Source: https://patents.justia.com/patent/8247018
Timestamp: 2019-06-24 08:49:24
Document Index: 635783849

Matched Legal Cases: ['Application No. 60', 'arts 0', 'arts 3', 'arts 0', 'arts 4', 'arts 0', 'arts 5', 'arts 1', 'art 6', 'arts 1', 'arts 7', 'arts 1', 'arts 8', 'arts 1']

US Patent for Methods for quality control Patent (Patent # 8,247,018 issued August 21, 2012) - Justia Patents Search
Justia Patents Medical Or Dental Purpose Product; Parts; Subcombinations; Intermediates (e.g., Balloon Catheter, Splint)US Patent for Methods for quality control Patent (Patent # 8,247,018)
Dec 20, 2006 - Authentiform Technologies, LLC
The present invention relates to method for quality control of surface coated objects used independently or in conjunction with product authentication; methods for assuring proper product handling; methods for assuring that product contents' match product's label, comprising the use of microparticulate taggants having different detectable physical properties, wherein each combination of properties is used as an encoding bit to create codes.
Latest Authentiform Technologies, LLC Patents:
NUCLEIC ACID-BASED AUTHENTICATION CODES
This application is a Continuation-in-Part of U.S. patent application Ser. No. 11/455,817 filed Jun. 20, 2006, which claims priority to U.S. Provisional Patent Application No. 60/692,225 filed Jun. 20, 2005.
The present invention relates to methods for quality control of surface coating in a manufacturing process. In particular, the invention provides a method to detect density, efficiency and/or uniformity of coating applied to the surface of a manufactured article. The invention further relates to incorporation of a unique product signature for authenticating, tracking or tracing articles manufactured according to the quality control procedures of the invention. The invention further relates to providing a means to detect proper and/or improper handling or storage of articles manufactured according to the quality control procedure of the invention. The present invention also relates to a method for assuring that product contents' match product's label and extends the utility of using the count or relative count of microparticles or symbols to create an authentication code in order to minimize the occurrence of packaging mismatch errors.
In surface coating processes, the density, efficiency and/or uniformity of the coating(s) are parameters that typically affect performance of products such as stents, hemostatic sponges or other medical devices. Typically, biologics or drugs are incorporated in such coatings, and measuring the density, uniformity, or coating efficiency associated with these compounds is often difficult or impossible without destruction of at least a portion of the coating.
Further, manufacturing processes often involve exposure of articles to critical environmental conditions, such as temperature, humidity, or electromagnetic radiation. It is not always easy to assure that every article from a manufacturing line has been properly exposed to critical environmental conditions, or that every article has not been exposed to unacceptable environmental conditions. Sometimes, only portions of the article are inadequately or unacceptably exposed. Similarly, handling of products after release often requires that they are not exposed to unacceptable environmental conditions.
Additionally, manufacturing processes often involve quality control processes to assure that product contents match the product's label. Failure of such control processes may result in occurrence of packaging mismatch, with potential adverse consequences to the product's end user.
Products that can benefit from quality control of the density, efficiency and/or uniformity of the coating include single-use surgical devices, implantables, sutures, products sterilized according to custom procedure by customers after purchase, hysteroscope, drug coated contact lenses, reagent coatings for diagnostic products, and enteric coatings on pharmaceuticals.
Products that can benefit from monitoring required environmental exposure or exposure to unacceptable environmental conditions include products stored and distributed in cold-chain systems, sunscreens, and consumer products with finite shelf life.
Products that can benefit quality control processes to assure that product contents match the product's label include consumer products, pharmaceutical products, medical diagnostics, and medical devices.
Further, counterfeiting of manufactured goods, including those that incorporate coated surfaces is a global issue. It is estimated that 5% of all world trade in branded goods is counterfeit (ten Ham, Drug Saf., 2003, 26: 991-7). A counterfeit product often appears confusingly similar to that of a genuine product. The material of a counterfeit product may be the same as, or different from the material of a genuine product. Often the counterfeiting product has inferior quality as compared to that of a genuine product. There is a continuing need to develop novel methods to combat counterfeiting at the manufacturing stage and for detection counterfeit goods in the distribution chain.
Despite these efforts, drug and medical devices counterfeiting remains a worldwide problem. There is a continuing need to develop novel methods to combat counterfeit drugs and devices at the manufacturing stage and for detection in the distribution chain. One effective way to fight counterfeiting is to mark a product with an authentication or product identification code that is not easily imitated or counterfeited. The present invention provides a methodology for quality control of surface coatings that is also readily adaptable to product authentication by incorporating a unique product signature for authenticating, tracking or tracing articles manufactured according to the quality control procedures of the invention. The invention further relates to providing a means to detect proper and/or improper handling or storage of articles manufactured according to the quality control procedure of the invention.
The present invention also relates to a method for assuring that product contents' match product's label using microparticulate taggants having different detectable physical properties, wherein each combination of properties is used as an encoding bit to create codes. The present invention thus further extends the utility of using the count or relative count of microparticles or symbols to create an authentication code in order to minimize the occurrence of packaging mismatch errors by providing a coding system that can be incorporated into product contents, into or onto product packaging containers, and into or onto product labels. The coding system provides for multiple checkpoints to assure against mix-up errors.
Density, efficiency and/or uniformity of a coating are often important for product performance, and otherwise difficult to assess without complex and expensive instrumentation, often in conjunction with a destructive testing method. It is one object of the present invention to provide a method for quality control of surface coating in a manufacturing process, including the processes of spraying, brushing, dipping, and immersion, by a method that does not require destructive testing of the article.
It is another object of the invention to provide a method for simple, low cost and easy to implement quality control measure to assure that articles in a manufacturing process are within tolerances for environment exposure.
It is yet another object of the invention to provide a quality control measure that allow in-line, every-piece, real-time monitoring, real time adjustment of manufacturing parameters and further ensures easy identification of affected product for quarantine and/or disposal.
It is also another object of the invention to couple the quality control methodology of the present invention to a unique, hard to imitate product signature or product identification code useful to authenticate, track or trace manufactured articles. Methods of the invention are easy to implement and can be covert, and difficult to replicate, simulate, alter, or transpose, and resist tampering and inadvertent or intentional alteration.
It is also another object of the invention to provide a means to detect proper and/or improper handling or storage of the article (as may affect stability and product performance), whether in the manufacturing process or after supply and distribution of the article. In this object, a tracer which may be one or more elements of a product authentication code used to assure manufacturing processes undergoes a detectable change after exposure to environmental factors, such as high or low temperature thresholds, humidity, or radiation exposure.
These and other objectives are attained generally by associating a population of easy-to-measure entities with coating medium of the manufactured article, such that the counts or relative counts of entities correlate with deposition of at least one coating medium on the article. Preferably, in a manufacturing process wherein more than one component is coated on the article's surface, coating of each component is correlated with a different cluster of entities. Preferably, the entities are inert, non-toxic, and bioabsorbable.
In one embodiment of the invention, a coated article is provided with a product authentication code wherein the product authentication code is encoded by a signature array of a population of entities associated with the product, wherein the signature array comprises information about the counts or relative counts of entities of at least two distinct clusters of entities within the population, wherein the counts or relative counts of entities within at least one of said clusters correlates with the deposition of a coating on the article.
In yet another embodiment of the invention, a coated article is provided with a product authentication code wherein the product authentication code is encoded by a signature array of a population of entities associated with the product, wherein the signature array comprises information about the counts or relative counts of entities of at least two distinct clusters of entities within the population, wherein the counts or relative counts of entities within at least one of said clusters changes in response to exposure of the product to an environmental stimulus, such as maximum acceptable temperature, minimum acceptable temperature, maximum acceptable humidity, minimum acceptable humidity, or maximum acceptable level of electromagnetic radiation.
One aspect of the invention comprises the steps of: a) associating a population of entities with a product during the manufacturing process, wherein the counts or relative counts of entities correlates with the deposition of at least one coating component on the article; b) analyzing the product to obtain a measured value of the counts, relative counts, and/or uniformity of deposition of a least one such population of entities; c) comparing the measured counts, relative counts, and/or uniformity of deposition of entities with a corresponding expected counts, relative count, and/or uniformity of deposition acceptance value; and d) releasing products manufactured by the manufacturing process when the measured value is within and acceptance range of the expected value.
Another aspect of the invention comprises the steps of: a) associating a population of entities with a product during the manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable counts or relative counts of entities per cluster and wherein the counts or relative counts of entities within at least one of said clusters changes in response to exposure of the product to an environmental stimulus such as a maximum acceptable temperature, a minimum acceptable temperature, a maximum acceptable humidity, a minimum acceptable humidity, or a maximum acceptable level of electromagnetic radiation; b) analyzing the product to obtain a measured value of the counts of said cluster(s) that change(s) in response of exposure of the product to an environmental stimulus; c) comparing the measured counts with a corresponding expected counts acceptance value; and d) releasing products manufactured by the manufacturing process when the measured value is within an acceptable range of the expected value.
Another general aspect of the invention is an improvement to a product, wherein the improvement is a product authentication code that is coupled to a quality control methodology of the present invention.
In a particular embodiment of the invention, the population of entities comprises a combination or plurality of microparticles. In a preferred embodiment of this invention, the coating to be deposited is a biologic and the manufactured article is a medical device or product.
FIG. 2A illustrates how a signature array of a population of heterogeneous microparticles is constructed from the clusters of FIG. 1. Note that the signature array includes the counts or relative counts of entities within each of the at least two distinct clusters of entities.
FIG. 2B illustrates a signature array of a population of microparticles comprising ten (10) distinct clusters of microparticles classified into clusters by two discretely measurable common properties (i.e. their apparent size and relative infrared fluorescent intensity).
FIG. 4 shows that the signature array measured from a tablet marked with the population G2/R2 on the surface of the tablet matched the expected array.
FIG. 5 is a schematic illustrating that label with signature array enables a much larger field of view and optimizes the scanning capabilities as well as diminishing the complexity of graphic design on locating the code at a specific position due to a specific production line characteristic.
FIG. 6 is a schematic illustrating that all components of the product assembly are readable and can be scanned on production line on an individual basis to insure full product integrity for each product.
As used herein, the term “pharmaceutical product” includes drugs, pharmaceutical formulations and medical devices.
As used herein, the term “counterfeit” when applied as a description to a product or drug means a product made in imitation of a genuine product or drug with intent to deceive. As used herein, the terms “counterfeit drug” and “counterfeit pharmaceutical product” may be used interchangeably. For example, a counterfeit drug is a composition that has not received approval by a governmental authority (e.g., the Food and Drug Administration of the United States) to be safe and efficacious for medical purpose in human subjects, but is labeled as a genuine pharmaceutical product.
Another example of a counterfeit drug is a pharmaceutical composition that has been tampered, such as by dilution. A “counterfeit drug” also includes a composition that contains the same active ingredient(s) as that of a genuine pharmaceutical product, but is made by a party who is not legally entitled to do so, and that party passes off the composition as that of a genuine pharmaceutical product. A “counterfeit drug” as used herein also includes drug diversion or “grey market drug”. Drug diversion occurs when a counterfeiter acquires genuine, non-counterfeit drugs that are targeted for one market and sells them in a different market for a profit. The counterfeiter does this to circumvent the manufacturer's goal of controlling the supply of the drugs in a particular market. As a consequence, the counterfeiter benefits from the sales in that limited supply market or in the diverted sales market.
As used herein, “distinct clusters of entities” means clusters that are different because entities within one cluster having at least one discretely measurable common property that is not shared with the entities within the other cluster(s). Thus clusters of entities can be distinguished from one and another by the measurement of any of the discretely measurable common properties shared by entities within one cluster but not by entities within the other cluster(s)—the distinct discretely measurable common properties.
For example, the clusters of entities can be distinguished by sizes, density or solidity including elasticity, brittle fracture, water-content etc. The particle size can be measured, for example, in a flow cytometry apparatus by so-called forward or small-angle scatter light or by microscopic examination. The clusters of entities can also be distinguished by shape. The shape of the particle can be discriminated, for example, by flow cytometry, by high-resolution slit-scanning method or by microscopic examination. The shape of a printed dot, for example, can be measured by a scanner. The clusters of entities can further be distinguished by tags, such as by fluorescent dyes with different emission wavelengths. Even when they are labeled with the same tag(s), the clusters of entities can still be distinguished because of different concentrations, intensity, or amounts of the tag associated with the entities, or the different ratios of tags on individual entities. Clusters of entities can be distinguished even when all entities share one or more discretely measurable common properties (e.g., particle size and particle shape), but do not share at least one other discretely measurable common property (e.g., intensity or amount of fluorescent tag per entity).
Methods known to a person skilled in the art can be used to measure the quality or quantity of tags. In addition, the clusters of entities can be differentiated by other property or characteristic of the entities, such as being magnetic or not. When the entities are composed of or labeled with nucleic acid or peptide molecules, the clusters of entities can be differentiated by their sequences.
In order to detect the count or relative count of entities within distinct clusters of a population, the clusters of entities must first be distinguished based on the measurement of the distinct discretely measurable common property or properties. It is readily apparent to a skilled artisan that the detection of the count or relative count of entities within distinct clusters of a population thus depends on the accuracy and precision of the measurement of the distinct discretely measurable common property or properties.
If the distinct discretely measurable common property can not be reproducibly measured, the clusters can not be distinguished with confidence, thus the count or relative count of entities within distinct clusters can not be detected. Therefore, a condition precedent to detecting count or relative count of entities within distinct clusters of a population is the reproducible measurement of the distinct discretely measurable common property. In the present invention, at least two distinct clusters of entities are mixed in a population wherein the clusters are distinguishable by one or more distinct discretely measurable common properties that can be reproducibly measured. Thus, the counts or relative counts of entities within the distinct clusters of the population of the present invention are detectable.
One general aspect of the invention is a system that comprises information related to product authentication that is coupled to a quality control methodology. Information related to a product authentication code can be recorded, preferably stored in a database, and more preferably in a secured computer database. Information related to signature array can include, for example, the composition of the population of entities used to mark the product for authentication, the discretely measurable common properties of the distinct clusters of entities used to generate the signature array encoding the product authentication code, and optionally, the expected count or relative count of entities within each of the distinct clusters, etc. Information related to a product authentication code can include the information represented by the product authentication code, such as the chemical composition, the concentrations of the effective or active ingredients, the date or place of manufacture, the source of distribution, the batch number, or the shelf life, etc. Such information is readily retrievable, for example, by means of a computer operation. In a preferred embodiment, the system that comprises information related to product authentication is a computer.
Another general aspect of the invention is a method of marking a product for product authentication that is coupled to a quality control methodology, comprising the steps of: a) associating a population of entities with the product, wherein the population comprises at least two distinct clusters of entities having detectable counts or relative counts of entities per cluster; and b) assigning a signature array of the population of entities to the product as a product authentication code, wherein the signature array comprises information about the counts or relative counts of entities of at least two distinct clusters of entities within the population.
In a particular embodiment, the method of marking a product for product authentication that is coupled to a quality control methodology further comprises a step of correlating the count or relative count of entities within one or more clusters of the population with a specific piece of information about the product, such as the amount, concentration, or presence or absence of a product component.
A wide range of entities are suitable for the present invention, so long as they are compatible with or non-deleterious to the product being marked. Examples of entities that can be used in the present invention, such as microparticles, nucleic acids molecules, or peptides/polypeptides, etc. are described supra.
The product marked can be solid, or semi-solid. However, this invention relates to marking of solid and semi-solid products in so far as it promotes quality control and product authentication. Examples of solid products include pharmaceuticals in tablets, capsules and powders; solid formulations of agrochemicals such as, but not limited to, insecticides, herbicides, fungicides and fertilizers; textiles and leather goods such as clothing and accessories; recordings such as audio and visual recordings including gramophone records, tape cassettes, floppy discs, video cassettes, memory cards, compact discs or other tangible forms of electronic information dissemination; electrical goods such as television sets, computers, DVD players, portable music devices, and radios; motor vehicle components and cameras; paper such as documents, confidential papers, notes, securities, labels, and packaging; chemical products such as inks, biocides, and rubbers; cosmetics such as creams; food products, and medical devices.
In one preferred embodiment of the invention, the marked product is a pharmaceutical product. The marking of a pharmaceutical product with a product authentication code of the invention can be useful to notify the user, dispenser and/or law enforcement personnel of the composition of the pharmaceutical product enabling the notified parties to determine if the product being tested is the genuine pharmaceutical product from the correct source in the correct concentration. The particles may be attached in or on to the articles to be authenticated through various means known in the art. Particle retention can be achieved using appropriate materials, for example, a mesh incorporated into the product or binding agents such as starches or sprays having adhesive properties.
It will be appreciated that the population of entities can be associated with the product in a wide variety of ways. The population of entities can be present in or on all or part of the coating of the product. The entities can be incorporated directly into the coating of the target product using any suitable technique.
In some embodiments when the entities are included in the coating of a pharmaceutical tablet, the entities are in the coating of the pharmaceutical product in an amount of below that is preferably about 0.1% (by weight) or less of the final tablet's total formulation weight. For example, where the entities are a population of microparticles, preferably the microparticles are included in the final coating formulation such that the total quantity of microparticles is less than 100 ppm, less than 50 ppm, less than 25 ppm, less than 10 ppm or less than 5 ppm of the total formulation composition.
In certain preferred embodiments where possible and where the entities are coated on a pharmaceutical product or medical device which has already been approved by a governmental agency that regulates pharmaceuticals (such as, for example, the Food and Drug Administration of the United States of America), the entities are included in an amount (e.g., such as an allowable impurity amount) which would not require a re-filing with, or re-approval by, the governmental agency of the pharmaceutical product or medical device that has been reformulated to include the heterogeneous population of microparticles. Preferably, the amount of the entities associated with the pharmaceutical composition is below the impurity level as provided by the International Conference on Harmonisation (ICH) guidelines.
In other embodiments when the entities are associated with a pharmaceutical formulation, the entities are ingestible and/or non-toxic in amounts used, and when associated with a coating of a medical device, the entities are biodegradable, biocompatible, and/or non-toxic.
In certain further embodiments, the entities can be associated with the product by being present in the product container, packaging or labeling, or a combination thereof. For example, the population of entities can be applied to the inner, outer, or both inner and outer portions of a container for the pharmaceutical product or medical device. The entities can be incorporated into the container during the manufacturing process of the container, and/or the entities can be applied to the inner and/or outer portions of the container or alternatively added during fill. According to this embodiment, the container can take any appropriate form.
In specific embodiments, the entities are included in a label or an article that can be affixed to the container containing the product. For example, where the entities are microparticles, inks containing the microparticles can be used to print the labeling directly onto the container, or printed dots can be printed directly onto the container. Alternatively, printed dots or inks containing the microparticles can be used to print the product authentication code onto a printable article or medium, which can be subsequently applied on a variety of interior and exterior surfaces of the product or the container of the product. Preferably, the printable article is adhesive. Inks, printable articles or media and methods to print microparticles onto a printable article or medium are know to those skilled in the art, see for example, U.S. Pat. No. 5,450,190.
Thus, in one aspect, the present invention relates to a method for minimizing the occurrence of packaging mismatch errors comprising the steps of: a) associating a population of entities with a product label to be applied to a container during a manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable counts or relative counts of entities per cluster, wherein a signature array that comprises information about the counts or relative counts of entities of the at least two distinct clusters of entities is recorded; b) determining that the signature array is consistent with proper match between the label and the container; and c) rejecting labeled containers that are determined to be mismatched. Optionally, steps b and c are performed “on the fly” during a manufacturing labeling operation. Optionally, the container also incorporates a signature array for matching with the signature array of the label. Optionally, the container and or the label also incorporate machine-readable features (e.g., a bar code) for matching with any or all signature arrays.
In another aspect, the present invention relates to a method for minimizing the occurrence of packaging mismatch errors comprising the steps of: a) associating a population of entities with the bulk of a product prior to filling labeled containers during a manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable counts or relative counts of entities per cluster, wherein a signature array that comprises information about the counts or relative counts of entities of the at least two distinct clusters of entities is recorded; b) determining that the signature array is consistent with proper match between the product bulk and the container; and c) rejecting filled containers that are determined to be mismatched. Optionally, steps b & c are performed “on the fly” during a manufacturing labeling operation. Optionally, step b is performed prior to step c, and no containers are filled if a mismatch is identified. Optionally, the container and/or the label also incorporate a signature array for matching with the bulk.
Regarding the avoidance of packaging mismatch, the current technology available today requires a specific code like 2 D Data Matrix, Bar Code or Number/Letters to be printed on pressure sensitive labels or directly on containers (bottle, bag, jar, carton, leaflet, etc.). These printed codes are then read by scanners or vision systems on the production assembly line to verify the match between the label/component versus the product contents. The code to be printed and read by scanners or vision systems creates challenges of design and manufacturability, in that size, color, contrast, and position of the code impact its readability on a production line and aesthetics of the final package design.
The use of the signature array of the present invention does not require a specific size, position and contrast, and code information can cover a large surface of the label without compromising the product esthetics. For ease of application, this signature array can be integrated into the ink used for printing the label. Further, covering all or a large space on the label assures a wide range of field of view for scanners or vision systems to read the signature array, which enables faster reading on the production line. Additionally, there is greater flexibility in positioning scanners on the production line.
In yet another aspect, the signature array(s) of the present invention serve as authentication marks on and/or in finished products produced using the aforementioned methods for minimizing the occurrence of packaging mismatch errors.
For example, the entities can be microencapsulated into a layer of microcapsules, and then applied to the container containing a product. During microencapsulation, very thin coatings of inert natural or synthetic polymeric materials are deposited around the entities to form a layer of microcapsules. The coating material can be chosen from a number of natural and synthetic polymers that are non-reactive with the entities, and is preferably nontoxic. Other components such as surfactants and plasticizers, may also be added to microcapsules.
The product authentication code of the invention can be used in combination with one or more other means for product authentication, identification, or quality control. For example, it can be combined with authentication or identification methods, such as a radio frequency identification (RFID) tag, spectroscopic inks, hologram, reflective paper, laser etched paper, or a bar code on the package, container or label of the product. It can also be combined with a molecular marker or surface/formulated dye incorporated into the product. Additionally, where identification methods are used to track and manage pre-assembly, assembly and post-assembly manufacturing operations, the methods of the present invention can be used in combination.
Another general aspect of the invention relates to a product for sale in commerce, wherein the finished product comprises a product authentication code defined by a signature array of a population of entities associated with the product, wherein the signature array comprises information about the counts or relative counts of entities of at least two distinct clusters of entities within the population and wherein the product authentication code is coupled to a quality control methodology. In a preferred embodiment, the product is a pharmaceutical product.
Depending on the pre-definition or the coding information for the signature array, the array can be detected by measuring one or more discretely measurable properties of each and all entities within the population of entities, a representative number of entities within the population, or a specific set of one or more clusters of entities within the population.
In a specific embodiment as illustrated in FIG. 3, when the population of heterogeneous microparticles is incorporated into the coating of a solid product, the coating is first solubilized. Optionally the entire solid product can be solubilized. The microparticles within the product are extracted, dissolved or suspended in a solvent. The discretely measurable properties of microparticles can then be analyzed, for example, by using a flow cytometer or the like. Alternatively a static cytometer like the CELLSPOTTER® Analyzer from Immunicon can be used as the analyzing device. Preferably, the analyzing device (analyzer) is small and handheld. The analyzer can measure the discretely measurable properties of the microparticles, plot the measured properties in a signature array, and preferably compare the signature array with a saved expected value or values.
In certain embodiments of the present invention, the discretely measurable properties of the entities can be measured in the presence of the product. For example, when the population of heterogeneous microparticles is incorporated into a coating, the fluorescent intensity of the fluorescent tag associated with the microparticle or the particle size of the microparticle can be measured directly by a reader system as is described in US20050100204 the disclosure of which is hereby incorporated by reference.
In a typical reader, UV light is used to trigger the fluorescence of the microparticles. A “BLOB” of an area of the product where the individual fluorescent microspheres are located is used to capture all the microparticles' colors, identify and quantify the gradients of each color detected, as well as the density (for amplitude) of the pigmentation of the microparticles. To ensure repeatability, the reader/vision system is first calibrated with a specific color calibration using a color standard. Currently, “BLOB” function offers similar capability by returning percentage of colors (for RGB in percentage) of the pixels inside the area located in the “BLOB”. BLOB stands for “Binary Large Object”. As generally understood in the art, a blob is a collection of binary data stored as a single entity in a database management system. Blobs are typically images, audio or other multimedia objects, though sometimes binary code is stored as a blob. In this case, it is the collection of images stored in a vision system's internal memory (data base) to enable binary analysis to trigger specific context based visualization on the configuration of the BLOB ANALYSIS TOOL of the vision system.
A preferred reader, scanner, camera or vision system of the present invention would be capable of detecting UV. Such scanners/readers are readily available in the market place from companies such SICK (scanners), MICROSCAN (scanners) COGNEX/DVT (Vision) as well as SIEMENS (Scanners and Vision).
The preferred analyzer can measure the discretely measurable properties of the microparticles, plot the measured properties in a signature array, and preferably compare the signature array with a saved expected value or values. Those of ordinary skill in the art will recognize that a reader system as is described in US20050100204, is used by way of example only, because it can be applied to assess information associated with the entities of the present invention. The skilled artisan will also recognize that there are a variety of methods to assess information associated with the entities of the present invention.
The microparticles can also be collected by specific properties associated with the microparticles, such as the physical or chemical characteristic of the particles, magnetic, lipophilic, hydrophobic, or charge property of the particles. In a particular embodiment, WO2004063752 discloses a method for separating or quantitatively determining target particles in a sample. The method changes the amount of charge on the surface of the particles and utilizes the changed charge for separation and quantitative determination of the particles. Such a method can be used in the present invention to collect the microparticles that are incorporated into the product. The preceding relates to the instant invention to the extent that coating QC can be effected destructively if according to a reasonable sampling plan.
In some situations, microparticles tend to form agglomerates when being mixed into a liquid. Effective means of deagglomerating and dispersing can be used to overcome the bonding forces among microparticles after wetting or reconstitution. Such means include, but are not limited to, deagglomerating treatment with ultrasound, rotor stator mixers (e.g. ultra turrax), piston homogenizers, gear pumps or beat mills, colloid mills or ball mills. Again, the preceding does relate to the instant invention to the extent that coating QC can be effected destructively if according to a reasonable sampling plan.
In some embodiments, multiple discretely measurable properties of the entities within a population can be measured by a single measurement. For example, the discretely measurable properties of each microparticle within the population, such as the intensity of a dye, including a fluorescent dye associated with the particle, the number of particles, or the particle size of particles, can be obtained using the reader system as is described in US20050100204. The measured properties can then be plotted using readily available computer software programs.
The simultaneous measurement of two or more discretely measurable properties of the entities is preferred when there is a concern that other components present in the environment of the entities may interfere with the specific measurement of the discretely measurable properties of the entities. For example, where the reader system as is described in US20050100204, the measurement is set to detect the size of particles having a certain fluorescent tag, the interference from the formulation components is minimized because the formulation components lack the fluorescent tag and will not be measured.
Those of ordinary skill in the art will recognize that populations of heterogeneous entities can be labeled with tags that can be measured with acceptable levels of interference from coating formulation components, that can be separated from interfering product components by convenient means, or that have a combination of the forgoing properties.
The discretely measurable properties of the entities can be measured by methods known to those skilled in the art. For example, laser scanning cytometry or flow cytometry is routinely used for simultaneous measurement of multiple properties of a microparticle, such as the size or shape of the particle, or fluorescence signals derived from a fluorophore or plurality of fluorophores associated with the particle. Flow cytometry is applicable to cases where, further to a QC sample plan, the microparticles are first eluted from the surface coating of the pharmaceutical product and subjected to cytometric analysis.
The experimental errors of the measurement can result in uncertainty about whether the measured signature array indeed matches expected values. To increase the level of confidence, multiple signature arrays may be associated with a single product, optionally, at, on or within different portions of the product to allow multiple measurements and comparisons of the measured signature arrays with expected values. The multiple signature arrays can be identical or distinct.
In an illustrative embodiment, even a simple miscoating of the product can be detected by the reduced microparticle count per unit surface area of microparticles associated with the product to form a signature array.
In a particular embodiment, the population of entities or a cluster of the population is incorporated into an ingredient or component of the product coating during the manufacturing process. Thus, the presence of the expected signature array or information about the cluster detected from the product is indicative of the presence and quantity of the ingredient or component in the product.
In the present Example 1, the signature array of heterogeneous fluorescent microparticle entities was associated with a pharmaceutical product by application of a coating to the surface of an insoluble tablet formulation, wherein the microparticles used were of two different sizes and labeled with either the same or two different fluorescent dyes. A person skilled in the art can readily appreciate that other coatings for pharmaceutical tablet can be used and that other types of entities can also be used following similar procedures to those of this example.
Microparticles labeled with fluorescent dyes purchased from Invitrogen Corporation (Carlsbad, Calif.). Individual vials of microparticles from LINEARFLOW flow cytometry intensity calibration particle kits were obtained as follows: Deep Red 2.5 μm (L14818; lot #38976a), Deep Red 6 μm (L14819; lot #39308a), Green 2.5 μm (L14821; lot #21833w), and Green 6 μm (L14822; lot #41635a). These particles were labeled by the manufacturer with different dyes: a fluorescent dye at 633 nm excitation/660 nm emission (Deep Red, Dye1) and a fluorescent dye at 488 nm excitation/515 nm emission (Green, Dye 2) respectively. Each kit contained six vials of polystyrene particle suspensions stained with the corresponding dyes at different intensity levels that were visualized as six discrete peaks on a fluorescence histogram when analyzed using a Becton Dickinson FACSCALIBER flow cytometer and CELLQUESTPRO analysis software.
The microparticles were formulated to yield signature arrays that would match some or all of the values shown in the “Input” column of Table 1, which is the percent of total fluorescent events per fluorescence detector channel on the FACSCALIBUR flow cytometer. Microparticles with “G” events were detected in the FL1 channel and “R” events in the FL2 channel. The signature array of each of the G and R populations was designed to match half of the input values. Thus, the signature array of the G+R population, which was a mixture of the G and R population in equal volume, would match all of the input values.
To reveal the underlying signature array information, the tablet was washed with 400 μl DPBS into 1.5 ml microfuge tubes and then centrifuged for 10 minutes at 14,000 rpm in a microfuge. The supernatant was removed from each tube by aspiration until approximately 50 μl fluid remained. One hundred fifty microliters of fresh DPBS/0.1% triton X100 was added back to each sample prior to transfer into separate 12×75 mm polystyrene tubes (FALCON) for FACS. As shown in Table 1, the measured signature arrays corresponding to G, R, and G+R populations matched half or all of the Input values.
Green - B 38.3 37.7 43.5 0.0 C 9.1 8.3 7.5 0.0 D 3.5 3.9 3.3 0.0 E 32.6 34.5 31.4 0.0 F 16.6 15.6 14.1 0.0 Red - B 26.5 27.7 0.0 27.8 C 36.0 36.3 0.0 34.5 D 8.8 9.1 0.0 9.8 E 5.8 5.1 0.0 5.6 F 22.9 21.8 0.0 22.3
To test the reproducibility of associating a signature array by the methods of this Example, the population G2/R2 as described in Table 2b of Example 2 was formulated, and mixed 5:1 with a solution of saturated sucrose. Six microliters of said mixture was applied to the sucrose-coated surface of each of six test tablets, then left to dry overnight in the dark under ambient conditions. Three tablets were then washed with 400 μl DPBS per tablet into 1.5 ml microfuge tubes. The other three tablets were washed with 400 μl DPBS/0.1% triton X100. Next, the samples were prepared for FACS analysis as described above.
FIG. 4 shows that the signature arrays measured from the solid formulation containing the population G2/R2 after washing with DPBS matched that from the controls consistently. Listed in the X-axis are the 14 distinct clusters within the G2/R2 population. For each cluster, the first three bar plots from the left represent the relative counts of entities measured from the three tablets; and the fourth bar plot represents the relative counts of entities measured from the G2/R2 population directly, i.e., the population incorporated directly into PBS as a control. The relative count is defined as the count of entities per cluster relative to the sum of counts of entities having the same size, i.e., 2.5 μm or 6 μm.
This Example 1 demonstrates that a signature array can be associated with an article of product by deposition on the article's surface in a way such that both a visible authenticating mark and an invisible signature array can be revealed. Such a signature array can be associated with a logo or other visibly identifying mark, which are commonly placed on the surface of commercial pharmaceutical products. This Example 1 further illustrates that the measurement of the signature array can function as a manufacturing quality control parameter, either as a binary indicator of coating or failing to coat a unit of product, or quantitatively as a surrogate for directly determining the quantity of material deposited in a coating. Those of ordinary skill in the art of pharmaceutical sciences recognize that the visible component is not required to achieve association of the signature array using modifications of the method of this Example.
Counts of Entities Correlate with the Deposition of a Coating Sprayed on a Stent
This Example illustrates a process for making a product using attributes of the signature array of the present invention wherein counts of entities within sets of clusters correlate with the deposition of a coating sprayed on a stent, while maintaining all of the benefits that said array has for authenticating the product. Particularly, this Example demonstrates a process that is useful for monitoring the deposition of a drug coating sprayed on stent, such as, for example, the CYPHER® Sirolimus-eluting Coronary Stent. CYPHER® provides a metal scaffold to open a blocked artery and a coating of the anti-rejection-type medication, sirolimus, that helps limit the overgrowth of normal cells while the artery heals, reducing the chance of re-blockage in the treated area. It is understood by one of ordinary skill in the art that this method or obvious adaptation of it can be applied to other coated manufactured articles.
Polystyrene microparticles sold as LINEARFLOW flow cytometry intensity calibration particle kits were purchased from Invitrogen Corporation (Carlsbad, Calif.). Individual vials of microparticles from the following kits were used as a heterogeneous population of entities: Deep Red 2.5 μm (L14818; lot #38976a), Deep Red 6 gm (L14819; lot #39308a), Green 2.5 μm (L14821; lot #21833w), and Green 6 μm (L14822; lot #41635a). These particles were supplied by Invitrogen with different dyes: a fluorescent dye at 633 nm excitation/660 nm emission (Deep Red, Dye 1) and a fluorescent dye at 488 nm excitation/515 nm emission (Green, Dye 2) respectively. The three individual vials with the highest fluorescence intensity within the 2.5 μm sets (Invitrogen designation vials “D”, “E”, and “F”) and the four individual vials with the highest fluorescence intensity within the 6.0 μm sets (Invitrogen designation vials “C”, “D”, “E”, and “F”) were used as clusters of entities to prepare heterogeneous populations of entities according to the volumes given in Table 1.
Those skilled in the art recognize that a bioabsorbable microparticle of similar size and labeled with non-toxic dyes are preferred to replace these polystyrene microparticles in applications where stents are to be implanted in human subjects. The two factors that drive choice of a size range are detectability and safety; smaller being preferred. Polystyrene microparticles were used in this example for illustrative purposes and because they are compatible with a handy detector device (flow cytometer) and available commercially. The primary set of desirable properties for preferred microparticles are biocompatibility with the organs and systems with which the product will contact, i.e., there is lower stringency for a label in an enteric coating that will pass in stool compared to a stent coating that will desorb during the implanted device's lifetime. Additional important features are solvent and chemical resistance, low surface energy and low protein adsorption, elastomericity (allowing for application performance), and ease with which the materials can accommodate multiple dyes and/or discrete physical features. See for example: Larken E. Euliss, Julie A. DuPont, Stephanie Gratton and Joseph DeSimone; Imparting size, shape, and composition control of materials for nanomedicine (pdf), Chemical Society Reviews First published as an Advance Article on the web Sep. 20, 2006. Jason P. Rolland, Benjamin W. Maynor, Larken E. Euliss, Ansley E. Exner, Ginger M. Denison, and Joseph M. DeSimone Direct Fabrication and Harvesting of Monodisperse, Shape-Specific Nanobiomaterials (pdf), JACS Mar. 28, 2005. Jason P. Rolland, Erik C. Hagberg, Ginger M. Denison, Kenneth R. Carter, and Joseph M. DeSimone; High-Resolution Soft Lithography: Enabling Materials for Nanotechnologies (pdf), Angewandte Chemie, Nov. 5, 2004
Populations of Invitrogen LINEARFLOW flow cytometry intensity calibration microparticles comprising 7 clusters
2.5 μm Suspension D 100 100 200 200 2.5 μm Suspension E 200 200 100 100 2.5 μm Suspension F 100 100 200 200 6 μm Suspension C 200 200 100 100 6 μm Suspension D 100 100 200 200 6 μm Suspension E 200 200 100 100 6 μm Suspension F 200 200 200 200 Total Volume 1100 1100 1100 1100
Populations of Invitrogen LINEARFLOW flow cytometry intensity calibration microparticles comprising 14 clusters prepared from combinations of 7-cluster arrays described in Table 2a.
G1/R1 (μl) G1/R2 (μl) G2/R1 (μl) G2/R2 (μl) G1/R1 400 400 G1/R2 400 400 G2 400 400 R2 400 400 Total Volume 800 800 800 800 G = LINEARFLOW Green particles (2.5 μm @ 4.6e107 particles/ml; 6 μm @1.9e107 particles/ml). R = LINEARFLOW Deep Red particles (2.5 6 μm @ 4.6e107 particles/ml; 6 μm @2.1e107 particles/ml).
G=LINEARFLOW Green particles (2.5 μm @4.6e107 particles/ml; 6 μm @1.9e107 particles/ml).
R=LINEARFLOW Deep Red particles (2.5 6 μm @4.6e107 particles/ml; 6 μm 2.1e107 particles/ml). Each of the populations of microparticles according to Table 2b, G1/R1, G1/R2, G2/R1, and G2/R2, contain 14 distinct clusters of entities, but each is a unique signature array.
A combination of two polymers, 67% polyethylene-co-vinyl acetate (PEVA) and 33% poly n-butyl methacrylate (PBMA), is mixed with sirolimus to make up the basecoat formulation sufficient for application to approximately 1000 stents. Each of the four arrays (G1/R1, G1/R2, G2/R1, and G2/R2) were mixed into separate fractions of this basecoat formulation such that a minimum of 50,000 total microparticle counts is contained in the volume of basecoat formulation that is required to be applied to each stent.
In accordance with a prescribed manufacturing process, bare metal stents were treated with parylene C. Fifty treated stents were spray coated for a period of time (X minutes) such that the required amount of the G1/R1 labeled drug/polymer basecoat formulation coating adheres to the entire surface (i.e., luminal and abluminal) of the stent. Groups of 50 treated stents were similarly treated with each of G1/R2, G2/R1, and G2/R2 labeled drug/polymer basecoat formulation coating. To simulate a manufacturing coating process deficiency, treated stents were spray coated for half the above period of time (X/2 minutes) such that half the required amount of the G1/R1 labeled drug/polymer basecoat formulation coating is adhered to the entire surface of the stent. Groups of fifty treated stents were spray coated for X/2 minutes with each of G1/R2, G2/R1, and G2/R2 labeled drug/polymer basecoat formulation coating. A drug-free topcoat of PBMA polymer was applied to all of the groups of stents, as would normally be included in the manufacturing process to control the release kinetics of sirolimus after stent implantation.
The total microparticle counts and the membership within microparticle clusters was determined for each stent from each group by measuring the microparticle counts on the surface of the stent as it rotates past a measurement instrument, and results are shown in Table 3.
Signature array counts correlate with the deposition of a coating sprayed on a stent
Meets Release Signature ID Mean Total Count Criteria
Coating time = X
G1/R1 Confirmed ~100% Expected Yes G1/R2 Confirmed ~100% Expected Yes G2/R1 Confirmed ~100% Expected Yes G2/R2 Confirmed ~100% Expected Yes Coating time = X/2 G1/R1 Confirmed ~50% Expected No G1/R2 Confirmed ~50% Expected No G2/R1 Confirmed ~50% Expected No G2/R2 Confirmed ~50% Expected No
Those of ordinary skill in the art of pharmaceutical sciences recognize that a similar method as that described in this Example 2 may be employed for quality control and release testing of many processes used to coat solid supports of many types. Additionally, it is evident to the skilled practitioner that this Example 2 allows for the methods of this invention to substitute for other costly and or more complicated analytical methods that might otherwise be used to assure such coatings. Also, the method of the present invention can be performed “in-line” thereby allowing for real time monitoring of the coating process, thereby avoiding that the manufactured batch to be placed on hold awaiting release results, and should a problem be identified, the entire batch is not affected.
Detecting an Expected Code Indicates Proper Mixing of Components that are Deposited on a Hemostatic Sponge by Immersing the Sponge
This Example illustrates a process for making a product using attributes of the signature array of the present invention to determine proper mixing of components to be deposited on the solid matrix of a product, while maintaining all of the benefits that said array has for authenticating the product. Particularly, this Example demonstrates a process that would be useful for manufacturing a hemostatic sponge by immersing the sponge in a bath in order to coat the sponge with a biologically active component.
A hemostatic sponge has, for example, a solid matrix support comprising a woven mesh of bioabsorbable materials, such as polydioxanone or polyglactin 910 found in PDS II or VICRYL sutures, respectively, that is coated with the hemostatic proteins, thrombin and fibrin. For the purpose of illustration, it is assumed that a step in the manufacturing process is to combine two separate non-aqueous suspensions of the proteins thrombin (Portion A) and fibrin (Portion B) in a 9 parts labeled Portion A to 1 part labeled Portion B ratio. A subsequent step is to immerse the solid matrix support (in the non-aqueous suspension?), and product quality control release is dependent upon proper mixing of the suspensions and adequate uniform coating of the sponge after removal from the immersion and drying.
Populations of fluorescent microparticles from Invitrogen Corporation as described in Example 1 above were prepared by mixing the quantities shown in Table 4. Sub-population Y was added to Portion B at effectively 10× the dilution (i.e., 250 μl of Sub-population Y per 1 ml Portion B) that Sub-population X was added to Portion A (i.e., 25 μl of Sub-population X per 1 ml Portion A), such that when 3 replicates are made of 9 parts labeled Portion A plus 1 part labeled Portion B, the following target ratio is empirically determined by thoroughly vortexing the samples and determining relative cluster membership by fluorescence flow cytometry:
Ratio=(Total counts obtained for all clusters in Sub-population Y)/(Total counts obtained for all clusters in Sub-population X).
Populations of Invitrogen microparticles for product quality control and release testing
Sub- Sub- Population Population X (μl) Y μl)
Green 2.5 μl 100 Deep Red 2.5 μl 200 suspension D suspension D E 200 E 100 F 100 F 200 Green 6 μl 200 Deep Red 6 μl 100 suspension C suspension C D 100 D 200 E 200 E 100 F 200 F 200 Total Volume 1100 Total Volume 1100
To simulate both the proper manufacturing process and potential mixing manufacturing errors, a constant volume of Portion A was mixed with varying amounts of Portion B according to the ratios listed Table 5. Thus, in addition to the correct 9:1 ratio, three cases were simulated wherein the addition of the active ingredient fibrin was incorrectly low (Trials 2, 3 and 4) and three cases were simulated wherein said addition was incorrectly high (Trials 6, 7, and 8). Also included was a simulation of inadvertent failure to add any of Portion B (Trial 1).
Simulation of the manufacturing process addition error
Trial # Portion A Portion B 1 9 parts None
2 9 parts 0.5 parts 3 9 parts 0.75 parts 4 9 parts 0.875 parts 5 9 parts 1 part 6 9 parts 1.125 parts 7 9 parts 1.25 parts 8 9 parts 1.5 parts
In accordance with proper manufacturing process, three replicate coatings were achieved with each Trial suspension by immersing a single solid matrix support in each replicate case for a fixed time and at a temperature (T1) such that the required amount of the labeled Portion A/Portion B suspension was adhered at specified density to the support surface. To simulate a manufacturing deficiency, three replicate coatings wee achieved with each Trial suspension by immersing a single solid matrix support in each replicate case for a fixed time and at a temperature (T2) such that half required amount of the labeled Portion A/Portion B suspension was adhered to the support surface versus the specified density.
To simulate quality control release testing of the coated solid supports, the total microparticle counts and the membership within microparticle clusters was determined for each sponge from each group by using a measurement device that is installed at the last station of the manufacturing line and results are shown in Table 6. For the purposes of this simulation, coatings determined outside of the acceptance range of +/−20% versus the target are deemed unacceptable and do no meet release criteria, which results in a pass/reject decision for each piece where the rejected pieces are dropped into a reject chute for further evaluation while all others proceed normally.
Signature array counts correlate with proper mixing of a coating
Mean Meets Release Ratio Mean Total Count Signature ID Criteria
° C. = T1 Trial 1 ~0 ~100% Expected Incorrect No Trial 2 ~0.5 ~100% Expected Incorrect No Trial 3 ~0.75 ~100% Expected Incorrect No Trial 4 ~0.875 ~100% Expected ~Correct Yes Trial 5 ~1.0 ~100% Expected Correct Yes Trial 6 ~1.125 ~100% Expected ~Correct Yes Trial 7 ~1.25 ~100% Expected Incorrect No Trial 8 ~1.5 ~100% Expected Incorrect No ° C. = T2 Trial 1 ~0 ~50% Expected Incorrect No Trial 2 ~0.5 ~50% Expected Incorrect No Trial 3 ~0.75 ~50% Expected Incorrect No Trial 4 ~0.875 ~50% Expected ~Correct No Trial 5 ~1.0 ~50% Expected Correct No Trial 6 ~1.125 ~50% Expected ~Correct No Trial 7 ~1.25 ~50% Expected Incorrect No Trial 8 ~1.5 ~50% Expected Incorrect No
Those of ordinary skill in the art of pharmaceutical sciences recognize that a similar method as that described in this Example 3 may be employed for quality control and release testing of many mixtures used to coat solid supports of many types. Additionally, it is evident to the skilled practitioner that this Example 3 allows for the methods of this invention to substitute for other costly and or more complicated analytical methods that might otherwise be used to assure proper mixing of formulation components and subsequent coating of supports with those mixtures. Also, the method of the present invention can be performed “in-line” thereby allowing for real time monitoring of the coating process, thereby avoiding the manufactured batch being placed on hold awaiting release results, and should a problem be identified, the entire batch is not affected.
Uniformity of a Detected Code Indicates Uniform Coating of Components that are Deposited on a Hemostatic Sponge
This Example illustrates a process for making a product using attributes of the signature array of the present invention to detect uniform coating of components to be deposited on a solid matrix of a product, while maintaining all of the benefits that said array has for authenticating the product. Particularly, this also demonstrates a process that would be useful for manufacturing a hemostatic sponge.
A hemostatic sponge is as described in Example 3, above, and product release is dependent upon uniform coating of the support after removal from the immersion and drying. To simulate both the proper manufacturing process and potential errors of non-uniform coating in manufacture, a constant volume of Portion A was mixed with Portion B in the correct 9:1 ratio as shown for Trial 5 of Table 5 in Example 3. In accordance with proper manufacturing process, three replicate coatings were achieved by fully immersing a single solid matrix support in each replicate case for a fixed time (T1) and at a temperature such that the required amount of the labeled Portion A/Portion B suspension is adhered at specified density to the support surface. To simulate a manufacturing deficiency, three replicate coatings were achieved by fully immersing a single solid matrix support time T1/4, then withdrawing the support ¼ its length for each increment of the following increments, T1/4. Thus, the first ¼ of the support has been immersed for T1×0.25, the second ¼ for T1×0.50, the third ¼ for T1×0.75 m and the final ¼ of the support for the full duration of T1.
To simulate quality control and release testing of the coated solid supports, the total microparticle counts and the membership within microparticle clusters was determined for each ¼ of the support area, and results are shown in Table 7.
Signature array counts correlate with the uniformity of a coating
Immersion Mean Total Count Meets Release Criteria
Full 1st ¼ ~100% Expected 2nd ¼ ~100% Expected 3rd ¼ ~100% Expected 4th ¼ ~100% Expected Yes By ¼ 1st ¼ ~25% Expected 2nd ¼ ~50% Expected 3rd ¼ ~75% Expected 4th ¼ ~100% Expected No
Those of ordinary skill in the art recognize that a similar method as that described in this Example may be employed for quality control and release testing of many mixtures used to coat solid supports of many types. Additionally, it is evident to the skilled practitioner that this Example allows for the methods of this invention to substitute for other costly and or more complicated analytical methods that might otherwise be used to assure uniform coating of supports. Also, the method of the present invention can be performed “in-line” thereby allowing for real time monitoring of the coating process, thereby avoiding that manufactured batch be placed on hold awaiting release results, and should a problem be identified, the entire batch is not affected.
Using Microparticulate Taggants Having Different Detectable Physical Properties to Assure that Product Contents' Match Product's Labels
The present invention also relates to a method for using microparticulate taggants having different detectable physical properties to assure that product contents' match product's label, wherein each combination of properties is used as an encoding bit to create codes. The present invention thus further extends the utility of using the count or relative count of microparticles or symbols to create an authentication code in order to minimize the occurrence of packaging mismatch errors by providing a coding system that can be incorporated into product contents, into or onto product packaging containers, and into or onto product labels. The coding system provides for multiple checkpoints to assure against mix-up errors.
One advantage of this method is that the signature array can be used on all the components of the product and assure the entire integrity of all product components once assembled. Take for example all the components for a bottle of shampoo: the bottle, the lid, the front label and back label as well as the liquid shampoo could each have an individual signature array (or logically-linked set of signature arrays) and be individually scanned, at different sections of a production line, to ensure product integrity for each individual product assembly. Thus, each of the finished product's components has an integrated, “personalized” signature, such that more cumbersome procedures like scanning the box containing lids, the box containing the bottle, as well as the tote of shampoo are no longer necessary to assure the right components prior to beginning assembly of these components in production. The methods of the present invention avoid a mix-ups that are otherwise difficult to capture in production and could lead to the wrong product reaching the consumer.
As shown in FIG. 6, all components of the product assembly are readable and can be scanned on production line on an individual basis to insure full product integrity for each product.
Using Printed Symbol Taggants and a Tracer that Changes in Response to Exposure of the Product to an Environmental Stimulus as an Element of a Product Authentication Code
The present invention also relates to a method for assuring the proper handling of a product, whether in the manufacturing process or after supply and distribution of the article. In this Example, a tracer which may be one or more elements of a product authentication code used to assure manufacturing processes undergoes a detectable change after exposure to environmental factors, such as high or low temperature thresholds, humidity, or radiation exposure.
In the present Example, labels are printed to be affixed top a medical device prior to steam sterilization, wherein the labels bear a responsive signature array element to assure exposure to steam temperature adequate for sterilization. Multiple sets of distinct populations of printable symbols are generated and selected for printing using flexographic digital printing. As shown in Table 8, five conventional characters (“T”, “&”, “J”, “7”, and “M”) are indexed for printing in one of three indexed different fonts (normal, bold, or italic) and one of three indexed distinguishable styles (normal, strikethrough, or underscore) to create 45 (5×3×3) distinct clusters that can be used to create populations of printed symbols for product authentication. In order for the array to have an environmentally responsive element, all bold characters are printed on white labels using Sun Chemicals ThermaFLAG StS AIC23019, which changes from white to black upon exposure of the printed ink to a steam environment adequate to affect sterilization article bearing the label.
Indexing of the 5 conventional characters, the 3 distinguishable fonts, and the 3 identifiable styles
Index Type Index Type Index Type 1 T 1 Normal 1 Normal 2 & 2 Bold 2 Strikethrough 3 J 3 Italic 3 Underline 4 7 5 M
Characters of a signature array were selected using an algorithm written in MICROSOFT EXCEL spreadsheet that generated a population of heterogeneous printed symbols as a string, as follows. A look-up table was constructed for the 45 clusters of printed symbols, i.e., all possible combinations of Character×Font×Style, expressed as index position. The corresponding character was incorporated into the look-up table, corresponding to cluster number, as shown in the first two columns of Table 9. A user-specified signature array was designated by randomly selecting particular clusters out of the 45 possible clusters and arbitrarily assigning a frequency of appearance in the specified array for each of the selected cluster. Three representative user-specified signature arrays were designated as shown in Table 9: Array 1, Array 2, and Array 3. For each of 10,000 cells in the spreadsheet, a random number (Random 1) with values between 0 and 1 was generated and multiplied by the number of clusters, then 0.5 was added to the result, and the net result rounded to yield a random cluster number between 1 and 45 (Selected Cluster). Then, a random number with values between 0 and 1 (Random 2) was generated and compared to the fractional frequency specified for the Selected Cluster. If Random 2 was less than said specified frequency, the character corresponding to the Selected Cluster was selected for printing. For example, if Random Number 2 was less than 0.2 in a case where Cluster 3 had been selected randomly from all clusters, “J” was selected for printing, otherwise a value “FALSE” was returned and no character selected; hence, 20% of the time, “J” would be selected when Cluster 3 was the Selected Cluster. If a Selected Cluster had a specified frequency 0, Random Number 2 was never less than 0 and a value “FALSE” was always returned and no character selected. With each recalculation of the spreadsheet, strings of approximately 200+ characters of each array were selected. Representative strings for each of the arrays are as follows:
MJTTMMTTTJTMMMMMMJJMMJTMTMJTMMMTM JMJJJMJTMJJJJMJMMJMMJMMMMMTJJ JJMJTMJJMTTJJJMJMJJTMJJMMJTTJMTJJMJJMTJMTMTJJTTMJMTMJJMMJMMJMJJTJJMJMMJJTMMJ . . .
MJMTMMMMTJMMTMJTMTTMTMJMJTMTJTMMMMJTTMMJTMTJMTJJJMMMMTJTM TMMMJMJTMMJTJJJMJMTTMTTMJTMMMJ MMTMJTTMMJTTJMTMMMMTMJJJMTMMTM MTMMTMJMJJMJMMTJTJTTMMTTT. . .
77J&T7T&77&7JMT77JJ7TMT7T77777T7JT777&&&7JT7&JT&T 7777&777T&TT&MT&T777T7T7J&&T7J777T&&&77&7&J7T777M&77TJ&T77&&TMT&777TT&77MTM7777J77&MM77T77JM77&TT77&7TJ&T&7T7 . . .
Prior to sterilization, bold characters are missing from the array and there is no correlation between specified and observed character frequency for each of the three representative signature arrays. However, after exposure of the labels to a steam sterilization environment, bold characters appear and there is a close correlation between specified and observed character frequency for each of the three representative signature arrays.
Those of ordinary skill in the art of the present invention recognize that the clusters of printable symbols of the present invention are not limited to the representative characters, fonts, or styles shown in Table 5. For example, symbols like symbols or Greek alphabet characters or others can replace the Roman alphabet characters used in this example. Whole words or logos may replace or be used with individual characters or symbols in any index position. Color, grayscale level, font size, highlighting or the like can replace or be used with the fonts and styles used in this example. It is apparent that a variety of distinct clusters, by no means limited to the 45 clusters illustrated in Table 7, can be constructed from combinations of the forgoing discretely measurable common properties for the printed symbols.
A skilled practitioner recognizes that printing a code of the present invention is not limited to a label. A variety of other suitable surfaces for printing said code can be found on product packages, shrink wrap, containers (such as the vials or prepackaged syringes), on medical devices (such as in the coating of stents or on the casing of implantable defibrillators).
1. A method of authenticating a coated product, comprising the steps of: a) associating a population of entities with the product, wherein the population comprises at least two distinct clusters of entities having detectable absolute counts or relative counts of entities per cluster; b) assigning a signature array of the population of entities to the product as a product authentication code, wherein the signature array comprises information about the absolute counts or relative counts of entities of at least two distinct clusters of entities within the population; wherein information about the signature array and the product authentication code is recorded and wherein absolute count is the count or number measured in all or a portion of said coated product and relative count is a ratio between two or more absolute counts; c) analyzing the product to obtain a measured signature array of the population of entities associated with the product; d) comparing the measured signature array with that which is expected based on the recorded information; and e) accepting the product as authenticated when the measured signature array matches that which is expected.
2. The method of claim 1, wherein recorded information about the product is selected from the amount, concentration, or presence or absence of a product component.
3. The method of claim 1, wherein each of the at least two distinct clusters of entities has one or more discretely measurable common properties that are shared by entities within said cluster, but not by entities within any other cluster.
4. The method of claim 3, wherein the one or more discretely measurable common properties are properties of one or more tags associated with the entities.
5. The method of claim 4, wherein the one or more tags associated with the entities is selected from the group consisting of: colors, fluorescent dyes, ultraviolet radiation dyes, luminescent compositions, microparticles, haptens, nucleotides, polypeptides, scents, and a combination thereof.
6. The method of claim 3, wherein the one or more discretely measurable common properties of the entities are the size of the entities, the style of the entities, or the shape of the entities.
7. The method of claim 1, wherein the population of entities comprises microparticles.
8. The method of claim 7, wherein the microparticles are labeled with at least two discretely measurable fluorescent dyes.
9. The method of claim 8, wherein the at least two discretely measurable fluorescent dyes are present on the same microparticle.
10. The method of claim 8, wherein the microparticles are labeled with a fluorescent dye in at least two detectable different intensity levels.
11. The method of claim 1, wherein the population of entities comprises one or more types of entities selected from the group consisting of microparticles, nucleic acid molecules, peptides, polypeptides, hapten, or a combination thereof.
12. The method of claim 1, wherein during the step of associating a population of entities with the product, the population is associated with the product by incorporation on or in the coating medium of the product.
13. The method of claim 1, wherein the product is a solid pharmaceutical product.
14. The method of claim 1, wherein the entities are bioabsorbable and non-toxic in amounts used.
15. The method of claim 13, wherein the product is a medical device or a consumer product.
16. A method for quality control and release of products from a manufacturing process, comprising the steps of: a) associating a population of entities with a product during the manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable absolute counts or relative counts of entities per cluster, wherein a signature array that comprises information about the absolute counts or relative counts of entities of the at least two distinct clusters of entities is recorded and wherein absolute count is the count or number measured in all or a portion of said product thereof and relative count is a ratio between two or more absolute counts; b) analyzing the product to obtain a measured signature array of the population of entities associated with the product; c) comparing the measured signature array with that which is expected based on the recorded information; and d) releasing products manufactured by the manufacturing process when the measured signature array matches that which is expected.
17. The method of claim 16, wherein recorded information about the product is selected from the amount, concentration, or presence or absence of a product component.
18. The method of claim 16, wherein each of the at least two distinct clusters of entities has one or more discretely measurable common properties that are shared by entities within said cluster, but not by entities within any other cluster.
19. The method of claim 16, wherein the one or more discretely measurable common properties are properties of one or more tags associated with the entities.
20. The method of claim 19, wherein the one or more tags associated with the entities is selected from the group consisting of: colors, fluorescent dyes, ultraviolet radiation dyes, luminescent compositions, microparticles, haptens, nucleotides, polypeptides, scents, and a combination thereof.
21. The method of claim 16, wherein the one or more discretely measurable common properties of the entities are the size of the entities, the style of the entities, or the shape of the entities.
22. The method of claim 16, wherein the population of entities comprises microparticles.
23. The method of claim 22, wherein the microparticles are labeled with at least two discretely measurable fluorescent dyes.
24. The method of claim 23, wherein the at least two discretely measurable fluorescent dyes are present on the same microparticle.
25. The method of claim 24, wherein the microparticles are labeled with a fluorescent dye in at least two detectable different intensity levels.
26. The method of claim 16, wherein the population of entities comprises one or more types of entities selected from the group consisting of microparticles, nucleic acid molecules, peptides, polypeptides, hapten, or a combination thereof.
27. The method of claim 16, wherein during the step of associating a population of entities with the product, the population is associated with the product by incorporation on or in the coating medium of the product.
28. The method of claim 16, wherein the product is a solid pharmaceutical product.
29. The method of claim 16, wherein the entities are bioabsorbable and non-toxic in amounts used.
30. The method of claim 16, wherein the product is a medical device or a consumer product.
31. A method for assuring the proper handling of a product comprising the steps of: a) associating a population of entities with a product during a manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable absolute counts or relative counts of entities per cluster and wherein the absolute counts or relative counts of entities within at least one of said clusters changes in response to exposure of the product to an environmental stimulus and wherein absolute count is the count or number measured in all or portion of said product and relative count is a ratio between two or more absolute counts; b) analyzing the product to obtain a measured value of the counts of said cluster(s) that change(s) in response to exposure of the product to an environmental stimulus; c) comparing the measured counts with a corresponding expected counts acceptance value; and d) releasing products manufactured by the manufacturing process when the measured value is within an acceptable range of the expected value.
32. The method of claim 31, wherein the environmental stimulus is a maximum acceptable temperature, a minimum acceptable temperature, a maximum acceptable humidity, a minimum acceptable humidity, or a maximum acceptable level of electromagnetic radiation.
33. The method of claim 31, wherein each of the at least two distinct clusters of entities has one or more discretely measurable common properties that are shared by entities within said cluster, but not by entities within any other cluster.
34. The method of claim 31, wherein the one or more discretely measurable common properties are properties of one or more tags associated with the entities.
35. The method of claim 31, wherein the one or more tags associated with the entities is selected from the group consisting of: colors, fluorescent dyes, ultraviolet radiation dyes, luminescent compositions, microparticles, haptens, nucleotides, polypeptides, scents, and a combination thereof.
36. The method of claim 31, wherein the one or more discretely measurable common properties of the entities are the size of the entities, the style of the entities, or the shape of the entities.
37. The method of claim 31, wherein the population of entities comprises microparticles.
38. The method of claim 37, wherein the microparticles are labeled with at least two discretely measurable fluorescent dyes.
39. The method of claim 38, wherein the at least two discretely measurable fluorescent dyes are present on the same microparticle.
40. The method of claim 38, wherein the microparticles are labeled with a fluorescent dye in at least two detectable different intensity levels.
41. The method of claim 31, wherein the population of entities comprises one or more types of entities selected from the group consisting of microparticles, nucleic acid molecules, peptides, polypeptides, hapten, or a combination thereof.
42. The method of claim 31, wherein during the step of associating a population of entities with the product, the population is associated with the product by incorporation on or in the coating medium of the product.
43. The method of claim 31, wherein the product is a solid pharmaceutical product.
44. The method of claim 31, wherein the entities are bioabsorbable and non-toxic in amounts used.
45. The method of claim 31, wherein the product is a medical device or a consumer product.
46. A method for minimizing the occurrence of packaging mismatch errors comprising the steps of: a) associating a population of entities with a product label to be applied to a container during a manufacturing process, wherein the population of entities comprises at least two distinct clusters of entities having detectable absolute counts or relative counts of entities per cluster, wherein a signature array that comprises information about the absolute counts or relative counts of entities of the at least two distinct clusters of entities is recorded and wherein absolute count is the count or number measured in all or portion of said product and relative count is a ratio between two or more absolute counts; b) determining that the signature array is consistent with proper match between the label and the container; and c) rejecting labeled containers that are determined to be mismatched.
47. The method of claim 46 further comprising the step of performing steps b and c in-line during a manufacturing labeling operation.
48. The method of claim 46, wherein the container also incorporates a signature array for matching with the signature array of the label.
49. The method of claim 46, wherein the container and or the label further comprises machine-readable features for matching with any or all signature arrays.
50. The method of claim 49, wherein the machine-readable feature is a bar code.
51. The method of claim 46, wherein each of the at least two distinct clusters of entities has one or more discretely measurable common properties that are shared by entities within said cluster, but not by entities within any other cluster.
52. The method of claim 51, wherein the one or more discretely measurable common properties are properties of one or more tags associated with the entities.
53. The method of claim 52, wherein the one or more tags associated with the entities is selected from the group consisting of: colors, fluorescent dyes, ultraviolet radiation dyes, luminescent compositions, microparticles, haptens, nucleotides, polypeptides, scents, and a combination thereof.
54. The method of claim 46, wherein the one or more discretely measurable common properties of the entities are the size of the entities, the style of the entities, or the shape of the entities.
55. The method of claim 46, wherein the population of entities comprises microparticles.
56. The method of claim 55, wherein the microparticles are labeled with at least two discretely measurable fluorescent dyes.
57. The method of claim 56, wherein the at least two discretely measurable fluorescent dyes are present on the same microparticle.
58. The method of claim 57, wherein the microparticles are labeled with a fluorescent dye in at least two detectable different intensity levels.
59. The method of claim 46, wherein the population of entities comprises one or more types of entities selected from the group consisting of microparticles, nucleic acid molecules, peptides, polypeptides, hapten, or a combination thereof.
60. The method of claim 46, wherein the product is a medical device, a pharmaceutical product or a consumer product.
61. The method of claim 46, wherein the entities are bioabsorbable and non-toxic in amounts used.
62. The method of claim 46, further comprising the steps of:
a) associating the signature array with the bulk of a product prior to filling the labeled containers;
b) determining whether or not the signature array is consistent with proper match between the product bulk and the container; and
c) rejecting filled containers for which the signature array is determined not to be consistent with proper match between the label and the container.
63. The method of claim 62 further comprising the step of performing steps b and c in-line during a manufacturing labeling operation.
64. The method of claim 62, wherein the container and or the label further comprises machine-readable features for matching with any or all signature arrays.
65. The method of claim 62, wherein the machine-readable feature is a bar code.
66. The method of claim 62, wherein each of the at least two distinct clusters of entities has one or more discretely measurable common properties that are shared by entities within said cluster, but not by entities within any other cluster.
67. The method of claim 66, wherein the one or more discretely measurable common properties are properties of one or more tags associated with the entities.
68. The method of claim 67, wherein the one or more tags associated with the entities is selected from the group consisting of: colors, fluorescent dyes, ultraviolet radiation dyes, luminescent compositions, microparticles, haptens, nucleotides, polypeptides, scents, and a combination thereof.
69. The method of claim 66, wherein the one or more discretely measurable common properties of the entities are the size of the entities, the style of the entities, or the shape of the entities.
70. The method of claim 62, wherein the population of entities comprises microparticles.
71. The method of claim 70, wherein the microparticles are labeled with at least two discretely measurable fluorescent dyes.
72. The method of claim 71, wherein the at least two discretely measurable fluorescent dyes are present on the same microparticle.
73. The method of claim 71, wherein the microparticles are labeled with a fluorescent dye in at least two detectable different intensity levels.
74. The method of claim 62, wherein the population of entities comprises one or more types of entities selected from the group consisting of microparticles, nucleic acid molecules, peptides, polypeptides, hapten, or a combination thereof.
75. The method of claim 62, wherein the product is a medical device, a pharmaceutical product, or a consumer product.
76. The method of claim 62, wherein the entities are bioabsorbable and non-toxic in amounts used.
1787995 January 1931 Reilly
4640035 February 3, 1987 Kind et al.
4677138 June 30, 1987 Margel
6071531 June 6, 2000 Jona et al.
6159504 December 12, 2000 Kumabe
6214766 April 10, 2001 Kurrle
6402986 June 11, 2002 Jones, II et al.
6586012 July 1, 2003 Yu et al.
6649414 November 18, 2003 Chandler et al.
6714299 March 30, 2004 Peterson et al.
6869015 March 22, 2005 Cummings et al.
6948068 September 20, 2005 Lawandy et al.
6968231 November 22, 2005 Silvian et al.
7052737 May 30, 2006 Kool et al.
7094305 August 22, 2006 Cleary
7129506 October 31, 2006 Ross et al.
7256398 August 14, 2007 Ross et al.
7378675 May 27, 2008 Ross et al.
7392950 July 1, 2008 Walmsley et al.
7394997 July 1, 2008 Mei et al.
7720254 May 18, 2010 Stierman et al.
7752137 July 6, 2010 Dillon
7831042 November 9, 2010 Stierman et al.
7885428 February 8, 2011 Stierman et al.
7995196 August 9, 2011 Fraser
20020048822 April 25, 2002 Rittenburg et al.
20020066543 June 6, 2002 Lilly
20030064105 April 3, 2003 Kim et al.
20030141375 July 31, 2003 Lawandy
20040166063 August 26, 2004 Siegel
20040185481 September 23, 2004 Numajiri
20050031838 February 10, 2005 Lagunowich et al.
20050112610 May 26, 2005 Lee et al.
20060054506 March 16, 2006 Natan et al.
20060131517 June 22, 2006 Ross et al.
20070086625 April 19, 2007 Polli et al.
20070172429 July 26, 2007 Gao et al.
20080034426 February 7, 2008 Stierman et al.
20090084859 April 2, 2009 Lapstun et al.
20100128925 May 27, 2010 Stierman et al.
103 45 458 October 2004 DE
0650546 October 1997 EP
1998710 December 2008 EP
1999873 December 2008 EP
2011008 January 2009 EP
2220346 October 1990 GB
6-298650 October 1994 JP
0151915 July 2001 WO
03039648 May 2003 WO
2004/041328 May 2004 WO
2004038645 May 2004 WO
2004/063752 July 2004 WO
2005/111127 November 2005 WO
2007002009 January 2007 WO
2007002016 January 2007 WO
2007021971 February 2007 WO
2007106512 September 2007 WO
2007106514 September 2007 WO
2007106515 September 2007 WO
2007149127 December 2007 WO
Barker, Robert L., et al., “Cytometric Detection of DNA Amplified with Fluorescent Primers: Application to Analysis of Clonal bcl-2 and IgH Gene Rearrangements in Malignant Lymphomas”, Blood, 83(4):1079-1085 (Feb. 15, 1994).
Euliss, Larken E., et al., “Imparting size, shape and composition control of materials for nanomedicine”, Chem. Soc. Rev. 35:1095-1104 (2006).
Finkel, Nancy H., et al., “The Barcoding Microworld”, Analytical Chemistry, 353A-359A (Oct. 1, 2004).
Flurer, Cheryl L., et al., “Chemical profiling of pharmaceuticals by capillary electrophoresis in the determination of drug origin”, Journal of Chromatography A 674:153-163 (1994).
Fulton, R. Jerrold, et al., “Advanced multiplexed analysis with the FlowMetrix system”, Clinical Chemistry, 43 (9):1749-1756 (1997).
Fulwyler, Mack J., et al., “Flow Microsphere Immunoassay for the Quantitative and Simultaneous Detection of Multiple Soluble Analytes”, Methods in Cell Biology 33: 613-629 (1990).
Green, Michael D., et al., “Short communication: Authentication of artemether, artesunate and dihydroartemisinin antimalarial tablets using a simple colorimetric method”, Tropical Medicine and International Health, 6(12):980-982 (Dec. 2001).
Ham, Martijin Ten, “Health Risks of Counterfeit Pharmaceuticals”, Drug Safety, 26(14):991-997 (2003).
McHugh, Thomas M., “Flow Microsphere Immunoassay for the Quantitative and Simultaneous Detection of Multiple Soluble Analytes”, Methods in Cell Biology, 42:575-595 (1994).
Olsen, Bernard A., et al., “Screening for Counterfeit Drugs Using Near-Infrared Spectroscopy”, Pharmaceutical Technology, 62, 64, 66, 68, 70-71 and 95 (Jun. 2002).
Pachaly, Von P., et al., “Einfache dunnschichtchromatographische Identitatsprufung von Wirkstoffen in Fertigarzneimitteln” Pharm. Ind. 55(3):259-267 (1993).
Rolland, Jason P., et al., “High-Resolution Soft Lithography: Enabling Materials for Nanotechnologies”, Angew. Chem. 116:5920-5923 (2004).
Rolland, Jason P., et al., “Direct Fabrication and Harvesting of Monodisperse, Shape-Specific Nanobiomaterials”, J. Am. Chem. Soc. (Mar. 28, 2005).
Scafi, Sergio Henrique Frasson, “Identification of counterfeit drugs using near-infrared spectroscopy”, Analyst, 126:2218-224 (Nov. 19, 2001).
Yang, G., et al., “Detection of hepatitis B virus in plasma using flow cytometric analyses of polymerase chain reaction-amplified DNA incorporating digooxigenin-11-dUTP”, Blood, 81:1083-1088 (1993).
Han, Mingyong, et al. “Quantum-dot-tagged microbeads for multiplexed optical coding of biomolecules,” Nature Biotechnology, 19:631-635 (2001).
Patent Publication Number: 20070160814
Assignee: Authentiform Technologies, LLC (Chapel Hill, NC)
Inventor: Thomas J. Mercolino (Stockton, NJ)
Application Number: 11/613,437
Current U.S. Class: Medical Or Dental Purpose Product; Parts; Subcombinations; Intermediates (e.g., Balloon Catheter, Splint) (427/2.1); Bar Code (235/462.01); Reader Processing Circuitry (235/462.25); Means To Decode A 2-d Bar Code (235/462.1); Including An Imager (e.g., Ccd Or Camera-type Reader) (235/462.11); Bar Width Determination (235/462.16); Radiation Tracer Methods (250/302); Paper Base (427/411); Measuring, Testing, Or Indicating (427/8); Particles, Flakes, Or Granules Coated Or Encapsulated (427/212); Having An Identification Code (700/225); Retained By Bonding Or Adhesive Means (215/232)