 mL cleaning solution for run
finalization and rinsing during reagent change
unopened at 2‑8 °C up to the stated expiration date
▪ 12102137001, AssayTip/AssayCup, 48 magazines x 84 reaction
after opening at 2‑8 °C 12 weeks cups or pipette tips, waste bags
on the analyzers 8 weeks ▪ 03023150001, WasteLiner, waste bags
Specimen collection and preparation ▪ 03027651001, SysClean Adapter M
Only the specimens listed below were tested and found acceptable. Additional materials for all analyzers:
Serum collected using standard sampling tubes or tubes containing ▪ 11298500316, ISE Cleaning Solution/Elecsys SysClean,
separating gel. 5 x 100 mL system cleaning solution
Li‑heparin, K2‑EDTA and K3‑EDTA plasma. Assay
Plasma tubes containing separating gel can be used. For optimum performance of the assay follow the directions given in this
Criterion: Recovery within 90‑110 % of serum value or slope document for the analyzer concerned. Refer to the appropriate operator’s
0.9‑1.1 + intercept within < ± 2x analytical sensitivity (LDL) + coefficient of manual for analyzer‑specific assay instructions.
correlation > 0.95. Resuspension of the microparticles takes place automatically prior to use.
Read in the test-specific parameters via the reagent barcode. If in
Stable for 7 days at 20‑25 °C, 30 days at 2‑8 °C, 6 months at exceptional cases the barcode cannot be read, enter the 15-digit sequence
‑20 °C (± 5 °C). Freeze only once.16 of numbers.
It is recommended that the samples be mixed by careful swirling or by Bring the cooled reagents to approximately 20 °C and place on the reagent
placing on a roller mixer (max. 5 min). Homogenization of samples using disk (20 °C) of the analyzer. Avoid foam formation. The system
electric vibration mixers must be limited to a maximum of 5 seconds. automatically regulates the temperature of the reagents and the
Longer mixing times lead to lower values being found. opening/closing of the bottles.
Contamination of the sample with saliva leads to falsely elevated results.16
Calibration
The sample types listed were tested with a selection of sample collection Traceability: This method has been standardized against the Enzymun‑Test
tubes that were commercially available at the time of testing, i.e. not all CYFRA 21‑1 method.
available tubes of all manufacturers were tested. Sample collection systems
from various manufacturers may contain differing materials which could Every Elecsys reagent set has a barcoded label containing specific
affect the test results in some cases. When processing samples in primary information for calibration of the particular reagent lot. The predefined
tubes (sample collection systems), follow the instructions of the tube master curve is adapted to the analyzer using the relevant CalSet.
manufacturer. Calibration frequency: Calibration must be performed once per reagent lot
Centrifuge samples containing precipitates before performing the assay. using fresh reagent (i.e. not more than 24 hours since the reagent kit was
registered on the analyzer).
Do not use heat‑inactivated samples.
Calibration interval may be extended based on acceptable verification of
Do not use samples and controls stabilized with azide. calibration by the laboratory.
Ensure the samples, calibrators and controls are at 20‑25 °C prior to Renewed calibration is recommended as follows:
measurement.
▪ after 8 weeks when using the same reagent lot
Due to possible evaporation effects, samples, calibrators and controls on
the analyzers should be analyzed/measured within 2 hours. ▪ after 7 days (when using the same reagent kit on the analyzer)
Materials provided ▪ as required: e.g. quality control findings outside the defined limits
See “Reagents – working solutions” section for reagents.
Quality control
Materials required (but not provided)
For quality control, use PreciControl Lung Cancer or PreciControl Tumor
▪ 11820974322, CYFRA 21‑1 CalSet, for 4 x 1.0 mL Marker.
▪ 11776452122, PreciControl Tumor Marker, for 4 x 3.0 mL In addition, other suitable control material can be used.
▪ 07360070190, PreciControl Lung Cancer, for 4 x 3.0 mL Controls for the various concentration ranges should be run individually at
▪ 11732277122, Diluent Universal, 2 x 16 mL sample diluent or least once every 24 hours when the test is in use, once per reagent kit, and
03183971122, Diluent Universal, 2 x 36 mL sample diluent following each calibration.
The control intervals and limits should be adapted to each laboratory’s
▪ General laboratory equipment individual requirements. Values obtained should fall within the defined
▪ cobas e analyzer limits. Each laboratory should establish corrective measures to be taken if
Additional materials for the cobas e 411 analyzer: values fall outside the defined limits.
▪ 11662988122, ProCell, 6 x 380 mL system buffer If necessary, repeat the measurement of the samples concerned.
Follow the applicable government regulations and local guidelines for
▪ 11662970122, CleanCell, 6 x 380 mL measuring cell cleaning quality control.
solution
▪ 11930346122, Elecsys SysWash, 1 x 500 mL washwater additive Calculation
The analyzer automatically calculates the analyte concentration of each
▪ 11933159001, Adapter for SysClean sample (either in ng/mL or μg/L).
▪ 11706802001, AssayCup, 60 x 60 reaction cups Limitations - interference
▪ 11706799001, AssayTip, 30 x 120 pipette tips The assay is unaffected by icterus (bilirubin < 1112 µmol/L or < 65 mg/dL),
▪ 11800507001, Clean‑Liner hemolysis (Hb < 0.93 mmol/L or < 1.5 g/dL), lipemia (Intralipid
Additional materials for cobas e 601 and cobas e 602 analyzers: < 1500 mg/dL) and biotin (< 205 nmol/L or < 50 ng/mL).
Criterion: Recovery within ± 10 % of initial value.
▪ 04880340190, ProCell M, 2 x 2 L system buffer
Samples should not be taken from patients receiving therapy with high
▪ 04880293190, CleanCell M, 2 x 2 L measuring cell cleaning biotin doses (i.e. > 5 mg/day) until at least 8 hours following the last biotin
solution administration.

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Elecsys CYFRA 21-1
No interference was observed from rheumatoid factors up to a
concentration of 1500 IU/mL.
There is no high-dose hook effect at CYFRA 21‑1 concentrations up to
2000 ng/mL.
In vitro tests were performed on 28 commonly used pharmaceuticals. No
interference with the assay was found.
In rare cases, interference due to extremely high titers of antibodies to
analyte‑specific antibodies, streptavidin or ruthenium can occur. These
effects are minimized by suitable test design. Benign lung
75 70 5 0 0 0
For diagnostic purposes, the results should always be assessed in disease
conjunction with the patient’s medical history, clinical examination and other CHFb) 40 29 11 0 0 0
findings.
Benign kidney
Limits and ranges 40 8 24 8 0 0
disease
Measuring range
Benign liver
0.100‑500 ng/mL (defined by the lower detection limit and the maximum of 40 35 4 1 0 0
the master curve). Values below the lower detection limit are reported as disease
< 0.100 ng/mL. Values above the measuring range are reported as Cancer 440
> 500 ng/mL (or up to 1000 ng/mL for 2‑fold diluted samples).
Lung cancer 120 53 33 27 5 2
Lower limits of measurement
Bladder
Lower detection limit of the test 40 13 9 12 5 1
cancer
Lower detection limit: ≤ 0.10 ng/mL
Breast cancer 40 32distribution
Elecsys CYFRA 21‑1 5 of values
3 by cohort
0 0
The Lower Detection Limit represents the lowest measurable analyte level
that can be distinguished from zero. It is calculated as the value lying two Cervical No.
40of 0.3-
28 2.38-
11 5.01-
1 20.01-
0 0
> 100
standard deviations above that of the lowest standard (master calibrator, cancer sub­ 2.37 5.0 20.0 100
standard 1 + 2 SD, repeatability study, n = 21). ng/mL
ESCCc) jects
40 ng/mL
21 ng/mL
12 ng/mL
6 ng/mL
1 0
Dilution GI tract
Samples with CYFRA 21‑1 concentrations above the measuring range can 40 23 10 6 1 0
cancer
be diluted with Diluent Universal. The recommended dilution is 1:2 (either
automatically by the analyzers or manually). The concentration of the Head and
diluted sample must be > 250 ng/mL. 40 29 11 0 0 0
neck cancer
After manual dilution, multiply the result by the dilution factor. Prostate
After dilution by the analyzers, the software automatically takes the dilution 40 37 1 2 0 0
cancer
into account when calculating the sample concentration.
Ovarian
Expected values 40 25 8 5 2 0
cancer
Normal CYFRA 21‑1 values are expected to be ≤ 2.37 ng/mL.
b) CHF = Congestive heart failure
The following table shows the results of three separate cohorts. The first
study represents the distribution of expected results from 240 apparently c) ESCC = Esophageal squamous cell carcinoma
healthy men and women equally divided into smokers and nonsmokers. Each laboratory should investigate the transferability of the expected values
The second study represents the distribution of expected results from to its own patient population and if necessary determine its own reference
195 benign disease conditions other than cancers, and the third study ranges.
represents the distribution of expected results from different cancers,
including lung cancer.
Elecsys CYFRA 21‑1 distribution of values by cohort
Clinical performance data
No. of 0.3- 2.38- 5.01- 20.01-
> 100 The effectiveness of the Elecsys CYFRA 21‑1 assay as an aid in monitoring of
sub­ 2.37 5.0 20.0 100 disease status in lung cancer patients was determined by assessing changes in
ng/mL
jects ng/mL ng/mL ng/mL ng/mL
CYFRA 21‑1 levels in serial serum samples from 83 patients compared to
Apparently changes in disease status. A total of 398 samples were measured, including 86
240
healthy baseline values and 315 monitoring values.
All normals 240 228 12 0 0 0 Subjects had ≥ 3 blood draws over time with a minimum follow‑up time of
Nonsmokers 120 111 9 0 0 0 30 days and no less than 7 days between consecutive blood draws. A
Smokers 120 117 3 0 0 0 positive change in CYFRA 21‑1 was defined as an increase in the value that
was at least 50 % greater than the previous value of the test. This level of
Normal 0 change takes into account the analytical variability of the assay. 44.1 %
125 119 6 0 0
females (26/59) of the patient samples with a positive change correlated with the
Nonsmokers 63 59 4 0 0 0 disease progression while 91.0 % (233/256) of the patient serial samples
Smokers 62 60 2 0 0 0 with no significant change in CYFRA 21‑1 value correlated with no
progression. The following table presents the data:
Normal males 115 109 6 0 0 0
Nonsmokers 57 52 5 0 0 0
Smokers 58 57 1 0 0 0
Benign
195
conditions

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 Elecsys CYFRA 21-1
Elecsys CYFRA 21‑1 elevation vs. disease progression
Disease progression cobas e 601 and cobas e 602 analyzers
Repeatability Intermediate
No Progression Total
progression precision
Sample Mean SD CV SD CV
Elecsys CYFRA Not elevated 233 33 267
21‑1 elevation ng/mL ng/mL % ng/mL %
Elevated 23 26 48
PreciControl LC1 2.97 0.068 2.3 0.146 4.9
Total 256 59 315
PreciControl LC2 27.5 0.336 1.2 0.497 1.8
No set cutoff exists for CYFRA 21‑1. The clinical performance of other Method comparison
percent changes in serial samples are presented below. Clinicians may A comparison of the Elecsys CYFRA 21‑1 assay (y) with the Enzymun‑Test
choose to use these other values to enhance the sensitivity or specificity of CYFRA 21‑1 method (x) using clinical samples gave the following
the assay, depending on their needs. correlations:
Cutoff values and corresponding performance measurements Number of samples measured: 76
Percent (%) Passing/Bablok17 Linear regression
change in Sensitivity Specificity NPVd) PPVe) y = 0.98x - 0.30 y = 0.95x - 0.10
Elecsys CYFRA (%) (%) (%) (%)
21‑1 τ = 0.941 r = 0.993
30 49.2 87.1 88.1 46.8 The sample concentrations were between 1.0 and 44 ng/mL.
40 44.1 89.8 87.5 50.0 Analytical specificity
The monoclonal anti‑cytokeratin 19 antibodies recognize a fragment of the
50 44.1 91.0 87.6 53.1 cytokeratin 19 peptide. There is no cross‑reactivity with cytokeratins 8
60 39.0 91.4 86.7 51.1 and 18.18
70 35.6 93.4 86.3 55.3 References
1 Okamura K, Takayama K, Izumi M, et al. Diagnostic value of CEA and
d) NPV = negative predictive value CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer
e) PPV = positive predictive value 2013;80(1):45-9.
Specific performance data
2 Boeck S, Wittwer C, Heinemann V, et al. Cytokeratin 19-fragments
Representative performance data on the analyzers are given below. (CYFRA 21-1) as a novel serum biomarker for response and survival in
Results obtained in individual laboratories may differ. patients with advanced pancreatic cancer. Br J Cancer
Precision 2013;108(8):1684-94.
Precision was determined using Elecsys reagents, pooled human sera and 3 Barak V, Goike H, Panaretakis KW, et al. Clinical utility of cytokeratins
controls in a modified protocol (EP5‑A) of the CLSI (Clinical and Laboratory as tumor markers. Clin Biochem 2004;37(7):529-540.
Standards Institute): 6 times daily for 10 days (n = 60); repeatability on 4 Bodenmueller H. The biochemistry of CYFRA 21-1 and other
MODULAR ANALYTICS E170 analyzer, n = 21. The following results were cytokeratin-tests. Scand J Clin Lab Invest 1995;55,Suppl 221:60-66.
obtained:
cobas e 411 analyzer 5 Stieber P, Dienemann H, Hasholzner U, et al. Comparison of
Cytokeratin Fragment 19 (CYFRA 21-1) Tissue Polypeptide Antigen
Repeatability Intermediate (TPA) and Tissue Polypeptide Specific Antigen (TPS) as Tumor
precision Markers in Lung Cancer. Eur J Clin Chem Clin Biochem
1993;31:689-694.
Sample Mean SD CV SD CV
ng/mL ng/mL % ng/mL % 6 Bodenmueller H, Donie F, Kaufmann M, et al. The tumor markers TPA,
TPS TPACYK and CYFRA 21-1 react differently with the keratins 8, 18
Human serum 1 2.68 0.06 2.1 0.13 4.7 and 19. Int J Biol Markers 1994;9:70-74.
Human serum 2 6.86 0.14 2.0 0.23 3.3 7 Ebert W, Dienemann H, Fateh-Moghadam A, et al. Cytokeratin 19
Fragment CYFRA 21-1 Compared with Carcinoembryonic Antigen,
Human serum 3 21.5 0.36 1.7 0.66 3.1 Squamous Cell Carcinoma Antigen and Neuron-Specific Enolase in
PreciControl TMd)1 5.04 0.10 2.0 0.12 2.4 Lung Cancer. Results of an International Multicentre Study. Eur J Clin
Chem Clin Biochem 1994;32(3):189-199.
PreciControl TM2 29.9 0.49 1.6 0.63 2.1
8 Ardizzoni A, Cafferata MA, Tiseo M, et al. Decline in serum
PreciControl LCe)1 2.90 0.046 1.6 0.129 4.5 carcinoembryonic antigen and cytokeratin 19 fragment during
PreciControl LC2 27.2 0.281 1.0 0.569 2.1 chemotherapy predicts objective response and survival in patients with
advanced non-small cell lung cancer. Cancer 2006;107(12):2842-2849.
d) TM = Tumor Marker 9 Ebert W, Muley T. CYFRA 21-1 in the follow-up of inoperable non-small
e) LC = Lung Cancer cell lung cancer patients treated with chemotherapy. Anticancer Res
1999;19(4A):2669-2672.
cobas e 601 and cobas e 602 analyzers
10 Vollmer RT, Govindan R, Graziano S, et al. Serum CYFRA21-1 in
Repeatability Intermediate precision advanced stage non-small cell lung cancer: an early measure of
Sample Mean SD CV Mean SD CV response. Clin Cancer Res 2003;9:1728-1733.
ng/mL ng/mL % ng/mL ng/mL % 11 Nakayama M, Satoh H, Ishikawa H, et al. Cytokeratin 19 fragments in
Human serum 1 2.60 0.04 1.5 2.65 0.07 2.7 patients with non-malignant respiratory diseases. Chest
2003;123(6):2001-2006.
Human serum 2 5.51 0.06 1.2 5.51 0.13 2.3 12 Fujita J, Ohtsuki Y, Bandoh S, et al. Elevation of cytokeratin 19
Human serum 3 57.0 0.62 1.1 56.0 1.10 2.0 fragment (CYFRA 21-1) in serum of patients with radiation pneumonitis,
possible marker of epithelial cell damage. Respirator Med
PreciControl TM1 5.06 0.11 2.1 5.12 0.13 2.6 2004;98(4):294-300.
PreciControl TM2 33.4 0.53 1.6 33.9 0.65 1.9
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 Elecsys CYFRA 21-1
13 Molina R, Agusti C, Filella X, et al. Study of a New Tumor Marker,
CYFRA21-1, in Malignant and Nonmalignant Diseases. Tumor Biol
1994;15:318-325.
14 Nakahama H, Tanaka Y, Fujita Y, et al. CYFRA 21-1 and ProGRP,
tumor markers of lung cancer are elevated in chronic renal failure
patients. Respirology 1998;3:207-210.
15 Stieber P, Hasholzner U, Bodenmueller H, et al. CYFRA 21-1: A new
marker in lung cancer. Cancer 1993;72:707-713.
16 Guder WG, Narayanan S, Wisser H, et al. List of Analytes;
Preanalytical Variables. Brochure in: Samples: From the Patient to the
Laboratory. GIT-Verlag, Darmstadt 1996:12. ISBN 3-928865-22-6.
17 Bablok W, Passing H, Bender R, et al. A general regression procedure
for method transformation. Application of linear regression procedures
for method comparison studies in clinical chemistry, Part III.
J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.
18 Bodenmueller H, Ofenloch-Hähnle B, Lane EB, et al. Lung Cancer
associated Keratin 19 Fragments: Development and Biochemical
Characterization of the new Serum Assay Enzymun-Test CYFRA 21-1.
Int J Biol Markers 1994;9:75-81.
For further information, please refer to the appropriate operator’s manual for
the analyzer concerned, the respective application sheets, the product
information and the Method Sheets of all necessary components (if
available in your country).
A point (period/stop) is always used in this Method Sheet as the decimal
separator to mark the border between the integral and the fractional parts of
a decimal numeral. Separators for thousands are not used.
Symbols
Roche Diagnostics uses the following symbols and signs in addition to
those listed in the ISO 15223‑1 standard (for USA: see dialog.roche.com for
definition of symbols used):
Contents of kit
Analyzers/Instruments on which reagents can be used
Reagent
Calibrator
Volume after reconstitution or mixing
GTIN Global Trade Item Number

COBAS, COBAS E, ELECSYS, CYFRA 21‑1 and PRECICONTROL are trademarks of Roche. INTRALIPID is a
trademark of Fresenius Kabi AB.
All other product names and trademarks are the property of their respective owners.
Additions, deletions or changes are indicated by a change bar in the margin.
© 2020, Roche Diagnostics

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