Phenylalanine (PKU) neonatal Screening Assay - IBL international

Instructions for Use
Phenylalanine (PKU)
neonatal Screening
Assay
Enzymatic Assay for the in-vitro-diagnostic quantitative determination
of L-Phenylalanine in human newborn blood spots.
For neonatal screening on Phenylketonuria.
RE80015 RE80019
480 2400
2-8°C
I B L I N T E R N A T I O N A L G M B H
Flughafenstrasse 52a Phone: +49 (0)40-53 28 91-0 IBL@IBL-International.com
D-22335 Hamburg, Germany Fax: +49 (0)40-53 28 91-11 www.IBL-International.com

Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
1. INTENDED USE
Enzymatic Assay for the in-vitro-diagnostic quantitative determination of L-Phenylalanine in human newborn
blood spots. For neonatal screening on Phenylketonuria.
2. SUMMARY AND EXPLANATION
Phenylketonuria (PKU) is one of the most often heriditary diseases of the metabolism of the amino acids. It
is transmitted autosomal recessive to the descendant with an incidence of circa 1:2600 to 1:25000
dependent on the observed population group.
The main cause of the disease – 90 to 99% of all cases – is a decrease or the absence of the activity of the
enzyme complex Phenylalaninehydroxylase which is responsible for the transformation of the essential
amino acid Phenylalanine into Tyrosine. The latter is a precursor of the Catecholamines, Melanine and the
thyroid hormones. Because of the blocking of this metabolism Phenylalanine is transformed by an
alternative pathway to Phenylpyruvate and –acetate which are excreted by the kidneys.
The disease becomes apparent by a mental retardation of the patients beginning in the first weeks of their
life. Responsible for this development is the improper myelinization of the neurons in the brain because of
the change in the protein metabolism. Other signs of the Phenylketonuria are the lacking of pigmentation of
the dermis and its adnexis because of the disturbance of the synthesis of Melanine and therefore its
predisposition of skin diseases.
It is important to make the diagnosis of Phenylketonuria in the newborns because the cerebral damage can
be prevented by a low Phenylalanine diet. Therefore a screening test for the detection of elevated
Phenylalanine concentrations in the blood has to be made between the 2rd and the 5th day of the infants
life. If this one is positive it is followed by a confirmatory assay to detect the special mutations on the
chromosome 12.
Many screening tests were developed for monitoring patients for Phenylketonuria. The first one called to its
inventor GUTHRIE is based on the neutralization of an growth inhibiting factor of Bacillus subtilis by high
Phenylalanine levels.
Because of some disadvantages of this method it is replaced by assays in which the Phenylalanine in the
blood of the patients takes part in a chemical reaction developing a fluorescinating or a coloured substance
which can be measured quantitavely. The procedures can be used more conveniently in comparison to the
more sophisticated and more expensive method of the HPLC.
3. TEST PRINCIPLE
The Phenylalanine of the blood spots is eluated quantitavely using Trichloracetic acid (3%) from the
cellulose paper. After that the Phenylalanine is transformed by the enzyme Phenylalaninedehydrogenase to
Phenylpyruvate. This reaction is coupled to the reduction of the coenzyme NAD+, present in the reaction
mixture. The reduced NADH transforms in a redox reaction the added yellow Tetrazolium salt to the violet
substrate Formazane. The amount of Formazane developed is proportional to the concentration of
Phenylalanine in the sample. The color of the substrate can be measured with a photometer at 570 nm.
4. WARNINGS AND PRECAUTIONS
1. For in-vitro diagnostic use only. For professional use only.
2. Before starting the assay, read the instructions completely and carefully. Use the valid version of the
package insert provided with the kit. Be sure that everything is understood.
3. In case of severe damage of the kit package please contact IBL or your supplier in written form, latest
one week after receiving the kit. Do not use damaged components in test runs, but keep safe for
complaint related issues.
4. Obey lot number and expiry date. Do not mix reagents of different lots. Do not use expired reagents.
5. Follow good laboratory practice and safety guidelines. Wear lab coats, disposable latex gloves and
protective glasses where necessary.
6. Reagents of this kit containing hazardous material may cause eye and skin irritations. See MATERIALS
SUPPLIED and labels for details. Material Safety Data Sheets for this product are available on the IBL-
Homepage or upon request directly from IBL.
7. Chemicals and prepared or used reagents have to be treated as hazardous waste according to national
biohazard and safety guidelines or regulations.
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
8. All reagents of this kit containing human serum or plasma have been tested and were found negative for
anti-HIV I/II, HBsAg and anti-HCV. However, a presence of these or other infectious agents cannot be
excluded absolutely and therefore reagents should be treated as potential biohazards in use and for
disposal.
5. STORAGE AND STABILITY
The kit is shipped at ambient temperature and should be stored at 2-8°C. Keep away from heat or direct sun
light. The storage and stability of specimen and prepared reagents is stated in the corresponding chapters.
6. SPECIMEN COLLECTION AND STORAGE
Blood Spots
Blood from the newborn’s heel should be collected only from the medial or lateral section of the plantar
surface. The usual precautions for blood collection should be observed. After puncture of the heel the first
drop of blood should be wiped away with a sterile gauze.
Touch the collection card against a large hanging drop of blood and allow a sufficient quantity of blood to
soak into the filter paper in one step and so to fill the pre-printed circle completely. Repeat the procedure to
fill the required number of pre-printed circles on the collection card.
Allow the blood spots to air-dry for 3 h at room temperature away from direct sunlight.
Because the standards are established with filter cards from Schleicher & Schuell No. 903 and
there is a significant influence of the results by the filter card material (see LIMITATIONS OF THE
PROCEDURE), it is recommended to use these cards also for the patient samples.
Don’t squeeze the puncture site during the collection because this will cause hemolysis or dilution
of the blood with tissue fluid. Don’t apply successive drops of blood to the same pre-printed circles.
Don’t touch or smear the blood spots.
Take care that the blood spot samples are visually okay (e.g. no blood smears, no coagulates, no
finger-prints on the spots).
The optimal collection point of time is 48 to 72 hours after birth. The blood sample should not be
collected before the 36. and not after 72. hour after birth. In this time frame failed sample collection
must be catch up without any further delay.
In case of discharge before the 36. hour after birth or relocation the first sample should be taken.
An earlier determination point of time as the 36. hour after birth raises the risk of false negative
diagnostic findings. In case of discharge before the 36. hour after birth the parents (Care
beneficiary) must be informed about exigency of second laboratory determination in due time.
Extract from German Child Direction (BAnz. Nr. 60).
National and country specific guidelines to sample collection point of time must be considered.
Storage:
2-8°C
Keep away from heat or direct sun light.
Stability:
6 mon
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
7. MATERIALS SUPPLIED
RE80019 RE80015 Symbol Component
5 x 1 x ENZ LYO
1 x 220 mL 1 x 45 mL ENZDIL
1 x 260 mL 1 x 55 mL SUBS
5 x 5 1 x 5 CAL A-E
5 x 2 1 x 2 CONTROL1+2
1 x 8 mL 1 x 2 mL DYE CONC
Enzyme lyophilized
Contains: phenylalanine dehydrogenase, Coenzyme NAD + , Buffer, stabilizers.
Enzyme Diluent
Ready to use. Contains: diethanolamine, Buffer, 0.01% NaN 3.
Substrate
Ready to use. Contains: tetrazolium salt, citrate buffer.
Standard A-E
~1; ~3; ~5; ~9; ~13 mg/dL
Calibrated against CDC (Center for Disease Control and prevention).
Contains: human blood. Schleicher & Schuell paper No. 903. 15 Blood Spots /
card. Exact concentrations see labels or QC certficate.
Control 1+2
Control 1: ~ 2.0 – 3.0 mg/dL
Control 2: ~ 4.0 – 6.0 mg/dL
Contains: human blood. Schleicher & Schuell paper No. 903. 15 Blood Spots /
card. Concentrations / acceptable ranges see labels or QC Certificate.
Dye Stock Solution Concentrate (51 x)
Contains: Acid Yellow 23 (C.I. 19140).
8. MATERIALS REQUIRED BUT NOT SUPPLIED
1. Micropipettes (Multipette Eppendorf or similar devices, < 3% CV). Volume: 25; 75; 100; 1000 µL
2. Round-bottom polystyrene test tubes (12 x 75 mm)
3. Rack for test tubes
4. Shaker for test tubes
5. Trichloracetic acid (3%; w/v); from 99.5% Trichloracetic acid, p.a. quality (e.g. Fluka, REF 91228)
6. 0.5 M NaOH solution; (e.g. 1 N NaOH Titrisol Sol., Merck, REF 9956)
7. Blood collection cards (Schleicher & Schuell 903 recommended)
8. Blood spot puncher, 5 mm (1/5´´) (e.g. Sauer, Hannover, Germany)
9. Microtiter Plate (flat bottom)
10. Microtiter plate shaker (300-500 rpm; Amplitude 1.5-3.0 mm)
11. Microtiter plate reader capable of reading absorbance at 570 nm (reference wavelength 690 nm)
12. Bidistilled or deionised water
13. Paper towels, pipette tips and timer
9. PROCEDURE NOTES
1. Any improper handling of samples or modification of the test procedure may influence the results. The
indicated pipetting volumes, incubation times, temperatures and pretreatment steps have to be
performed strictly according to the instructions. Use calibrated pipettes and devices only.
2. Once the test has been started, all steps should be completed without interruption. Make sure that
required reagents, materials and devices are prepared ready at the appropriate time. Allow all reagents
and specimens to reach room temperature (18-25°C) and gently swirl each vial of liquid reagent and
sample before use. Mix reagents without foaming.
3. Avoid contamination of reagents, pipettes and wells/tubes. Use new disposable plastic pipette tips for
each component and specimen. Do not interchange caps. Always cap not used vials. Do not reuse
wells/tubes or reagents.
4. Take care that the blood spot samples are visually okay (e.g. no blood smears, no coagulates, no fingerprints
on the spots).
5. It is advised to determine samples in duplicate to be able to identify potential pipetting errors.
6. Use a pipetting scheme to verify an appropriate plate layout.
7. Incubation time affects results. All wells should be handled in the same order and time sequences. It is
recommended to use an 8-channel Micropipettor for pipetting of solutions in all wells.
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
10. PRE-TEST SETUP INSTRUCTIONS
10.1. Preparation of Enyzme Stock Solution
The Stock Solution is stable for 5 d at 2-8°C. Prepare only the amount of Enzyme Solution that is
needed for the actual test run.
Pipette 12 mL of bidist. water into the vial of the Enzyme, cap the vial and mix gently to dissolve.
Mix 2 min. without foaming.
10.2. Preparation of Enyzme Solution
If you are using several vials of the Enzyme Stock Solution, it is highly recommended to pool the
solution and to establish the ready for use Enzyme Solution from this pool.
The Enzyme Solution is stable for 8 h at 18-25°C.
The stability can not be extended by storing at 2–8 °C.
Recommended amount for the Enzyme ready for use solution:
No. of Microtiter Plates
1 / 2 3 / 3 1 2 3 4 5
Stock Solution (mL) 0.8 1.6 2.4 4.8 7.2 9.6 12
Diluent (mL) 2.7 5.3 8.0 16.0 24.0 32.0 40.0
Dilute Enzyme Stock Solution with Enzyme Diluent according to the table. Mix 2 min carefully
without foaming.
10.3. Preparation of Colored Trichloracetic Acid (3%)
Dilute Dye Stock Solution (51x) with Trichloracetic acid (3%) 1:51 (e.g. add 2 mL Dye
Concentrate to 100 mL of Trichloracetic acid (3%)).
The solution is stable until the expiry date of the kit at 18-25°C.
10.4. Elution of Blood Spots
Punch Blood Spot Standards, Controls and samples (each 5 mm Ø = 1/5´´) and put each disc into
one of the polystyrene tubes. Label all tubes.
Pipette 100 µL of Colored Trichloracetic Acid (3%) into each tube. Assure that each disc is fully
immersed in the liquid.
Incubate 30–60 min at RT (18–25 °C) on an orbital shaker (300–500 U/min.; Amplitude 1.5–3 mm).
11. TEST PROCEDURE
1. Pipette 25 µL of 0.5 M NaOH into each well of the microtiter plate.
2. Pipette 75 µL of each Standard, Control and sample Blood Spot Eluate into the respective wells.
Shortly shake the plate.
3. Pipette 100 µL of freshly prepared Enzyme Solution into each well.
4. Incubate 30 min at RT (18–25°C).
5. Pipette 100 µL of Substrate into each well. Shake plate for 3 min on an orbital shaker (300-500 rpm;
Amplitude 1.5–3 mm).
6. Measure Optical Density with a photometer at 570 nm (Reference-wavelength: 690 nm) within 3-5 min
after pipetting of the Substrate Reagent.
12. QUALITY CONTROL
The test results are only valid if the test has been performed following the instructions. Moreover the user
must strictly adhere to the rules of GLP (Good Laboratory Practice) or other applicable standards/laws. All
kit controls must be found within the acceptable ranges as stated on the labels and the QC certificate. If the
criteria are not met, the run is not valid and should be repeated. Each laboratory should use known samples
as further controls. It is recommended to participate at appropriate quality assessment trials.
In case of any deviation the following technical issues should be proven: Expiration dates of (prepared)
reagents, storage conditions, pipettes, devices, incubation conditions and washing methods.
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
13. CALCULATION OF RESULTS
The obtained OD of the standards are plotted against their concentration. The standard curve is calculated
by a linear regression or a weighted linear regression function. Using computer programs, the curve is best
described by a 2-point linear regression fit with linear axes.
For the calculation of the regression curve, apply each signal of the standards (one obvious outlier of
duplicates might be omitted and the more plausible single value might be used).
The concentration of the samples can be read directly from the regression function.
Samples showing signals above the highest standard have to be confirmed by a reference method.
Conversion:
1 mg/dL = 60.5 µmol/L
Typical Calibration Curve
(Example. Do not use for calculation!)
Standard Phenylalanine (mg/dL) OD Mean
A 1.28 0.036
B 2.73 0.065
C 4.91 0.102
D 9.31 0.179
E 13.67 0.247
OD (570 nm/690 nm ref.)
0.30
0.25
0.20
0.15
0.10
0.05
Phenylalanine
y = 0.017x + 0.017
R 2 = 0.999
0.00
0 5 10 15
mg/dL
14. INTERPRETATION OF RESULTS
Based on the assumption that the expected values of phenylalanine follow a normal distribution blood spots
with phenylalanine concentrations greater than 2.5 mg/dL (98% percentile) would be subsequently
considered as "presumptive positive". Confirmation of the results would require repetition of the assay of 2%
of the studied population.
If the result of the repeated measurement (in duplicate) is above the threshold of 3.0 mg/dL, a new sample
should be collected and analyzed applying a confirmatory assay.
Based on classification scheme test results in the concentration range of 2.5 mg/dL to 3.0 mg/dL could
potentially be diagnosed false negative and should be affirmed by additional measurement.
Various societies for neonatal screening recommend different cut-off values for repetition of the
measurement and the application of confirmatory assays. Depending on the application of samples of
different populations of newborns it is highly recommended that each laboratory establishes its own range of
normal values and that this distribution of values is co-ordinated with the recommendations of the
responsible society of this geographic region.
The results themselves should not be the only reason for any therapeutical consequences. They have to be
correlated to other clinical observations and diagnostic tests.
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
15. EXPECTED VALUES
Distribution of Phenylalanine Concentrations in Arbitrary Blood Spot Samples of Newborns
_
x = 1.6 mg/dL
SD = 0.48 mg/dL
n = 6693
Population = Poland
percentile mg/dL
90% 2.16
95% 2.35
98% 2.51
99% 1.45
It is recommended that each laboratory establishes its own range of normal values.
16. LIMITATIONS OF THE PROCEDURE
Specimen collection has a significant effect on the test results. See SPECIMEN COLLECTION AND
STORAGE for details.
Screening Test. Any result with an elevated concentration has to be indicated as ‘presumptive positive’ and
has to be confirmed with further sampling and testing.
A false negative result of this assay cannot be excluded with absolute certainty. Any anamnestic or clinical
hint of Phenylketonuria has to lead to a repeated measurement.
A direct influence of applied drugs to the patients on the phenylalanine results cannot be excluded.
Therefore, it is highly recommended in these cases to review even a normal phenylalanine value with a
confirmation test if there are anamnestic or clinical signs of a phenylketonurie in a patient.
It is recommended to use S&S 903 filter cards for the blood spot samples. When using other filter cards, the
correction factor must be taken into account. For example, results with filter cards 2992 are ca. 20%
different:
Standards (2992) = 1.20 x (S&S 903) + 0.181; r = 0.996; n = 349
For cross-reactivities, see PERFORMANCE.
The following blood components do not have a significant effect on the test results up to the below stated
concentrations:
Hemoglobin
Bilirubin
Triglyceride
5 mg/dL
500 mg/dL
3000 mg/dL
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Phenylalanine (PKU) neonatal Screening Assay (RE80015/RE80019)
ENGLISH
17. PERFORMANCE
Analytical Specificity
(Cross Reactivity)
No cross-reactivities were found with the typical substances tested.
Functional Sensitivity
(Limit of Detection)
1.55 mg/dL Functional Sensitivity, 20%; y = 26.33 x - 0.6304 R 2 = 0.82
Precision Range (mg/dL) CV (%)
Intra-Assay 2.68 – 9.60 5.8 – 11.0
Inter-Assay 2.79 – 9.36 6.4 – 15.1
Samples showing concentrations above the highest standard have to be confirmed by
Linearity
a reference method. A dilution of the sample is not possible, because there does not
exist a blood without phenylalanine as diluent. Other diluents than extracts of
phenylalanine free blood will probably have matrix effects.
Mean (%) Range (%)
Recovery
107 92 - 127
% Recovery after spiking
Method Comparison
versus Other Assay
IBL-Assay = 0.88 x Other Assay – 0.21 r = 0.95; n = 98
18. PRODUCT LITERATURE REFERENCES
1 Richtlinien des Bundesausschusses der Ärzte und Krankenkassen über die Früherkennung von
Krankheiten bei Kindern bis zur Vollendung des 6. Lebensjahres („Kinder-Richtlinien“) BAnz. Nr. 60
(2005)
2 Rouse, B. et al. Maternal phenylketonuria syndrome: congenital heart defects, microcephaly and
developmental outcomes. J. Pediat. 136: 57 – 61 (2000)
3 Benit, P. et al. The mutant genotype is the main determinant of the metabolic phenotype in
Phenylalanine hydroxylase deficiency. Molec. Genet. Metab. 68: 43 – 47 (1999)
4 Kaufmann, S. A model of human Phenylalanine metabolism in normal subjects and in phenylketonuric
patients. Proc. Nat. Acad. Scr. 96: 3160 – 3164 (1999)
5 Sarkissian, C. N. et al. A different approach to treatment of phenylketonuria: Phenylalanine degradation
with recombinant Phenylalanine ammonia lyase. Proc. Nat. Acad. Sci. 96: 2339 – 2344 (1999)
6 Weglage, J. et al. Regression of neuropsychological deficits in early-treated phenylketonurics during
adolescence. J. Inherit. Metab. Dis. 22: 693 – 705 (1999)
7 Carter, K. C. et al. Mutation at the Phenylalanine hadroxylase gene (PAH) and its use to document
population genetic variation: the Quebec experience. Europ. J. Hum. Genet. 6: 61 – 70 (1998)
8 Guldberg, P. et al. A European multicenter study of Phenylalanine hydroxylase deficiency: classification
of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am. J.
Hum. Genet. 63: 71 – 79 (1998)
9 Van Spronsen, F. J. et al. Phenylketonuria: the in vivo hydroxylation rate of Phenylalanine into tyrosine is
decreased. J. Clin. Invest. 101: 2875 – 2880 (1998)
10 Rouse, B. et al. Maternal phenylketonuria collaborative study (MPKUCS) offspring: facial anomalies,
malformations and early neurological sequelae. Am. J. Med. Genet. 69: 89 – 95 (1997)
11 Guthrie, R. The introduction of newborn screening for phenylketonuria: a personal history. Europ. J.
Pediat. 155 (suppl. 1): 4 – 5 (1996)
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Symbols / Symbole / Symbôles / Símbolos / Símbolos / Σύµβολα
REF
LOT
Cat.-No.: / Kat.-Nr.: / No.- Cat.: / Cat.-No.: / N.º Cat.: / N.–Cat.: / Αριθµός-Κατ.:
Lot-No.: / Chargen-Bez.: / No. Lot: / Lot-No.: / Lote N.º: / Lotto n.: / Αριθµός -Παραγωγή:
Use by: / Verwendbar bis: / Utiliser à: / Usado por: / Usar até: / Da utilizzare entro: /
Χρησιµοποιείται από:
No. of Tests: / Kitgröße: / Nb. de Tests: / No. de Determ.: / N.º de Testes: / Quantità dei tests: /
Αριθµός εξετάσεων:
CONC Concentrate / Konzentrat / Concentré / Concentrar / Concentrado / Concentrato / Συµπύκνωµα
LYO
IVD
Lyophilized / Lyophilisat / Lyophilisé / Liofilizado / Liofilizado / Liofilizzato / Λυοφιλιασµένο
In Vitro Diagnostic Medical Device. / In-vitro-Diagnostikum. / Appareil Médical pour Diagnostics In
Vitro. / Dispositivo Médico para Diagnóstico In Vitro. / Equipamento Médico de Diagnóstico In
Vitro. / Dispositivo Medico Diagnostico In vitro. / Ιατρική συσκευή για In-Vitro ∆ιάγνωση.
Evaluation kit. / Nur für Leistungsbewertungszwecke. / Kit pour évaluation. / Juego de Reactivos
para Evaluació. / Kit de avaliação. / Kit di evaluazione. / Κιτ Αξιολόγησης.
Read instructions before use. / Arbeitsanleitung lesen. / Lire la fiche technique avant emploi. /
Lea las instrucciones antes de usar. / Ler as instruções antes de usar. / Leggere le istruzioni
prima dell’uso. / ∆ιαβάστε τις οδηγίες πριν την χρήση.
Keep away from heat or direct sun light. / Vor Hitze und direkter Sonneneinstrahlung schützen. /
Garder à l’abri de la chaleur et de toute exposition lumineuse. / Manténgase alejado del calor o la
luz solar directa. / Manter longe do calor ou luz solar directa. / Non esporre ai raggi solari. / Να
φυλάσσεται µακριά από θερµότητα και άµεση επαφή µε το φως του ηλίου.
Store at: / Lagern bei: / Stocker à: / Almacene a: / Armazenar a: / Conservare a: / Αποθήκευση
στους:
Manufacturer: / Hersteller: / Fabricant: / Productor: / Fabricante: / Fabbricante: / Παραγωγός:
Caution! / Vorsicht! / Attention! / ¡Precaución! / Cuidado! / Attenzione! / Προσοχή!
Symbols of the kit components see MATERIALS SUPPLIED.
Die Symbole der Komponenten sind im Kapitel KOMPONENTEN DES KITS beschrieben.
Voir MATERIEL FOURNI pour les symbôles des composants du kit.
Símbolos de los componentes del juego de reactivos, vea MATERIALES SUMINISTRADOS.
Para símbolos dos componentes do kit ver MATERIAIS FORNECIDOS.
Per i simboli dei componenti del kit si veda COMPONENTI DEL KIT.
Για τα σύµβολα των συστατικών του κιτ συµβουλευτείτε το ΠΑΡΕΧΟΜΕΝΑ ΥΛΙΚΑ.
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and results. Any modification of the test procedure or exchange or mixing of components of different lots could negatively affect the results. These
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Symbols Version 3.5 / 2012-01-20