Patent Publication Number: US-2016223575-A1

Title: Clinical analyzer wash and method

Description:
RELATED APPLICATIONS 
     This patent arises from a continuation of U.S. application Ser. No. 14/306,961, titled “Clinical Analyzer Wash and Method,” filed Jun. 17, 2014, which is a continuation of U.S. Pat. No. 12/714,601 (now U.S. Pat. No. 8,759,106), titled “Clinical Analyzer Wash and Method,” filed Mar. 1, 2010, which is a divisional application of and claims priority to U.S. application Ser. No. 10/158,495, titled “Clinical Tester Wash and Method,” filed May 29, 2002. U.S. application Ser. Nos. 14/306,961; 12/714,601; and 10/158,495 are hereby incorporated by reference in their entireties. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure relates generally to clinical test equipment and in particular the present disclosure relates to reduction of sample carryover in clinical test equipment. 
     BACKGROUND 
     Although various known clinical analyzers for chemical, immunochemical and biological testing of samples are available, clinical technology is rapidly changing due to increasing demands in the clinical laboratory to provide new levels of service. These new levels of service must be more cost effective to decrease the operating expenditures such as labor cost and the like, and must provide shorter turnaround time of test results. Modernization of analytical apparatus and procedure demands consolidation of workstations to meet the growing challenge placed on clinical laboratories. 
     Generally, analysis of a test sample involves the reaction of test samples with one or more reagents with respect to one or more analytes wherein it is frequently desired that the analysis be performed on a selective basis with respect to each test sample. Automated clinical analysis systems analyze a test sample for one or more characteristics. Automated clinical analyzers also provide results much more rapidly while frequently avoiding operator or technician error, thus placing emphasis on accuracy and repeatability of a variety of tests. Automated clinical analyzers presently available for routine laboratory tests include a transport or conveyor system designed to transport containers of sample liquids between various operating stations. 
     Some of the presently available automated clinical analyzers, such as automated immunoassay analyzers, utilize procedures involving a variety of different assay steps. A robotic arm automatically processes the test samples with a probe and a carousel, or robotic track, which positions the samples for processing. A typical analyzer has a sample probe to sample fluids and deposit the samples in a reaction vessel. One or more reagents are added to the vessel using reagent probes. Sample and reagent probe arms include probes that can be moved between sample or reagent locations, the reagent vessel and wash stations. 
     Clinical chemistry and immunoassay analyzers have traditionally been standalone systems. These systems can be combined using a common transport system to provide a more efficient integrated system. Previous standalone chemistry analyzers did not require sample-to-sample carryover performance requirements of an integrated clinical chemistry and immunoassay system. As laboratories integrate automated analytical systems, reduction of between-sample carryover becomes a critical goal. Many companies have elected to overcome this problem through use of disposable probe tips, but this approach is costly, wasteful and less reliable. Another safeguard is to prioritize test sequencing such that immunoassay sampling is done prior to all chemistry tests. This approach impacts chemistry turnaround time and lowers total workflow throughput. Yet another method to reduce sample carryover is to flush the system with large amounts of fluids (buffer, water, detergents). 
     For the reasons stated above, and for other reasons stated below which will become apparent to those skilled in the art upon reading and understanding the present specification, there is a need in the art for a reduction in sample carryover in clinical test equipment. 
     SUMMARY 
     The above-mentioned problems with sample carryover and other problems are addressed by the present disclosure and will be understood by reading and studying the following specification. 
     In one example, a clinical analyzer comprises a probe having an interior region and an exterior surface. The probe is used to selectively aspirate a fluid into the interior region. A first wash mechanism is coupled to the probe to dispense a wash fluid through the interior region of the probe for a first predetermined period. A second wash mechanism is located to dispense the wash fluid on the exterior surface of the probe for a second predetermined period. The second predetermined period extends beyond the first predetermined period. 
     In another example, a method of cleaning a probe comprises flushing an interior region of the probe with a wash fluid for X seconds, and simultaneously flushing an exterior surface of the probe with the wash fluid for Y seconds, wherein Y is greater than X. 
     A method for reducing sample carryover in an integrated chemistry and immunoassay analyzer comprises aspirating a first test sample from a first sample container using a probe, depositing the first test sample into a reaction vessel and performing a chemical analysis of the test sample. The probe is washed by pumping a wash fluid through an interior region of the probe and pumping the wash fluid on the exterior of the probe. The pumping of the wash fluid into the interior region is terminated prior to terminating the pumping of the wash fluid to the exterior. A second test sample is then aspirated from a second sample container using the probe. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a perspective view of an example clinical analyzer; 
         FIG. 1B  is a clinical chemistry analyzer of the analyzer of  FIG. 1A ; 
         FIG. 1C  is an immunoassay analyzer of the analyzer of  FIG. 1A ; 
         FIG. 2  illustrates a probe arm of the clinical analyzer of  FIG. 1 ; and 
         FIG. 3  is a simplified cross-section of a probe in a wash station. 
     
    
    
     DETAILED DESCRIPTION 
     In the following detailed description of the preferred examples, reference is made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration specific preferred examples in which the disclosure may be practiced. These examples are described in sufficient detail to enable those skilled in the art to practice the disclosure, and it is to be understood that other examples may be utilized and that logical, mechanical and electrical changes may be made without departing from the spirit and scope of the present disclosure. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present disclosure is defined only by the claims. 
     The term “test sample”, as used herein, refers to a test material that can be used directly as obtained from a source or following a pretreatment to modify the character of the sample. The test sample can be derived from any biological source, such as physiological fluid, including, whole blood, serum, plasma, saliva, ocular lens fluid, cerebral spinal fluid, sweat, urine, milk, ascites fluid, raucous, synovial fluid, peritoneal fluid, amniotic fluid or the like. 
     The term “carryover” refers to cross-contamination or contact transfer between test samples. Carryover is a byproduct of using a common sample probe for multiple test samples. 
     Between-sample carryover is a critical factor to ensure result integrity on automated analytical systems. Immunoassay analyzers traditionally meet a sample-to-sample carryover goal of less than 0.1 ppm. Clinical chemistry systems utilize methodologies that are less sensitive and rarely characterized using carryover requirements to this level. As laboratories consolidate analytical systems, however, the between-sample carryover demands for immunoassay analyzers become applicable to clinical chemistry systems as well. Achieving a between-sample carryover goal of less than 0.1 ppm for an integrated immunoassay and clinical chemistry system can impact marketability of other variables including specimen throughput, system consumables, test prioritization, and sample pre-aliquoting. 
     Extensive research on an integrated system of an example of the present disclosure identified critical variables associated with sample-to-sample carryover. High-speed video was used for qualitative characterization of the sample probe wash while concentrated samples of hepatitis surface-antigen (HbsAg) were used to quantitatively assess carryover performance. A probe wash protocol of an example of the disclosure passes the between-sample carryover limit of 0.1 ppm without sample pre-aliquoting, use of additional consumables, test prioritization, or significant impact to system specimen throughput. Critical variables include clinical chemistry sampling/aspiration volumes and external sample probe wash duration, sequencing relative to the internal sample probe wash. Other variables include positioning of the sample probe within the sample wash cup, sample wash cup design and external sample wash flow volumes/rates. 
     An example of a wash protocol dictates the between sample wash mechanism based on clinical chemistry sampling volume. The wash includes an external wash and an internal wash of the sample probe. All specimens with a maximum chemistry sampling volume below a predetermined threshold (such as 15 μL or less) are effectively washed using an extended single cycle wash mechanism. It is noted that a ‘dummy’ fluid volume may be aspirated in addition to the fluid sample volume. The dummy volume provides a buffer between the sample fluid and residual fluid in the probe. The dummy volume is not included in the sample volume levels described herein. The extended single cycle wash mechanism utilizes a one second external probe wash that ends 100 ms after the internal probe wash. This timing relationship between the internal and external wash sequencing is particularly crucial for acceptable carryover performance. Specimens that are processed with chemistry sampling volumes exceeding the threshold (15.1 μL or more) are washed using the same extended single cycle wash mechanism but also undergo an additional 3.2 seconds of supplemental external wash. The wash protocol of the present disclosure, as explained below, is not limited to a specific timing duration or over-lap time between the termination of internal and external washes. 
     Between-Sample Carryover was quantitatively evaluated using recombinant samples of concentrated hepatitis surface-antigen (HbsAg) in a pooled human serum matrix. Each concentrated HBsAg sample (with approximate immuno-reactivity of 4 mg/mL) was followed by pooled normal human serum (pre-screened non-reactive for HbsAg) and processed on a chemistry analyzer. The pooled human serum samples were evaluated on an immunoassay analyzer for HbsAg activity. Results were compared against serial dilutions of the concentrated stock. If the pooled human serum results exceeded that of the 0.1 ppm dilution of the concentrated stock, a test run was considered a failure. The magnitude of the failure was calculated by converting the reported concentration of the serum diluents into units of ppm from the reference dilution. Test conditions were created to represent worst-case performance and test result confidence. The clinical chemistry sample volume was defined at 35 μL, a typical maximum sample volume for a chemistry application. HbsAg samples were processed in duplicate to ensure result integrity. 
     Results demonstrated a sample carryover performance trend associated with sample probe aspiration volume. As the clinical chemistry sample volume increases, between-sample carryover failures also increase. Most systems fail between-sample carryover with a frequency higher than 50% (without optimization critical parameters) at the maximum clinical chemistry sampling volume of 35 μL. The relationship between sample volume and sample-to-sample carryover performance is significant to understanding the mode of failure. This is because trending demonstrates that internal contamination of the sample probe has an impact on sample-to-sample carryover. The sample probe aspirates a test sample from a sample tube and immediately dispenses the sample volume into a reaction vessel prior to entrance into a wash station. An over-aspiration or dummy volume is dispensed at the wash station but this volume is consistent and independent of chemistry sample volume (under the protocol test conditions). Since the frequency of the carryover increases with chemistry sample volume and since this sample volume is dispensed prior to external wash of the probe, it was theorized that the source of the carryover (leading to the between-sample failures) resulted from internal contamination of the sample probe. This theory was supported by a supplemental investigation that demonstrated that carryover failures were still prevalent without any dummy/over aspiration being dispensed at the sample wash station. Residual carryover remained on the external surface of the sample probe following sample probe washing, even when the probe did not dispense any concentrated sample at the wash station. The frequency of sample carryover failures can be reduced using supplemental probe washes. Unfortunately, supplemental washes require additional instrument cycles that can degrade system specimen throughput. 
     A second variable to carryover performance is wash sequencing at the sample wash station. Further analysis of wash conditions at the sample wash station lead to a study evaluating external wash sequencing relative to the internal wash. Success of the probe wash was less dependent on the external wash duration than it was on the stop sequencing of the external wash relative to the internal wash. If the internal wash stops after the external wash, carryover performance is significantly worse than if the external wash if ends after the internal wash. This relationship supports a theory that internal contamination of the probe is a source for the external between-sample carryover. One wash protocol utilizes a one second external probe wash that extends beyond the stop time of the internal wash to improve carryover performance at low sample volumes. A supplemental washing that would have required an additional instrument cycle is not required to meet carryover performance criteria. 
     Further studies demonstrated additional variables associated with between-sample carryover performance. These include wash cup design, hardware alignment at the sample wash station, and wash flow rates/volume. These variables are significant and require optimization for carryover performance. Failure to optimize these parameters can cause carryover failures. However, optimization, of these parameters will not create a passing condition without control of the critical variables of chemistry sampling volume and wash sequencing. 
     Referring to  FIG. 1A , a perspective view of a simplified integrated clinical test system  100  of an example of the present disclosure. The test system includes a clinical chemistry analyzer  102  and an immunoassay analyzer  104 , see  FIGS. 1B and 1C  for more detail. The two analyzers share a common sample transporter  106  that allows linear movement of test sample tubes  108  between the two analyzers. 
     Each analyzer has a sample probe arm  110 / 112  that includes a sample probe  114  (see  FIG. 2 ). The sample probe arms  110 / 112  can move in both a horizontal arc and vertical directions. The sample probe  114  aspirates a test sample from tube  108  located on the transporter  106 . The sample probe  114  is then moved to a sample vessel (not shown) and deposits the aspirated sample. After the sample has been discharged from the sample probe  114 , the sample probe arm  110 / 112  moves to a wash station  120  where the sample probe  114  is washed. The sample vessel is moved to a location where a reagent is added to the sample by a reagent probe of a reagent probe arm  122 . The reagent probe arm  122  is movable between a reagent location, the sample vessel and the wash station. The sample vessel may receive additional reagents and is then subjected to chemistry testing, as known to those skilled in the art. A second reagent probe of a second reagent probe arm  123  can be included to provide a second reagent to the sample vessel. 
     The sample tube  108  located on the transporter  106  is then moved to a location near the immunoassay analyzer  104 ,  FIG. 1C . The immunoassay analyzer is similar in operation to the clinical chemistry analyzer in that a test sample from the sample tube is aspirated using sample probe  114  of sample probe arm  110 / 112 . The sample probe arm  110 / 112  then moves to a sample vessel (not shown) and the sample probe  114  deposits the aspirated sample. After the sample has been discharged from the sample probe  114 , the sample probe arm  110 / 112  moves to a wash station (not shown) where the sample probe  114  is washed. The sample vessel is moved to a location where a reagent is added to the sample by a reagent probe of a reagent probe arm  115 . The reagent probe arm  115  is movable between a reagent location, the sample vessel and the wash station. The sample vessel may receive additional reagents and is then subjected to testing, as known to those skilled in the art. It is clear that sample carryover, or contamination, can occur if the sample probes  114  are not cleaned between aspirations of different test samples. 
       FIG. 2  illustrates a sample probe arm  110 . The sample probe arm  110  includes a sample probe  114  that can be moved about a horizontal arc and in a vertical direction. The sample probe  114  has a hollow bore that allows aspiration of a fluid and the subsequent introduction of a wash fluid. The mechanics of the sample probe arm  110  are not described in detail herein, but are generally known to those skilled in the art. For purposes of understanding the disclosure, the sample probe arm  110  is controllable to regulate the amount of sample aspirated and the amount and duration of wash fluid that flows through the sample probe  114 . 
     Referring to  FIG. 3 , a cross-sectional view of a sample probe  114  and wash cup  126  are illustrated. The size and shape of the sample probe  114  and wash cup  126  are illustrative only and not intended to reflect actual designs or sizes. Those skilled in the art with the benefit of the present description will appreciate that the designs of the sample probe  114  and wash cup  126  can vary without departing from the present disclosure. The sample probe  114  is substantially tube-shaped and includes an exterior surface  132  and an interior surface  130 . An interior wash dispenser  136 , or nozzle, is located to discharge a wash fluid into the interior region of the sample probe  114 . During a wash operation, the sample probe  114  is vertically positioned in the wash cup  126 . The wash cup  126  includes one or more exterior wash dispensers  138 , or nozzles, positioned to spray a wash fluid toward a center region of the wash cup  126  and onto the exterior surface  132  of the sample probe  114 . 
     The wash fluid pumped through the interior region of the sample probe  114  and on its exterior surface  132  is the same fluid and depends upon the material that is to be removed from the sample probe  114 . The wash fluid can be located in a common reservoir  140  and pumped to the nozzles using separate pumps  142  and  144 . Alternately, a single pump and controllable valves can be used to pump the wash fluid to the nozzles. The present disclosure is not limited to a specific pump design, provided the termination of the flow of the internal fluid and the external fluid can be separately controlled by pump(s) controller  150 . The term ‘pump’ is intended to include any mechanism that allows for controlled movement of a liquid, such as the wash fluid. 
     As explained above, a given probe needs to be sufficiently cleaned between aspirations to reduce liquid carryover. The liquid carryover can be that of a test sample or a reagent depending upon the probe. The internal wash is terminated prior to terminating the external wash. This termination overlap significantly reduces liquid carryover and allows clinical chemistry analyzers to meet the restrictive specifications of immunoassay analyzers. One example wash for chemistry sampling volume below a predetermined threshold (such as 15 μL or less) includes a one second external sample probe wash that ends 100 ms after the internal sample probe wash ends. The external wash can begin prior to the internal wash without departing from the present disclosure. 
     The present disclosure is not limited to an integrated clinical chemistry/immunoassay analyzer, and other analytical systems can utilize the relationship of between-sample carryover performance to improve sample wash parameters. This includes other clinical chemistry and immunoassay systems as well as hematology and other methodologies. The wash method can also be used utilized for reagent carryover washing, sample pretreatment instrumentation, and with laboratory automation systems. 
     CONCLUSION 
     A clinical analyzer has been described that includes a probe to aspirate a fluid. The probe is washed between aspirations to reduce carryover. The wash operation includes both an internal and an external wash, where the internal wash operation is terminated prior to terminating the external wash. In one example, the probe wash can be implemented on an integrated clinical chemistry/immunoassay analyzer. 
     Although specific examples have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that any arrangement, which is calculated to achieve the same purpose, may be substituted for the specific example shown. This application is intended to cover any adaptations or variations of the present disclosure. Therefore, it is manifestly intended that this disclosure be limited only by the claims and the equivalents thereof.