US20060094120A1 - Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays - Google Patents

Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays Download PDF

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US20060094120A1
US20060094120A1 US10/979,664 US97966404A US2006094120A1 US 20060094120 A1 US20060094120 A1 US 20060094120A1 US 97966404 A US97966404 A US 97966404A US 2006094120 A1 US2006094120 A1 US 2006094120A1
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alcohol
carbonate
ammonia
analyte
solution
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US10/979,664
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Douglas Clark
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Dade Behring Inc
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Dade Behring Inc
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Assigned to DADE BEHRING INC. reassignment DADE BEHRING INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CLARK, DOUGLAS P.
Assigned to DEUTSCHE BANK AG reassignment DEUTSCHE BANK AG GRANT OF SECURITY INTEREST Assignors: DADE BEHRING, INC.
Assigned to DADE BEHRING INC. reassignment DADE BEHRING INC. RELEASE OF SECURITY INTEREST Assignors: DEUTSCHE BANK AG, NEW YORK BRANCH
Priority to PCT/US2005/038641 priority patent/WO2006049999A1/en
Priority to ES05813040T priority patent/ES2370753T3/es
Priority to EP05813040A priority patent/EP1825255B1/en
Publication of US20060094120A1 publication Critical patent/US20060094120A1/en
Priority to US11/495,423 priority patent/US7294512B2/en
Priority to US11/861,002 priority patent/US20080070309A1/en
Abandoned legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/106664—Blood serum or blood plasma standard or control
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/108331—Preservative, buffer, anticoagulant or diluent
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/17—Nitrogen containing
    • Y10T436/173845—Amine and quaternary ammonium
    • Y10T436/175383—Ammonia
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/20—Oxygen containing
    • Y10T436/203332—Hydroxyl containing
    • Y10T436/204165—Ethanol
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/20—Oxygen containing
    • Y10T436/204998—Inorganic carbon compounds

Definitions

  • the present invention relates to standardized solutions containing stabilizers and analytes adjusted to specific levels for calibration of chemical analyzers.
  • this invention relates to an aqueous based stabilized standard solution for the calibration of clinical assays for assessing blood alcohol levels, total carbon dioxide, and ammonia.
  • automated biochemical analyzers employ a combination of analyte specific chemical reagents and reaction monitoring means to assay or determine the presence or concentration of a specific substance or analyte within a liquid sample suspected of containing that particular analyte.
  • Such analyzers are well known and almost universally employ some sort of a calibration curve to determine analyte concentration from the signal generated by the reaction monitoring means in response to the presence of the analyte.
  • calibration curves are established at regular intervals, to compensate for reagent particulars, and on individual analyzers, to compensate for equipment performance.
  • the range of analyte concentrations used in establishing a full calibration curve is typically chosen to extend below and beyond the range of analyte concentrations expected to be found within biological samples like blood, serum, plasma, urine and the like.
  • calibration solutions may be formulated using a matrix that is identical to or bioactively equivalent to serum.
  • Human serum has typically been used as starting material for calibration solutions; however, the techniques used for stripping away interfering chemicals often produce process artifacts and wide lot-to-lot variations making it difficult to manufacture these solutions reproducibly.
  • An additional disadvantage of calibration solutions containing human serum is that they cannot be stored for longer periods since serum contains many labile components which negatively affect the stability of the product. For this reason calibration materials are often provided in a dry state (lyophilized); however, inaccurate re-hydration of these materials commonly leads to inaccurate calibration measures. For these reasons, it is highly advantageous that calibration solutions be prepared using an aqueous or buffered solution as a base matrix.
  • U.S. Pat. No. 3,960,497 discloses the basic concepts of calibrating and verifying the calibration of a chemical analyzer using standard solutions having known values of the particular characteristic being measured.
  • U.S. Pat. No. 4,843,013 discloses a synthetic liquid control standard comprising an aqueous solution and several hemoglobin fractions, and sodium, potassium, lithium and calcium salts.
  • U.S. Pat. No. 5,342,788 discloses a serum-free standard solution containing TBG, albumin, and buffer. When T4 or T3 is added to this solution, an equilibrium is established between bound and free hormone resembling that observed in human serum. Stability of the synthetic standard solution is said to be superior to a solution based in human serum and furthermore, bovine TBG afforded superior stability than TBG derived from human serum.
  • U.S. Pat. No. 5,518,929 discloses aqueous solutions containing buffers and electrolytes adjusted for the calibration and quality control of both blood gases such as carbon dioxide and oxygen, using ion selective electrodes.
  • U.S. Pat. No. 5,795,789 discloses a stabilized standard solution for the calibration of clinical assays useful in assessing thyroid function, including total thyroxine, unbound thyroxine, total triiodothyronine, unbound triiodothyronine, and thyroid stimulating hormone.
  • the present invention is based upon the surprising discovery that a pH range can be established in a single liquid standard or calibration solution formulated simultaneously with specific amounts of blood alcohol (EtOH), total serum carbonate (CO 2 ), and blood ammonia (NH 4 ).
  • EtOH blood alcohol
  • CO 2 total serum carbonate
  • NH 4 blood ammonia
  • an extended period of usage or stability of the calibration solution may be achieved by including a combination of anti-microbial agents demonstrated to be active against gram-positive bacteria, gram-negative bacteria, spore-forming fungi, and non-spore-forming fungi without adversely affecting the utility of the calibration solution.
  • FIG. 1 is an illustration of ammonia stability in the alcohol, carbonate and ammonia multi-analyte calibrator of the present invention
  • FIG. 2 is an illustration of alcohol stability in the alcohol, carbonate and ammonia multi-analyte calibrator of the present invention
  • FIG. 3 is an illustration of carbonate stability in the alcohol, carbonate and ammonia multi-analyte calibrator of the present invention
  • FIG. 4 is a first illustration of ammonia instability in an alcohol, carbonate and ammonia multi-analyte calibrator outside the acceptable pH range of the present invention
  • FIG. 5 is a second illustration of ammonia instability in an alcohol, carbonate and ammonia multi-analyte calibrator outside the acceptable pH range of the present invention
  • FIG. 6 is a third illustration of ammonia instability in an alcohol, carbonate and ammonia multi-analyte calibrator outside the acceptable pH range of the present invention
  • FIG. 7 is an illustration of alcohol stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention with preservatives therein;
  • FIG. 7A is an illustration of alcohol stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention without preservatives therein;
  • FIG. 8 is an illustration of carbonate stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention with preservatives therein;
  • FIG. 8A is an illustration of carbonate stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention without preservatives therein;
  • FIG. 9 is an illustration of ammonia stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention with preservatives therein;
  • FIG. 9A is an illustration of ammonia stability in an alcohol, carbonate and ammonia multi-analyte calibrator of the present invention without preservatives therein.
  • Important clinical assays include blood alcohol, carbonate and ammonia.
  • ethanol-containing medicines have been used for treatment of multiple diseases. Excess consumption of alcohol however impairs those parts of the brain responsible for the most highly integrated body functions. Blood alcohol is usually measured for medico-legal reasons to determine if a person is intoxicated or in the diagnosis of coma in which alcohol may be the sole or contributing cause.
  • Total CO 2 concentration is greatly depressed in metabolic acidosis resulting from many different diseases, such as kidney failure, poisoning, diabetic ketoacidosis (DKA), and shock.
  • Total CO 2 concentration is mildly increased in respiratory acidosis coming as a consequence of any lung disease that prevents removal of carbon dioxide.
  • Common lung diseases that lead to respiratory acidosis include: chronic obstructive pulmonary disease, asthma, obesity hypoventilation syndrome, excessive fatigue of the diaphragm or muscles of the rib cage, or severe deformities of the spine and rib cage.
  • Total carbon dioxide in serum or plasma exists as dissolved CO 2 , carbamino derivatives of plasma protein and bicarbonate anion and these are generally acidified to covert all three forms to CO 2 gas for measurement.
  • Blood ammonia levels are used in pediatric patients for diagnosis of Reye's syndrome because blood ammonia is often elevated before liver enzymes and also in the diagnosis of certain inborn errors of metabolism. In adults, blood ammonia measurements are commonly used in management of hepatic coma and for monitoring nitrogen balance in patients being treated for hyper-alimentation.
  • a standard solution, or calibration solution with extended stability and being capable of simultaneous use in methods for determination of blood alcohol (EtOH), total serum carbonate (CO 2 ), and blood ammonia (NH 4 ) is provided which can be produced in a simple manner from easily obtainable starting materials.
  • the calibration solution according to the present invention contains only purified water as a base.
  • a key feature of the present invention is enhancing and maintaining the buffering capacity of the calibration solution by establishing pH in a range between about 7.8 and 8.6 thereby providing a multi-analyte, stabilized calibration solution containing known amounts of acidic alcohol, acidic carbonate and basic ammonia.
  • agents active against contaminating microbes may be included in the calibration solution to achieve a desired amount of stabilization.
  • agents may consist of any number of compounds which are effective against bacteria and fungi, are inert in the analytical system, and are unreactive towards components of the matrix of the calibration solution and the specific analytes contained therein.
  • Polymyxin B an antibiotic isolated from strains of Bacillus polymyxa, is added at a concentration of about 0.02 g/L; sodium pyrithione (Omadine) may be optionally added at a concentration of 0.2-0.4 g/L.
  • Polymyxin B is active mainly against bacteria and sodium pyrithione is active primarily against fungi. It may also be found useful to add a broad spectrum anti-microbial agent to reinforce the activities of the others. As an example, 0.2 g/L of a 20% aqueous solution of polyhexamethylene biguanide (Cosmocil CQ) or 0.2 g/L of streptomycin may be added as protection against both gram-positive and gram-negative bacteria. A proprietary preservative known as ProClin 300 and available from Sigma-Aldridge has also been advantageously used.
  • the specific analytes of interest are added to produce a calibrator having the desired levels of analyte therein, depending upon the particulars of the analyzer being calibrated.
  • Alcohol is preferably added in a range between 0-500 mg/dL, a range which covers the physiologically relevant concentrations found in human serum.
  • Carbonate is preferably used in a range between 0 and 50 mmol/L solution since these concentrations span the physiologically relevant range of total carbon dioxide concentrations found in human serum.
  • Ammonia is preferably used in a range between 0 and 1000 ⁇ mol/L solution since these concentrations span the physiologically relevant range of ammonia concentrations found in human serum.
  • Any combination of alcohol, carbonate and ammonia levels may be formulated in a calibration solution to achieve desired target values in a calibration solution, the only limitation being maintaining the pH level in a range between about 7.8 and 8.4.
  • FIGS. 1-3 illustrate the analyte concentration stability as measured over a 400 day period for the alcohol, carbonate and ammonia multi-analyte calibrator of the present invention.
  • FIG. 1 particularly illustrates ammonia stability as remaining within a ⁇ 3% range of a normal 1085 ⁇ mol/L ammonia value for two samples, stored in a closed container at both ⁇ 70° C. and at +4° C. As described above, the pH of the multi-analyte calibrator was adjusted to 8.2.
  • FIG. 2 particularly illustrates alcohol stability as remaining within a ⁇ 3% range of a normal 310 mg/dL alcohol value for the same two samples, stored in a closed container at both ⁇ 70° C. and at +4° C.
  • the pH of the multi-analyte calibrator was adjusted to 8.2.
  • FIG. 3 particularly illustrates carbonate stability as remaining within a ⁇ 5% range of a normal 46.5 mmol/L carbonate value for the same two samples, stored in a closed container at both ⁇ 70° C. and at +4° C.
  • the pH of the multi-analyte calibrator was adjusted to 8.2.
  • FIG. 4 illustrates the adverse effect on ammonia stability as a consequence of adjusting the pH of the alcohol, carbonate and ammonia multi-analyte calibrator of the present invention below 8.2 to 7.8.
  • ammonia stability approaches the ⁇ 3% range of a normal 1085 ⁇ mol/L value for the sample stored under normal conditions at +4° C.
  • Stability data for the sample stored under freezer conditions at ⁇ 70° C. were not completed in view of data gathered at pH 7.4 described below.
  • FIG. 5 illustrates the adverse effect on ammonia stability as a consequence of further lowering the pH of the multi-analyte calibrator to 7.4. After about 300 days, as indicated by the upwards arrow, ammonia stability falls outside the ⁇ 3% range of a normal 1085 ⁇ mol/L value for the sample stored under normal conditions at +4° C.
  • FIG. 6 illustrates the adverse effect on ammonia stability as a consequence of raising the pH of the multi-analyte calibrator above 8.2 to 8.6.
  • ammonia stability falls outside the ⁇ 3% range of a normal 1085 ⁇ mol/L value the sample stored under normal conditions at +4° C.
  • FIGS. 1-6 show that a alcohol, carbonate and ammonia multi-analyte calibrator having pH adjusted to a range between 7.8 and 8.6, centered at 8.2, as taught by the present invention, remains within acceptable stability conditions when stored at normal +4° C. in a closed container.
  • FIGS. 7 - 8 - 9 In order to emphasize this dependence of stability upon the pH of the solution and as not affected by any preservatives in the multi-analyte calibrator, accelerated, high temperature stability tests were conducted on a alcohol, carbonate and ammonia multi-analyte calibrator having pH adjusted to a range between 7.8 and 8.6, centered at 8.2, as taught by the present invention with preservatives, illustrated in FIGS. 7 - 8 - 9 . These FIGS. 7 - 8 - 9 may be compared with FIGS. 7 A- 8 A- 9 A, respectively, for the same alcohol, carbonate and ammonia multi-analyte calibrator but not having any preservatives included.
  • FIGS. 7 and 7 A illustrate alcohol stability as remaining within a ⁇ 5% range of a normal 310 mg/dL alcohol value for samples with and without preservatives, stored at both +4° C. and at +35° C.
  • the sets of data are essentially equivalent, with the exception of a probable outlier at about day 33 in FIG. 7A , indicating that the presence or absence of preservatives was not relevant.
  • FIGS. 8 and 8 A illustrate carbonate stability as remaining within a ⁇ 5% range of a normal 50 mmol/L carbonate value for samples with and without preservatives. Again, the sets of data are essentially equivalent, with the exception of a probable outlier at about day 15 in FIG. 8A .
  • FIGS. 9 and 9 A illustrate ammonia stability as falling outside a ⁇ 5% range of a normal 1085 ⁇ mol/L value for samples with and without preservatives at about day 15 for a sample stored at +35° C. but remaining generally within the a ⁇ 5% range through day 63 stored at 4° C.
  • Wearing acid gear face mask, gloves, gauntlets, and rubber apron
  • the following procedure may be employed to provide a “high level” multi-analyte calibration solution having about 5 g/L of Sodium Carbonate, 80 mg/L of Ammonium Bicarbonate, and 3 g/L of Ethyl Alcohol, these levels being about 20% higher than found in normal human serum.
  • Other, mid-range levels of sodium carbonate, ammonium bicarbonate, and ethyl alcohol may be achieved by simply adjusting the initial amounts of analyte added into the calibration solution.
  • the following procedure may be employed to provide a “zero level” multi-analyte calibration solution not having any Sodium Carbonate, Ammonium Bicarbonate, and Ethyl Alcohol therein, but useful in establishing a zero-level intercept on a calibration curve.
  • Stabilization of the multi-analyte calibration solution of the present invention having controlled and known amounts of sodium carbonate, ammonium bicarbonate, and ethyl alcohol therein may be determined using any of a number of generally accepted criteria.
  • acceptable stability is defined herein as the multi-analyte calibration solution levels of sodium carbonate, ammonium bicarbonate, and ethyl alcohol changing less than about 5% when the solution is stored in a capped container maintained at a constant temperature of about 4° C. for 400 days.
  • enzymatic carbonate (ECO 2 ) was measured using a phosphoenolpyruvate carboxylase-malate dehydrogenase coupled enzymatic reaction and a stable analog of the cofactor NADH.
  • the bicarbonate anion reacts with phosphoenolpyruvate in the presence of phosphoenolpyruvate carboxylase (PEPC) and Mg ++ to form oxaloacetate and inorganic phosphate.
  • PEPC phosphoenolpyruvate carboxylase
  • Mg ++ phosphoenolpyruvate carboxylase
  • the oxaloacetate is reduced to malate by malate dehydrogenase (MDH) with simultaneous oxidation of the reduced form of an analog (aNADH) of the cofactor, NADH.
  • MDH malate dehydrogenase
  • aNADH analog of the cofactor
  • the reduction in absorbance of aNADH is proportional to the total CO 2 concentration in the sample and is measured
  • Ammonia was measured using an adaptation of the dehydrogenase (GLDH) enzymatic method of van Anken and Schiphorst, Clin Chim Acta 1974; 56:151-157.
  • the substitution of NADPH for NADH eliminates interferences from other NADH-consuming reactions.
  • Glutamate dehydrogenase (GLDH) catalyzes the condensation of ammonia and a-ketoglutarate with simultaneous oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • Ethyl alcohol was measured using a modification of the alcohol dehydrogenase (ADH) enzymatic procedure originally described by Bonnichsen and Lundgren and later presented as a general procedure by Bergmeyer.
  • ADH alcohol dehydrogenase
  • This method uses tris (hydroxymethyl) aminomethane buffer as an aldehyde trapping agent.
  • Alcohol dehydrogenase (ADH) catalyzes the oxidation of ethanol to acetaldehyde, with the simultaneous reduction of nicotinamide adenine dinucleotide (NAD).
  • NAD nicotinamide adenine dinucleotide
  • An alkaline pH and an aldehyde trapping agent force the reaction to one mole of NADH for each mole of alcohol present.
  • the absorbance due to NADH is determined using a two-filter (340-383 nm) end-point technique.

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US10/979,664 US20060094120A1 (en) 2004-11-02 2004-11-02 Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays
PCT/US2005/038641 WO2006049999A1 (en) 2004-11-02 2005-10-25 Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays
ES05813040T ES2370753T3 (es) 2004-11-02 2005-10-25 Disolución para calibrar un analizador químico para ensayos de alcohol, carbonato y amoníaco.
EP05813040A EP1825255B1 (en) 2004-11-02 2005-10-25 Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays
US11/495,423 US7294512B2 (en) 2004-11-02 2006-07-28 Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays
US11/861,002 US20080070309A1 (en) 2004-11-02 2007-09-25 Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays

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US20060094120A1 (en) * 2004-11-02 2006-05-04 Clark Douglas P Solution for calibrating a chemical analyzer for alcohol, carbonate and ammonia assays
WO2021080598A1 (en) * 2019-10-25 2021-04-29 Instrumentation Laboratory Company Biocide compositions compatible with enzyme biosensors and methods of use thereof

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US3960497A (en) * 1975-08-19 1976-06-01 Beckman Instruments, Inc. Chemical analyzer with automatic calibration
US4278636A (en) * 1979-03-28 1981-07-14 Dragerwerk Aktiengesellschaft Calibrating device for a breath alcohol measuring instrument
US4678754A (en) * 1985-06-03 1987-07-07 Ciba Corning Corp. Liquid clinical control standard, and reagent products
US4843013A (en) * 1986-04-09 1989-06-27 Bionostics, Incorporated Multiple control standard for blood analysis
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ES2370753T3 (es) 2011-12-22
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US20060263885A1 (en) 2006-11-23

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