Patent ID: 12235250

DETAILED DESCRIPTION OF THE INVENTION

A chemical production module, dose synthesis module, and HPLC-based quality control module for a PET biomarker radiopharmaceutical production system are described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided to ensure that this disclosure is thorough and complete, and to ensure that it fully conveys the scope of the invention to those skilled in the art.

Thus, in some embodiments of an HPLC-based quality control testing system according to the present general inventive concept, the system comprises an injection valve to direct the flow of a sample radiopharmaceutical solution within the system; a sample radiopharmaceutical solution syringe-pump to direct the sample radiopharmaceutical solution to said injection valve; a high performance liquid chromatography pump to direct a mobile phase solvent to said injection valve; a pH detector to measure the pH of the sample radiopharmaceutical solution; a first sample collection vessel to receive a first aliquot of the sample radiopharmaceutical solution from said injection valve, said first sample collection vessel to hold the first aliquot of the sample radiopharmaceutical solution for measurement of the radioactivity of the sample radiopharmaceutical solution; a second sample collection vessel to receive a second aliquot of the sample radiopharmaceutical solution from said injection valve, said second sample collection vessel to hold the second aliquot of the sample radiopharmaceutical solution for endotoxicity testing; an endotoxin detector to perform endotoxicity testing on the second aliquot of the sample radiopharmaceutical solution held in said second sample collection vessel (in some embodiments, this endotoxin detector includes a kinetic hemocyte lysate-based assay); a fixed-volume fluid loop in fluid communication with said injection valve, said fixed-volume fluid loop to receive a third aliquot of the sample radiopharmaceutical solution from said injection valve; a high performance liquid chromatography column to receive the third aliquot of the sample radiopharmaceutical solution, said high performance liquid chromatography column to separate molecularly distinct species within the third aliquot of the sample radiopharmaceutical solution into a number of separated molecularly distinct species; a refractive index detector to measure the amount of each separated molecularly distinct species from said high performance liquid chromatography column; an ultraviolet-light detector to measure the optical qualities of the third aliquot of the sample radiopharmaceutical solution; and a radiation detector, said radiation detector including at least two radiation probes, said at least two radiation probes including: a first radiation probe to measure the radioactivity of the first aliquot of the sample radiopharmaceutical solution held in said first sample collection vessel; and a second radiation probe to measure the radioactivity of each separated molecularly distinct species from said high performance liquid chromatography column. Further, in some embodiments, the ultraviolet-light detector measures the optical qualities of the third aliquot of the sample radiopharmaceutical solution before the third aliquot of the sample radiopharmaceutical solution enters said high performance liquid chromatography column.

In some of the example embodiments described below, a chemical production module, dose synthesis module, and HPLC-based quality control module operate in conjunction with a complete PET biomarker production system. In one example embodiment of the present general inventive concept, illustrated inFIG.1, a PET biomarker production system comprises an accelerator10, which produces the radioisotopes; a chemical production module (or CPM)20; a dose synthesis module (or DSM)30; and an HPLC-based quality control module (or QCM)50. Once the accelerator10has produced a radioisotope, the radioisotope travels via a radioisotope delivery tube112to the DSM30attached to the CPM20. The CPM20holds reagents and solvents that are required during the radiopharmaceutical synthesis process. In the DSM30, the radiopharmaceutical solution is synthesized from the radioisotope and then purified for testing and administration. Following synthesis and purification, a portion (the “sample portion”) of the resultant radiopharmaceutical solution is transported by way of a quality-control transfer line400to the QCM50, and another portion flows into a dose vessel200. Within the QCM50, a number of diagnostic instruments perform automated quality control tests on the sample portion.

FIG.2shows a flow diagram of one example embodiment of a dose synthesis module according to the present general inventive concept. In this embodiment, the radioisotope involved is flourine-18 (F-18), produced from the bombardment in a cyclotron of heavy water containing the oxygen-18 isotope. However, the present general inventive concept also embraces radiopharmaceutical synthesis systems generating and using other radioisotopes, including carbon-11, nitrogen-13, and oxygen-15.

As shown inFIG.2, the radioisotope enters a reaction chamber or reaction vessel110from the radioisotope delivery tube112. At this stage, the radioisotope F-18 is still mixed with quantities of heavy water from the biomarker generator. A number of other reagents and substances are introduced into the reaction vessel110by way of several inputs, including, in some embodiments, some or all of the following: a first organic reagent input120, a second organic reagent input122, an aqueous input130, and a gas input. In some embodiments, after the radioisotope enters the reaction vessel110from the radioisotope delivery tube112, a first organic ingredient is introduced to the reaction vessel110from the first organic reagent input120. In some embodiments, the first organic ingredient includes a solution of potassium complexed to 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane (commonly called Kryptofix 222™, hereinafter “kryptofix”) or a similar crown ether. In many embodiments, the potassium-kryptofix complex or similar organometallic complex is carried by acetonitrile as solvent. The potassium activates the F-18 fluoride radioisotope, while the kryptofix binds the potassium atoms and inhibits the formation of a potassium-fluoride complex. Next, the gas input140fills the reaction vessel110with an inert gas such as dry nitrogen. Then, the mixture in the reaction vessel110is heated by to remove residual heavy water by evaporating the azeotropic water/acetonitrile mixture. In some embodiments, a vacuum helps to remove the vaporized water. Next, the second organic input122adds a second organic ingredient to the mixture in the reaction vessel110. In many embodiments, the second organic ingredient is mannose triflate in dry acetonitrile. The solution is then heated at approximately 110 degrees Celsius for approximately two minutes. By this stage, the F-18 has bonded to the mannose to form the immediate precursor for [18F]FDG, commonly 18F-fluorodeoxyglucose tetraacetate (FTAG). Next, aqueous acid—in many embodiments, aqueous hydrochloric acid—is introduced through the aqueous input130. The hydrochloric acid removes the protective acetyl groups on the18F-FTAG, leaving18F-fludeoxyglucose (i.e. [18F]FDG) in what may now be called the synthesized, pre-purified radiopharmaceutical solution.

The [18F]FDG having been synthesized, it must be purified before testing and administration. The [18F]FDG in solution passes from the reaction vessel110through a solid phase extraction column160. In some embodiments of the present invention, the solid phase extraction column160comprises a length filled with an ion exchange resin, a length filled with alumina, and a length filled with carbon-18.

Once the now-purified radiopharmaceutical solution has exited the solid phase extraction column160, the radiopharmaceutical solution is collected in a product collection vial210. In many embodiments, the product collection vial210includes a vent285to allow air or gas to escape the product collection vial210as the product collection vial210fills with radiopharmaceutical solution. The production collection vial210collects all of the purified radiopharmaceutical solution as a single bolus before portions of the purified radiopharmaceutical solution are distributed to other destinations as described infra. From the product collection vial210, a first portion of the purified radiopharmaceutical solution is directed through a quality-control transfer line400to a QCM50. From the product collection vial210, a second portion of the purified radiopharmaceutical solution is directed through a sterile filter170and through a first post-sterile-filter pathway into a sterility sample vial230. A first part of the second portion of the purified radiopharmaceutical solution in the sterility sample vial230remains in the sterility sample vial230, and a second part of the second portion of the purified radiopharmaceutical solution in the sterility sample vial230travels by way of a second post-sterile-filter pathway into a product injection vial250. The second part of the second portion of the purified radiopharmaceutical solution collected in the product injection vial250is generally the radiopharmaceutical solution that will be administered to one or more patients. In many embodiments, the second part of the second portion of the purified radiopharmaceutical solution collected in the product injection vial250constitutes a majority of the radiopharmaceutical solution produced in the synthesis process.

As described, a second portion of the purified radiopharmaceutical solution is directed through a sterile filter170before passing through a first post-sterile-filter pathway into the sterility sample vial230. In some embodiments, the integrity of the filter170is tested by passing inert gas through the filter170at increasing pressure. A pressure sensor measures the pressure of the inert gas upon the filter170and detects whether the filter170is still intact. In some embodiments, the filter170is expected in to be capable of maintaining integrity under pressures of at least 50 pounds per square inch (psi).

FIG.3displays a schematic view of one example embodiment of a dose synthesis module (DSM)30′. The DSM30′ includes a reaction vessel110awhere the radiopharmaceutical solution is synthesized. A radioisotope input112aintroduces the radioisotope F-18 into the reaction vessel110athrough a radioisotope input channel1121. At this stage, the radioisotope is still mixed with quantities of heavy water from the biomarker generator. Next, an organic input124aintroduces a solution of potassium-kryptofix complex in acetonitrile into the reaction vessel110athrough an organic input channel1241. A combination nitrogen-input and vacuum154pumps nitrogen gas into the reaction vessel110athrough a gas channel1540aand a valve1541, which valve is at that time in an open position. The mixture A in the reaction vessel110ais heated in nitrogen atmosphere to azeotropically remove water from the mixture A, the vaporized water being evacuated through the gas channel1540aand the vacuum154. Next, the organic input124aintroduces mannose triflate in dry acetonitrile into the reaction vessel110athrough the organic input channel1241. The solution is heated at approximately 110 degrees Celsius for approximately two minutes. By this stage, the F-18 has bonded to the mannose to form the immediate precursor for [18F]FDG, FTAG. Next, aqueous hydrochloric acid is introduced into the reaction vessel110athrough an aqueous input132aand an aqueous channel1321. The hydrochloric acid removes the protective acetyl groups on the intermediate18F-FTAG, leaving18F-fludeoxyglucose (i.e. [18F]FDG).

Having been synthesized, the [18F]FDG in solution passes from the reaction vessel110athrough a post-reaction channel1101into a solid phase extraction column160a, where some undesirable substances are removed from the solution, thereby clarifying the radiopharmaceutical solution. In some embodiments of the present invention, the solid phase extraction (SPE) column160acomprises a length with an ion exchange resin, a length filled with alumina, and a length filled with carbon-18. The radiopharmaceutical passes through the SPE column160awith a mobile phase that in many embodiments includes acetonitrile from the organic input124a. As some of the mobile phase and impurities emerge from the SPE column160a, they pass through a second post-reaction channel1542and through a three-way valve175and waste channel1104into a waste receptacle220. As the clarified radiopharmaceutical solution emerges from the SPE column160a, the radiopharmaceutical solution next passes through the second post-reaction channel1542and through the three-way valve175into a filter channel1103and then through a filter170a. The filter170aremoves other impurities (including particulate impurities), thereby further clarifying the radiopharmaceutical solution. In some embodiments the filter170aincludes a Millipore filter with pores approximately 0.22 micrometers in diameter.

Once the radiopharmaceutical solution has passed through the filter170a, the clarified radiopharmaceutical solution travels via the post-clarification channel1105into the sterile dose administration vessel200a, which in the illustrated embodiment is incorporated into a syringe202. In some embodiments, the dose administration vessel is filled beforehand with a mixture of phosphate buffer and saline. As the clarified radiopharmaceutical solution fills the sterile dose administration vessel200a, a sample portion of the solution B is diverted through an extraction channel1401to the quality-control transfer line400.

After the sample portion of the solution passes into the quality-control transfer line400, any excess solution remaining in the dose administration vessel200ais extracted by a vent156through a first venting channel1560band thence conveyed through an open valve1561and through a second venting channel1560ainto the waste receptacle220. The vacuum154evacuates residual solution from the transfer channel1402through a now-open valve1403and a solution evacuation channel1540b.

In some embodiments of the present invention, the CPM20holds sufficient amounts of reagents and solvents that are required during the radiopharmaceutical synthesis process to carry out multiple runs without reloading. Indeed, in some embodiments the CPM20is loaded with reagents and solvents approximately once per month, with that month's supply of reagents and solvents sufficient to produce several dozen or even several hundred doses of radiopharmaceutical. As the reagents and solvents are stored in the CPM20, it is easier than under previous systems to keep the reagents and solvents sterile and uncontaminated. In some embodiments, a sterile environment is supported and contamination inhibited by discarding each DSM30after one run; and thus in these embodiments the DSM30is adapted to be disposable.

Thus, each batch of reagents and solvents, loaded periodically into the CPM20, will supply a batch of multiple doses of radiopharmaceutical, each dose produced in a separate run. Some quality control tests are performed for every dose that is produced, while other quality control tests are performed for every batch of doses. For example, in one embodiment of the present invention, the filter integrity test, the color and clarity test, the acidity test, the volatile organics test, the chemical purity test, and the radiochemical purity test are performed for every dose. On the other hand, some quality control tests need be performed only once or twice per batch, such as the radionuclide purity test (using a radiation probe to measure the half-life of the F-18 in the [18F]FDG), the bacterial endotoxin test, and the sterility test. These tests are performed generally on the first and last doses of each batch. Because these per-batch quality control tests are conducted less frequently, they may not be included in the QCM, but rather may be conducted by technicians using separate laboratory equipment.

FIG.4shows a flow chart illustrating one example embodiment of an HPLC-based QCM50according to the present general inventive concept. The example embodiment of an HPLC-based QCM50illustrated inFIG.4is to test a first portion of purified radiopharmaceutical solution (hereinafter “the sample radiopharmaceutical solution” or simply “sample”) from a DSM. As shown inFIG.4, in some embodiments an HPLC-based QCM50according to the present general inventive concept includes an HPLC pump503, which draws mobile phase solvent from a mobile phase solvent reservoir509and through a degasser504; a syringe-pump assembly520to load into the HPLC-based QCM50the sample radiopharmaceutical solution from a quality-control transfer line400; an HPLC column515; an injection valve516; and fixed volume fluid loop517. In some embodiments, including the example embodiment illustrated inFIG.4, the HPLC-based QCM50according to the present general inventive concept includes a radiation detector522with one or more radiation probes; in the illustrated example embodiment shown inFIG.4, the radiation detector522includes at least one radiation probe542. Further, in some embodiments, the HPLC-based QCM50includes an UV/VIS detector502to test the optical qualities of the sample. In some embodiments, the HPLC-based QCM50includes an RI detector505to test the radionuclidic identity of the sample.

In the normal operation of one example embodiment of the present general inventive concept, as illustrated inFIGS.4and5, a sample radiopharmaceutical solution enters the syringe-pump assembly520from the quality-control transfer line400. Within the syringe-pump assembly520, the sample radiopharmaceutical solution is stored within a syringe525. Then, a portion of the sample radiopharmaceutical solution is propelled by the syringe525or a similar mechanism and thereby is loaded, in a steady, even, and substantially reproducible manner, into a first QCM pathway527. In some embodiments, the syringe-pump assembly520draws water or other solvent, such as LAL reagent water, from a reagent water reservoir501. The sample radiopharmaceutical solution moves through the first QCM pathway527and passes through a first injection valve line561to enter the injection valve516. Another portion of the sample radiopharmaceutical solution within the syringe525is directed within the syringe-pump assembly520to enter a second QCM pathway523; this second portion of the sample radiopharmaceutical solution passes through the second QCM pathway523into an endotoxin testing sample vessel521. Any remainder third portion of the sample radiopharmaceutical solution within the syringe525is directed within the syringe-pump assembly520to enter a third QCM pathway529, which conveys the remainder third portion of the sample radiopharmaceutical solution to a waste vessel507.

In some embodiments, in the normal course of conducting quality control tests on the sample radiopharmaceutical solution, an aliquot of the sample radiopharmaceutical solution is tested for endotoxicity. In some embodiments, sample aliquot collected in the test vial521is tested for endotoxicity by diluting the sample aliquot and subjecting the diluted sample aliquot to an endotoxicity test. In some embodiments, the endotoxicity test is conducted by an automated endotoxin detector. In some embodiments, the endotoxicity test is conducted by an automated endotoxin spectrophotometer. In some embodiments, the endotoxicity test comprises the use of a kinetic hemocyte lysate-based assay for the detection and quantification of microbial contaminants. In some embodiments, other forms of endotoxicity tests are used.

As illustrated inFIGS.4and5, there are six fluid-carrying lines that lead into or out of the injection valve: the first injection valve line561, the second injection valve line562, the third injection valve line563, the fourth injection valve line564, the fifth injection valve line565, the sixth injection valve line566.

The first injection valve line561conveys the sample radiopharmaceutical solution from the syringe-pump assembly520into the injection valve516.

The second injection valve line562conveys solution from the injection valve516to a pH detector513. In some embodiments, the pH detector513includes a solid state detector. In some embodiments, the pH detector513includes an in-line solid state pH detector. After the solution passes through the pH detector513, the solution is directed to the waste vessel507.

The third injection valve line563conveys to the injection valve516mobile phase solvent drawn by the HPLC pump503from the mobile phase solvent reservoir509through the degasser504. The fourth injection valve line564conveys fluid from the injection valve516to the HPLC column515.

The fifth injection valve line565conveys fluid from the injection valve516into the fixed-volume fluid loop517, and the sixth valve line566conveys fluid from the fixed-volume fluid loop517into the injection valve516. Thus, three of the injection valve lines561,563, and566are input lines, and three of the injection valve lines562,564, and565are output lines.

In various embodiments, the injection valve516directs incoming fluid (generally the sample radiopharmaceutical solution or the mobile phase solvent) from an input line to an output line.FIGS.4and5show the injection valve516in two different states. In the first state (also called State A), shown inFIG.4, the injection valve516is positioned such that a channel within the injection valve516directs fluid from the first injection valve line561to the second injection valve line562; that is, in State A, sample radiopharmaceutical solution passes from the first QCM pathway527, through the first injection valve line561, through the injection valve516, and then through the second injection valve line562to the pH detector513. In State A, mobile phase solvent from the HPLC pump503passes through the third injection valve line563into the injection valve516. Within the injection valve516, mobile phase solvent from the third injection valve line563is directed into the fifth injection valve line565and then into the fixed-volume fluid loop517. The mobile phase solvent within the fixed-volume fluid loop517continues through the sixth injection valve line566back into the injection valve516, where the mobile phase solvent is directed into the fourth injection valve line564and thereafter conveyed to the HPLC column515.

During the quality control testing process, at a point where sample radiopharmaceutical solution is flowing from the syringe-pump assembly520through the pH detector501and through the first injection valve line561, the injection valve516is rotated 60 degrees into the second state (or State B), shown inFIG.5. In State B, the sample radiopharmaceutical solution passes from the first injection valve line561, through the injection valve516, and then into the fifth injection valve line565; from the fifth injection valve line565, the sample radiopharmaceutical solution enters the fixed-volume fluid loop517. As fluid continues to flow while the injection valve516is in State B, sample radiopharmaceutical solution flowing through the fixed-volume fluid loop517exits the fixed-volume fluid loop517and re-enters the injection valve516through the sixth injection valve line566; the sample radiopharmaceutical solution is then directed into the second injection valve line562, and the sample radiopharmaceutical solution passes through the second injection valve line562to the pH detector513and the waste vessel507.

While sample radiopharmaceutical solution is flowing through the fixed-volume fluid loop517, the injection valve516is rotated a second time, so that the injection valve is again in State A (as inFIG.4). At this point in time, mobile phase solvent from the HPLC pump503passes through the third injection valve line563and into the injection valve516; within the injection valve516, the mobile phase solvent from the third injection valve line563is directed into the fifth injection valve line565. The mobile phase solvent within the fifth injection valve line565enters the fixed-volume fluid loop517, pushing the sample radiopharmaceutical solution within the fixed-volume fluid loop517out of the fixed-volume fluid loop517and through the sixth injection valve line566into the injection valve516. Within the injection valve516, the sample radiopharmaceutical solution from the fixed-volume fluid loop517is directed into the fourth injection valve line564. (In some embodiments, the fixed-volume loop517has a volume of approximately 20 microliters. However, those of skill in the art will recognize that other volumes the fixed-volume loop517are possible and are contemplated by the present invention.)

Conveyed along the fourth injection valve line564, the sample radiopharmaceutical solution from the fixed-volume fluid loop517passes by a radiation probe542, which is part of or connected to a radiation detector522. Next, the sample radiopharmaceutical solution passes by or through a UV/VIS detector502to test the optical clarity of the sample radiopharmaceutical solution. In some embodiments, the UV/VIS detector502comprises a ultra-violet and visible light spectrometer. In some embodiments, the UV/VIS detector502comprises a UV spectrophotometer. In some embodiments, the UV/VIS detector502comprises a UV spectrophotometer with a deuterium light source. In some embodiments, the UV/VIS detector502comprises a UV spectrophotometer with a tungsten-halogen light source. In some embodiments, the UV/VIS detector502comprises a UV spectrophotometer like the Smartline UV Detector 2500, manufactured by KNAUER. In some embodiments, the HPLC-based QCM50includes a detector comprises a spectrophotometer that detects a range of the electromagnetic spectrum that includes infrared light. In some embodiments, the HPLC-based QCM50includes multiple detectors, including, in some embodiments, multiple UV/VIS detectors or, in some embodiments, multiple spectrophotometers or spectrometers.

In some embodiments, the UV/VIS detector502tests the sample radiopharmaceutical solution for the presence of residual Krypotofix. Generally, a purified radiopharmaceutical solution will be considered to pass quality control testing for Kryptofix if the residual concentration of Kryptofix in the final product is less than or equal to 50 micrograms per milliliter solution.

In some embodiments, the radiopharmaceutical solution from the fixed-volume fluid loop517passes by or through the UV/VIS detector502before entering the HPLC column515, as shown inFIG.4. In some embodiments, the radiopharmaceutical solution from the fixed-volume fluid loop517passes by or through a UV/VIS detector after entering and passing though the HPLC column515.

In the illustrated example embodiment shown inFIG.4, after passing by or through the UV/VIS detector502, the sample radiopharmaceutical solution passes into the HPLC column515. The HPLC column515separates [18F]FDG within the sample radiopharmaceutical solution from any other radioactive products or other organic impurities. In this way, the HPLC column515assists testing the radiochemical identity of the sample radiopharmaceutical solution—that is, the HPLC column515helps to identify the ratio of [18F]FDG (or other desired radiopharmaceutical compound) to other radioactive products (such as free F-18 ion and [18F]FTAG). The HPLC column515separates the [18F]FDG from other compounds based on their different retention time, making possible the identification of the [18F]FDG based on retention time and allowing other instruments to analyze the [18F]FDG separately from other compounds. Thus, in some embodiments, after exiting the HPLC column515, the sample radiopharmaceutical solution passes through a refractive index detector (RI detector)505. The RI detector505detects, measures and quantifies the presence of compounds as they are eluted from the HPLC column515. [18F]FDG is identified based on its retention time, as are other compounds present in the sample radiopharmaceutical solution. In general, [18F]FDG has a slightly shorter retention time compared to FDG that lacks a radioisotope. In some embodiments, the radiochemical purity of the separated [18F]FDG within the sample radiopharmaceutical solution is also measured after the elution of the separated [18F]FDG within the sample radiopharmaceutical solution from the HPLC column515.

In many embodiments, the RI detector505also measures the residual concentration in the sample radiopharmaceutical solution of solvents such as acetonitrile and ethanol. Generally, a purified radiopharmaceutical solution will be considered to pass quality control testing if the residual concentration of acetonitrile in the sample radiopharmaceutical solution is less than or equal to 400 ppm.

In some embodiments, an HPLC-based QCM50according to the present general inventive concept includes a radiation detector522with at least one radiation probe542. As shown inFIGS.4and5, the radiation probe542measures the radioactivity of the separated [18F]FDG within the sample radiopharmaceutical solution eluted from the HPLC column515. The radiation probe542also measures the radioactivity of other radioactive products (such as free F-18 ion and [18F]FTAG) eluted from the HPLC column515.

Generally, after the sample radiopharmaceutical solution is eluted from the HPLC column515and tested for radiochemical identity, radiochemical purity, and the presence of residual impurities, the sample radiopharmaceutical solution is conveyed to the waste vessel507. In some embodiments, HPLC-based QCM50according to the present general inventive concept also includes, on the line carrying the sample radiopharmaceutical solution from the HPLC column515to the waste vessel507, a backpressure valve506.

The present general inventive concept comprises an HPLC-based quality control system for conducting a number of automated tests on a radiopharmaceutical solution, and in particular on a synthesized and purified radiopharmaceutical solution for use in positron emission tomography. An HPLC-based quality control system according to the present general inventive concept provides a quality control testing system that makes efficient use of sample volume. The present general inventive concept is compatible with and able to test a variety of radioisotopes and radiopharmaceutical compounds. Further, the automated nature of an HPLC-based quality control system according to the present general inventive concept allows for quality control tests to be conducted quickly and with minimal impact on user workflow; the automated system relieves a technician from having to perform a number of the quality control tests. Overall, and especially when used as part of an integrated PET biomarker radiopharmaceutical production system as described above, the present general inventive concept permits a radiopharmaceutical manufacturer to produce product and conduct quality control tests on the product with lower per dose costs.

While the present invention has been illustrated by description of one embodiment, and while the illustrative embodiment has been described in detail, it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail. Additional modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and methods, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of applicant's general inventive concept.