Patent Publication Number: US-2006002594-A1

Title: Method for producing a pharmaceutical product

Description:
RELATED APPLICATIONS  
      This application is related to, and claims priority in, co-pending U.S. Provisional Application Ser. No. 60/621,992, filed Oct. 25, 2004, the disclosure of which is incorporated herein by reference. This application is also related to, and claims priority in, co-pending U.S. Provisional Application Ser. No. 60/578,245, filed Jun. 9, 2004, the disclosure of which is incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates to the manufacture of pharmaceutical and pharmaceutical-like product. More particularly, the present invention relates to processes or methods for manufacturing pharmaceutical and pharmaceutical-like product.  
      2. Description of Related Art  
      Contemporary quality control methods for pharmaceutical and pharmaceutical-like product involve the use of batch sampling techniques. The batch-sampling techniques test samples from batches of the product, such as through the use of wet chemistry, after the product has been made. Contemporary batch sampling techniques use frequent and sometimes random batch sampling for various characteristics of the final product, such as, for example, quality, concentration and homogeneity. However, these batch-sampling techniques suffer from drawbacks because of their inefficiency and inaccuracy.  
      Batch-sampling assumes that all of the product attributes in a particular batch are normally distributed and have the same or very similar characteristics as the sampled product from the batch. Where the chosen samples do not meet the required tolerances, an entire batch can be discarded or re-processed for additional sampling and testing. If the chosen unacceptable samples do not have the same characteristics as other acceptable product in the batch, then acceptable product may be discarded along with the rejected samples or at least need to undergo more costly testing. Batch-sampling can be particularly inaccurate where the error or flaw in the process is random, non-repeating or of a non-linear nature. Such flaws or errors in the manufacturing process may provide for only a fraction of the product of the batch being unacceptable but result in an entire batch being discarded or re-tested, as a result of the use of batch sampling.  
      Another significant drawback of batch-sampling techniques is where the chosen samples meet the required tolerances, but where a fraction of the batch is actually unacceptable and not representative of the tested sample. In such a situation, unacceptable product may be provided to the consumer because of the inherent flaw in the quality control method.  
      An additional drawback in batch-sampling techniques is that the testing is done at the end of the process and provides little, if any, information for corrective action to be taken with regard to the manufacturing process and its various steps. The batch-sampling technique can provide overall information for sampled product, but does not indicate at which point or which particular step in the process that a flaw is occurring, such as, for example, inadequate dosing or detrimental heating.  
      Another drawback of batch-sampling technique is that it is done off-line of the manufacturing process, which adds time to the overall manufacturing process, and can also be labor intensive. The cost in time and labor is increased where more stringent standards are applied to a particular product so the batch-sampling technique utilizes a higher portion of samples for testing.  
      Accordingly, there is a need for an apparatus and process for manufacturing pharmaceutical and pharmaceutical-like product that reduce or eliminate these manufacturing and quality control drawbacks of the contemporary devices and techniques.  
     SUMMARY OF THE INVENTION  
      It is an object of the present invention to provide a more efficient process or method for manufacturing pharmaceutical and pharmaceutical-like product.  
      It is another object of the present invention to provide such a process that provides real-time process monitoring.  
      It is yet another object of the present invention to provide such a process that provides real-time feedback and control of the process and product quality.  
      It is yet a further object of the present invention to provide such a process that provides monitoring of each of the product that is manufactured.  
      It is still another object of the present invention to provide such a process that minimizes or eliminates off-line quality control inspection and facilitates real-time release of the product.  
      It is yet still another object of the present invention to provide such a process that produces a pharmaceutical product that allows for the use of various forms of spectroscopy and/or chemical imaging to monitor the dose.  
      It is still a further object of the present invention to provide such a process that eliminates an incorrect dose.  
      It is yet another further object of the present invention to provide a process that employs Process Analytical Technology to improve the manufacture of pharmaceutical product.  
      These and other objects and advantages of the present invention are provided by a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The pharmaceutical product each has a carrier substrate and a dosage of active agent. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to each of the carrier substrates by the pharmaceutical machine. The dose confirmation system performs spectroscopy and/or chemical imaging on each of the carrier substrates to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs near infrared spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs mid-infrared spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs UV or visible spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs fluorescence spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs laser induced fluorescence spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs photoluminescence spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs Raman spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a monitoring system for a pharmaceutical machine that produces pharmaceutical product is provided. The monitoring system has a dose confirmation system operably connected to the pharmaceutical machine. The dose confirmation system determines an amount of the dosage of active agent that has been added to the pharmaceutical product. The dose confirmation system performs terahertz spectroscopy on at least one of the pharmaceutical product to determine the amount of the dosage of active agent.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing spectroscopy on each pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to each of a plurality of carrier substrates by the pharmaceutical machine based on the spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing near infrared spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the near infrared spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing mid-infrared spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the mid-infrared spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing UV or visible spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the UV or visible spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing fluorescence spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the fluorescence spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing laser induced fluorescence spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the laser induced fluorescence spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing Raman spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the Raman spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing terahertz spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the terahertz spectroscopy.  
      In another aspect, a method of providing quality control for a pharmaceutical machine is provided that includes, but is not limited to, performing photoluminescence spectroscopy on at least one pharmaceutical product that is processed by the pharmaceutical machine and determining an amount of a dosage of active agent that has been added to the pharmaceutical product by the pharmaceutical machine based on the photoluminescence spectroscopy.  
      In another aspect, a monitoring system or method of quality control is provided wherein optical profilometry is performed on each of a plurality of carrier substrates to determine the amount of dosage of active agent that has been dispensed thereon.  
      A focal plane array detector can be used for performing chemical imaging through use of the spectroscopy being performed. The dose confirmation system may perform the chemical imaging while each of the carrier substrates continues to move along the pharmaceutical machine. The dosage monitoring system can have a dose inspection system that determines a second amount of the dosage of active agent that will be added to each of the carrier substrates by the dispensing system. Each of the carrier substrates can move continually along the apparatus as the dose inspection system determines the second amount of the dosage of active agent. The dispensing system may dispense the dosage of active agent as a droplet.  
      The dose inspection system can have a camera or digital/video recording device (herein referred to as “camera”) and a flow cell. The dose inspection system may also have a trigger operably connected to the camera. The trigger actuates the camera to obtain a first image of the droplet in-flight.  
      The dosage monitoring system can have a dose confirmation system that determines the first amount of the dosage of active agent that has been added to each of the carrier substrates by the dispensing system, and performs spectroscopy and/or chemical imaging on each of the carrier substrates to determine the first amount of the dosage of active agent. The spectroscopy or chemical imaging may be near infrared, mid-infrared, ultraviolet/visible, fluorescence, laser induced fluorescence, Raman, terahertz, photoluminescence, or any combinations thereof.  
      The dose confirmation system can also have a second camera that obtains a second image of each of the carrier substrates. A position of the dosage on each of the carrier substrates may be determined based on the second image. Each of the carrier substrates can continue to move along the apparatus as the second camera obtains the second image.  
      This application is related to the following applications which have been filed contemporaneously herewith and the disclosures of which are hereby incorporated by reference in their entirety: APPARATUS AND METHOD FOR PHARMACEUTICAL PRODUCTION, Attorney Docket No. 0001534USU; APPARATUS AND METHOD FOR PRODUCING A PHARMACEUTICAL PRODUCT, Attorney Docket No. 0001534USU1; PHARMACEUTICAL PRODUCT, Attorney Docket No. 0001534USU2; APPARATUS AND METHOD FOR PRODUCING OR PROCESSING A PRODUCT OR SAMPLE, Attorney Docket No. 0001534USU3; and APPARATUS FOR PRODUCING A PHARMACEUTICAL PRODUCT, Atty. Docket No. 0001534USU4.  
      Other and further objects, advantages and features of the present invention will be understood by reference to the following: 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a perspective view of a preferred embodiment of a pharmaceutical manufacturing machine of the present invention;  
       FIG. 2  is a schematic representation of the automation components of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   a  is a representation of a path of continuous movement of the dispensing module of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   b  is a representation of another path of continuous movement of the dispensing module of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   c  is a perspective view of a dispenser assembly of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   d  is a perspective cross-sectional view of the dispenser assembly of  FIG. 2   c;    
       FIG. 2   e  is a perspective view of the pump module of the dispenser assembly of  FIG. 2   c;    
       FIG. 2   f  is a perspective view of the motor module of the dispenser assembly of  FIG. 2   c;    
       FIG. 2   g  is a perspective cross-sectional view of another embodiment of a nozzle of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   h  is a schematic representation of another embodiment of a dispensing assembly of the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 2   i  shows the range of droplets that can be dispensed from the assembly of  FIG. 2   h;    
       FIG. 2   j  shows the dispensing assembly of  FIG. 2   h  with multiple nozzles or apertures;  
       FIG. 3  is a plan view of a pharmaceutical product manufactured by the machine of  FIG. 1 ;  
       FIG. 4  is a high speed video image of a dose droplet dispensed by the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 5  is a process flow diagram for the process performed by the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 6  is a graph of the dose droplet measurements by video imaging and processing for a run of 300 tablets;  
       FIG. 6   a  is a graph comparing dose droplet measurements made by the video imaging, high performance liquid chromatography and weight;  
       FIG. 6   b  is a graph of the volumetric determinations by the video imaging and processing compared to drug content measured by high performance liquid chromatography;  
       FIG. 6   c  is a graph of the amount of active agent as predicted by the video imaging compared to that measured by high performance liquid chromatography for a 1 mg dosage;  
       FIG. 6   d  is a graph of the amount of active agent as predicted by the video imaging compared to that measured by high performance liquid chromatography for a 2 mg dosage;  
       FIG. 6   e  is a graph of the amount of active agent as predicted by the video imaging compared to that measured by high performance liquid chromatography for a 4 mg dosage;  
       FIG. 7  is a near-infrared chemical image of a carrier tablet with the dose droplet as processed by the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 7   a  is an alternative near-infrared chemical image of a carrier tablet with the dose droplet as processed by the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 7   b  is a UV induced fluorescence chemical image of a carrier tablet with the dose droplet as processed by the pharmaceutical manufacturing machine of  FIG. 1 ;  
       FIG. 7   c  is a luminescence image of a carrier tablet with only HPC present and no image processing;  
       FIG. 7   d  is a luminescence image of a carrier tablet with an active agent and HPC present with image processing;  
       FIG. 8  is a perspective view of an alternative embodiment of a pharmaceutical manufacturing machine of the present invention;  
       FIG. 8   a  is a perspective view of another alternative embodiment of a pharmaceutical manufacturing machine of the present invention;  
       FIG. 8   b  is a schematic illustration of an alternative embodiment of a spectroscopic detection system;  
       FIG. 8   c  is a schematic illustration of one of the control devices for the spectroscopic detection system of  FIG. 8   b;    
       FIG. 8   d  is a perspective, assembly view of the transport system for the spectroscopic detection system of  FIG. 8   b;    
       FIG. 8   e  is a top plan view of the sample table for the spectroscopic detection system of  FIG. 8   b;    
       FIG. 8   f  is a sectioned, side plan view of the sample table of  FIG. 8   e;    
       FIG. 8   g  is a partial section, side plan view of the sample table of  FIG. 8   e , illustrating the placement of a pharmaceutical sample in one of the sample table receptacles;  
       FIG. 8   h  is a bottom plan view of the sample table of  FIG. 8   e;    
       FIG. 8   i  is a partial side plan view of the sample table of  FIG. 8   e;    
       FIG. 8   j  is a side plan view of the position table for the spectroscopic detection system of  FIG. 8   b;    
       FIG. 8   k  is a partial front plan view of the position table of  FIG. 8   j;    
       FIG. 81  is a partial top plan view of the transport system base for the spectroscopic detection system of  FIG. 8   b;    
       FIG. 8   m  is a partial side plan view of the base of  FIG. 81 ;  
       FIG. 8   n  is a partial sectioned, side plan view of the transport system assembly of  FIG. 8   d;    
       FIG. 8   o  is a schematic illustration of the spectroscopic detection system of  FIG. 8   b  with associated display device or means;  
       FIG. 9  is a schematic representation of components of the pharmaceutical manufacturing machine of  FIG. 8 ;  
       FIG. 10  is a schematic representation of the communication between the components of the pharmaceutical manufacturing machine of  FIG. 8 ;  
       FIG. 11  is a plan view of a preferred embodiment of a carrier tablet of the present invention;  
       FIG. 12  is a cross-sectional view of the carrier tablet of  FIG. 11  taken along line  12 - 12  of  FIG. 11  with a dose droplet;  
       FIG. 13  is a plan view of an alternative embodiment of a carrier tablet of the present invention; and  
       FIG. 14  is a cross-sectional view of the carrier tablet of  FIG. 13  taken along line  14 - 14  of  FIG. 13  with a dose droplet. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      Referring to the drawings, and in particular  FIGS. 1 through 3 , a preferred embodiment of the pharmaceutical manufacturing apparatus or machine of the present invention is shown and generally referred to by reference numeral  10 . The machine  10  has a plurality of components that are operably connected to manufacture a pharmaceutical product  3000  and preferably a batch of pharmaceutical product, as will be described later in greater detail. A batch of pharmaceutical product  3000  is a quantity of product, which has been produced during a defined cycle of manufacture, such as, for example, a fixed number or one or more runs over a fixed time period. The machine  10  has various components arranged along a straight or substantially straight line. However, the present invention contemplates other arrangements and positionings of the various components, such as, for example, in circular or rectangular paths.  
      The arrangement and positioning of the components of machine  10  provide a smaller footprint for space savings, as well as providing a more efficient and ergonomic machine that facilitates operation. Machine  10  can have components stacked on each other or at differing heights to take advantage of vertical space, as well as facilitating operation, such as, for example, enabling the use of gravity in the process performed by the machine.  
      The machine  10  has a loading system  100 , a holding system  200 , a conveyor system  300 , a drug dispensing system  400 , a coating system  600 , a printing system  700 , a product acception-rejection system  800 , and a control system  900 . Each of these systems  100  through  900  are operably connected to each other to efficiently and ergonomically provide pharmaceutical product  3000  that is ready for packaging, and which have each undergone real-time monitoring, and preferably real-time feedback and adjustment or control.  
      The machine  10  delivers the pharmaceutical product  3000 , which is a combination of a carrier tablet or other substrate  1000  and a liquid dose  2000 , as shown in  FIG. 3 . As will be described later in greater detail, the liquid dose  2000  is dispensed by drug dispensing system  400  in the form of a dose droplet  2100  (shown in  FIG. 4 ) that is dispensed onto the carrier tablet  1000 . It should be understood that the liquid dose  2000  can have a variety of properties, such as, for example, low-viscosity, high-viscosity, solution or suspension, such that the term liquid is not intended to be limiting.  
      The liquid dose  2000  has an active, active agent or therapeutic active agent, and is capable of being dispensed by the machine  10  onto the carrier tablet  1000 . The terms active, active agent or therapeutic active agent include, but are not limited to, drugs, proteins, peptides, nucleic acids, nutritional agents, as described herein. These terms include pharmaceutically acceptable agents, bioactive agents, active agents, therapeutic agents, therapeutic proteins, diagnostic agents, or drug(s) as defined herein, and follows the guidelines from the European Union Guide to Good Manufacturing Practice. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. The substance may also include a diagnostic agent, such as an imaging agent and/or a radioactive labeled compound. Their use may be in a mammal, or may be in a human. The pharmacological activity may be prophylactic, or for treatment of a disease state. The agents herein include both small molecule therapeutics, as well as peptides and proteins. The pharmaceutical compositions described herein may optionally comprise one or more pharmaceutically acceptable active agent, bioactive agent, active agent, therapeutic agent, therapeutic protein, diagnostic agent, or drug(s) or ingredients distributed within.  
      It should further be understood that the present invention is not intended to be limited to the use of any particular active agents, formulations or resulting pharmaceutical or pharmaceutical-like product. The liquid dose  2000  can be a solution or suspension; and the resulting pharmaceutical or pharmaceutical-like product can be immediate release, slow release, or controlled release. The liquid dose  2000  can be aqueous, non-aqueous or mixtures thereof. Non-aqueous solutions or suspensions include, but are not limited to, organic solvents, propellants, liquefied gases and volatile silicons. The terms pharmaceutical or pharmaceutical-like product is also not intended to be limiting. The present invention contemplates the use of any active agents and/or combinations of active agents that are suited for dispensing by the machine  10 .  
      Dose droplet  2100  preferably forms a film  2200  upon the outer surface  1100  or substantially along the outer surface of the carrier tablet  1000  (shown in  FIG. 12 ). As will be described later, the liquid dose  2000  is preferably heated so that excess amounts of liquid are evaporated and the active agent becomes captured in the film  2200 . The carrier tablet  1000 , the liquid dose  2000  and resulting pharmaceutical product  3000  undergoes real-time monitoring, feedback and adjustment, which improves quality control.  
      In the preferred embodiment shown in  FIG. 1 , loading system  100  has a loading container or hopper  110  in communication with a loading chute  120 . Hopper  110  is preferably movable so that carrier tablets  1000  can be loaded into the hopper and then the hopper can be moved into communication with the loading chute  120 . Loading chute  120  is in communication with holding system  200  and conveyor system  300  so that the carrier tablets  1000  can be moved from the hopper  110  into the holding system  200  for movement along and through machine  10  by way of conveyor system  300 .  
      The hopper  110  and loading chute  120  can use various devices and methods, such as, for example, powered wheels or wedges, powered belts, or gravity, to move each of the carrier tablets  1000  into their designated positions in holding system  200 . In machine  10 , a portion of loading system  100  is preferably disposed above a portion of conveyor system  300  to take advantage of gravity, in combination with a mechanical loading device.  
      In the preferred embodiment, holding system  200  has a plurality of holding members or trays  210  with tablet positions  220  having a size and shape that allows for holding of each of the carrier tablets  1000 . Preferably, each of the holding trays  210  are rectangular, and the tablet positions  220  are arranged in an array of equi-distantly spaced rows and columns. As will be explained later, this array facilitates operation of the dispensing system  400  in adding the dose droplets  2100  to the carrier tablets  1000 . However, the present invention contemplates the use of other structures and methods for securing each of the carrier tablets  1000  and the resulting pharmaceutical product  3000  as they travel along machine  10 .  
      Preferably, each of the holding trays  210  has two rows of thirty tablet positions  220 . However, alternative sizes, capacities and shapes of the holding trays  210  and the tablet positions  220  may be used to accommodate different shapes and/or sizes of carrier tablets  1000  and to increase efficiency.  
      Holding system  200  tracks individual carrier tablets  1000  by their designation in each of the tablet positions  220 . This allows machine  10  to perform various real-time monitoring, feedback and adjustment activities upon each of the carrier tablets  1000 , dose droplets  2100  and pharmaceutical product  3000 , and also to make determinations as to whether each of the tablets, droplets or resulting product have met the quality control standards that are designated for a particular pharmaceutical product. The tracking of each of the carrier tablets  1000 , dose droplets  2100  and/or pharmaceutical product  3000  throughout the process carried out by machine  10 , allows for acceptance or rejection during the process. The present invention also contemplates tracking of unacceptable tablets for removal by acception-rejection system  800  based on the real-time monitoring.  
      Various tracking or identification methods can be used by holding system  200  for each of the carrier tablets  1000 . In the preferred embodiment of machine  10 , holding trays  210  have a bar code  230  that can be scanned to provide identification and information to control system  900 , and which can also be used to track and monitor the individual carrier tablets  1000 , dose droplets  2100  and/or pharmaceutical product  3000  throughout the process. As will be discussed later in greater detail, the data compiled throughout the process is stored by control system  900 . The data is based upon the individual carrier tablets  1000 , dose droplets  2100  and/or pharmaceutical product  3000 , as opposed to contemporary quality control methods that use batch-sampling.  
      In the embodiment of machine  10 , holding system  200  positions each of the carrier tablets  1000  so that dispensing system  400  can add the dose droplet  2100  to the outer surface  1100  (shown in  FIG. 11 ), which is facing away from the holding tray  210 . The present invention contemplates the dispensing system  400  also adding the dose droplet  2100  to the opposing outer surface  1200  of the carrier tablet  1000  (shown in  FIG. 12 ). This would allow for a greater capacity of liquid dose  2000  being carried by the carrier tablet  1000  (on both of its outer surfaces  1100  and  1200 ), as well as providing a more uniform and symmetrical pharmaceutical product  3000 .  
      Dosing of both sides of the carrier tablet  1000  would also provide the ability for different liquid doses  2000 , e.g., different active agents, to be dispensed upon a single tablet, such as, for example, where the different liquid doses are incompatible and cannot be mixed together in liquid form or where the different liquid doses cannot be layered on top of each other. The present invention contemplates dispensing system  400  adding one or more different liquid doses  2000  to carrier tablets  1000  through layering, through depositing on opposing outer surfaces  1100  and  1200 , and/or both.  
      Machine  10  can also be used to re-process the carrier tablets  1000  any number of times through the dispensing system  400  in order to add each of the different liquid doses  2000 . Machine  10  may have additional dispensing systems  400  in series that will add each of the different liquid doses  2000  to the carrier tablets  1000 .  
      Holding system  200  can alternatively provide for dispensing the liquid dose  2000  (or different liquid doses) on both sides of the carrier tablets  1000  by providing dispensing system  400  with access to both sides of the carrier tablet. Examples of such alternative methods of dispensing include, but are not limited to, inverting holding tray  210  so that each of the carrier tablets  1000  are transferred into a second holding tray  210  so that the opposing outer surfaces  1200  are now facing away from the second holding tray or using a holding tray that holds each of the carrier tablets around their perimeters or outer circumferences so that both outer surfaces  1100  and  1200  are simultaneously accessible.  
      The flipping or inverting of each of the carrier tablets  1000  or their holding tray  210  can be done near the end of the process so that the opposing outer surface  1200  is re-processed by the same components or a second set of components could be added to machine  10  to continue the process with respect to the opposing outer surface. Additionally, the inverting of each of the carrier tablets  1000  or their holding tray  210 , can be done by holding system  200  to allow for other operations or processes to be performed on opposing outer surface  1200 , such as, for example, coating or printing both sides of the pharmaceutical product  3000 .  
      Conveyor system  300  provides for movement of holding trays  210  along machine  10  and through the various stages or systems of the machine. In the preferred embodiment of machine  10 , conveyor system  300  provides for movement of holding trays  210  along a substantially horizontal path. However, the present invention contemplates movement of the holding trays  210  in other directions such as, for example, in a vertical path, where spacial economy, the use of gravity or other reasons suggest or dictate such a direction of movement.  
      Conveyor system  300  has a drive conveyor  310 . Drive conveyor  310  is controlled by control system  900 , shown in  FIG. 1 , and is preferably variable speed. Holding trays  210  are preferably removably connected to drive conveyor  310 . Holding trays  210  are securely connected to the drive conveyor  310  so that each of the tablet positions  220  remains constant with respect to the drive conveyor in order to provide accuracy in dispensing and monitoring of the carrier tablets  1000 , dose droplets  2100  and pharmaceutical product  3000 . In the preferred embodiment of machine  10 , drive conveyor  310  is a circulating conveyor belt that traverses the length of machine  10  and, more preferably, is a serial real-time communications system drive unit. However, the present invention contemplates other types and methods of moving the holding trays  210 , such as, for example, parallel drive chains, tracks, belts or wheels to which the holding trays can be removably connected.  
      The present invention also contemplates the use of a number or series of holding trays  210  that are pivotally secured to each other to form a belt-like structure or tray belt, which can be operably connected to the drive conveyor  310 . Machine  10  can have a plurality of tray belts with different sizes and/or shapes of tablet positions  220  to accommodate different sizes and/or shapes of carrier tablets  1000 . The tray belt is a length or line of holding trays  210  that is connectable at opposing ends to form a loop. When the holding trays  210  are to be replaced for a different pharmaceutical product  3000 , the tray belt is fed along the drive conveyor  310  and then secured at its opposing ends to form the belt along the machine  10 . To expedite the connection of the second tray belt to drive conveyor  310 , the second tray belt can preferably be connected to the end of the first tray belt that is being removed, as that first tray belt is driven along and off of the drive conveyor.  
      The present invention also contemplates the use of any number of drive conveyors  310 . For example, different systems of machine  10  can have independent drive conveyors  310  that allow for independent control of the speed of the drive conveyors, such as, for example, to more rapidly remove the pharmaceutical product  3000  from the end of the process. In such an alternative embodiment, control system  900  would preferably control the various independent drive conveyors  310 , and be able to coordinate their movement.  
      In the preferred embodiment, dispensing system  400  provides for the addition of the liquid dose  2000  to each of the carrier tablets  1000 , and provides for real-time monitoring, feedback and adjustment. To dispense the liquid dose  2000 , dispensing system  400  has a gantry  410  that laterally spans above and across drive conveyor  310 , and is longitudinally movable with respect to the drive conveyor. The movement of gantry  410 , including speed and position, is controlled by control system  900 .  
      The gantry  410  has a dispensing module  420  movably connected thereto. The dispensing module  420  is movable along the longitudinal axis of the gantry  410 , which laterally traverses across the drive conveyor  310 . The movement of the dispensing module  420 , including speed and position, is also controlled by the control system  900 .  
      Based upon the movement of the gantry  410 , and its own movement with respect to the gantry, the dispensing module  420  is capable of movement along X and Y axes with respect to the drive conveyor  310  and the holding trays  210 . Additionally, the present invention contemplates movement of the gantry  410 , the dispensing module  420 , and/or both, along a Z-axis with respect to the drive conveyor  310  and the holding trays  210 . The movement of the dispensing module  420  allows it to accurately dispense the dose droplet  2100  on each of the carrier tablets  1000  that are in the array of tablet positions  220  on holding tray  210 . Control system  900  can also adjust the movement of the dispensing module  420  and the gantry  410  to accommodate different sizes and shapes of holding trays  210 , as well as different arrays of tablet positions  220  on the holding trays.  
      The use of the gantry  410  to move the dispensing module  420  along X and Y axes (and the Z axis if desired), provides for smooth movement and accurate alignment of the dispensing module with each of the carrier tablets  1000 . This is especially significant in the preferred embodiment of machine  10  where the drive conveyor  310  continues to move the holding tray  210  through the dispensing system  400  as the dose droplets  2100  are being dispensed. The continuous movement of each of the carrier tablets  1000  along machine  10  as the dispensing step is occurring speeds up the manufacturing process. Additionally, smooth continuous movement of the holding tray  210  and the carrier tablets  1000  thereon, as opposed to dispensing onto the carrier tablets via indexing or discontinuous movement, provides for less wear and tear on the machine  10  and its components, particularly the drive conveyor  310 . Dispensing module  420  preferably moves in an X-like path to accurately dispense on each of the carrier tablets  1000 . The size and shape of the X-like path depends upon the dispensing speed and the spacing of tablet positions  220 , as shown in  FIGS. 2   a  and  2   b . It should be further understood by one of ordinary skill in the art that the dispensing module  420  can be moved along alternative paths that preferably allow for continuous movement of the carrier tablets  1000  during dispensing.  
      The accuracy of the alignment of the dispensing module  420  with each of the carrier tablets  1000 , and the efficiency of the movement of the module, is facilitated by the use of the rectangular array of tablet positions  220  along holding tray  210  and the control of the movement of the module and gantry  410  in a rectangular coordinate system. However, the present invention contemplates the use of other structures and methods that could also be used to move the dispensing module  420  with respect to each of the carrier tablets  1000 , as the drive conveyor  310  continues to move through the dispensing system  400 , such as, for example, a multiple axis robotic arm and/or along different coordinate systems.  
      In the preferred embodiment of machine  10 , the dispensing system  400  has a pair of dispensing modules  420  connected to gantry  410 . The use of more than one dispensing module  420  provides for increased speed and efficiency in dispensing of the liquid dose  2000 . Additionally, the use of more than one dispensing module  420  would allow the dispensing system  400  to add different liquid doses  2000  to a carrier tablet  1000  without cleaning or replacing the module, such as, for example, in layering or on opposing outer surfaces  1100  and  1200  through re-processing the carrier tablet back through the dispensing system.  
      Dispensing module  420  dispenses a desired amount of active agent onto the carrier tablet  1000 . In the preferred embodiment of machine  10 , the dispensing module  420  has a pump  425 , a flow cell  430 , and a dispensing head  435 . The present invention contemplates a single dispensing module  420  that has duplicate components, such as, for example, a pump  425  and a flow cell  430  that are in fluid communication with a pair of dispensing heads  435 , and/or other combinations or numbers of components for any number of dispensing modules.  
      The pump  425  is connected to a liquid dose source  440 . In the preferred embodiment of the machine  10 , the liquid dose source  440  is a movable container  445  that is connected to the pump  425  via removably connectable conduit  447 , so that the liquid dose  2000  can be quickly and efficiently replaced.  
      The present invention contemplates the use of a liquid dose source  440  with replaceable cartridges, containers or canisters (not shown) that can be easily inserted in, or connected to, the liquid dose source. For lower dosages where only small amounts of the liquid dose  2000  are being dispensed, the liquid dose source  440  with replaceable cartridges, containers or canisters is especially useful for facilitating operation of machine  10 .  
      The pump  425  is preferably a metered, positive displacement pump (shown in  FIGS. 2   c  through  2   f ), which causes the dispensing head  435  to dispense a single dose droplet  2100 . The metered, positive displacement pump  425  is controlled by the control system  900 , and facilitates the accuracy and control of dispensing a single dose droplet  2100  of the desired size so that the proper dosage of active agent is added to the carrier tablet  1000 . However, the present invention contemplates the use of other types of pumps, such as, for example, a time-pressure pump or reciprocating piston pump connected to a dispensing module that can provide the same degree of accuracy and speed in dosing the carrier tablet  1000 .  
      Pump  425  has a motor module  4250  and a piston module  4280 , as shown in  FIGS. 2   e  and  2   f . The motor module  4250  has a motor  4255 , a connection port  4260  and an adjustment mechanism  4265 . The piston module  4280  has a piston assembly  4285  and a cylinder  4290 . When the piston module  4260  is operably connected to the motor module  4250  through connection port  4260 , the piston on piston assembly  4285  is driven which imparts both reciprocating and rotary motion to the piston. The magnitude of the piston stroke is manually adjustable by the adjustment mechanism  4265 . The present invention contemplates automatic adjustment through use of the real time monitoring, feedback and control as described herein.  
      Pump  425 , as controlled by the control system  900 , can skip select tablet positions  220 , where the carrier tablets  1000  contained therein have been designated as rejected. Machine  10  provides for inspection of the carrier tablets  1000  before they undergo the dispensing process described above. In the preferred embodiment, the tablet inspection is performed by a camera  426  and gantry assembly (not shown), which provide images of each of the carrier tablets  1000  for inspection by control system  900 .  
      Alternative inspection devices and methods can be used which determine the condition of the carrier tablet, as well as ensure that it is properly positioned in tablet position  220 . Selective dispensing by pump  425  improves efficiency by not wasting any liquid dose  2000  on any carrier tablets  1000  that have already been deemed to not meet the required tolerances of the pharmaceutical product  3000  or are not properly positioned for receiving the dose droplet  2100 .  
      The pump  425  is connected to the flow cell  430 . The flow cell  430  determines the concentration of the active agent in liquid contained in container  445  that is going to be dispensed through the dispensing head  435 , which will be used in the real-time monitoring of the dose droplets  2100 . This concentration information is provided to the control system  900 .  
      The dispensing head  435  has a dispensing nozzle  450  (shown in  FIG. 2   d ) through which the pressurized, metered amount of liquid dose  2000  is dispensed, and forms the dose droplet  2100 . The dose droplet  2100  dispenses onto the outer surface  1100  of the carrier tablet  1000 .  
      Nozzle  450  provides for exact amounts of liquid dose  2000  being dispensed. The liquid dose  2000  is preferably dispensed by a very precise, positive displacement, piston pump  425  that pumps the liquid through tubing to the nozzle  450 . The proper selection of liquid composition, viscosity, the materials of construction and orifice size of the nozzle  450  are significant and/or critical parameters to the reproducibility of droplets formed.  
      Nozzle  450  can also be made from a hydrophobic material and/or have a hydrophobic coating to facilitate formation and dispensing of dose droplet  2100  by compensating for liquid vehicle composition/formulation and surface tension.  
      In an alternative embodiment shown in  FIG. 2   g , nozzle  450  has an internal plunger  4510  that is retracted to allow the exact amount of liquid dose  2000  to enter the dispensing chamber  4520  under pressure of pump  425 . Preferably, plunger  4510  is spring-loaded by a spring  4530 , or other biasing device, and can be retracted by air pressure, such as, for example, by a solenoid driven pressure source. The liquid dose  2000  is dispensed as a result of the retraction of the plunger  4510 . Under automatic control, the time that the plunger  4510  is in the open position, the pressure maintained on the reservoir of liquid dose and the vehicle composition are significant and/or critical parameters to the reproducibility of the droplets formed.  
      Chamber  4520  is preferably selectively sealed so that the chamber and liquid dose  2000  contained therein remain under pressure. A heater  4540  may be utilized to facilitate the ejection process. Nozzle  450  may have a micro-adjuster  4550  or other adjustment mechanism, manual or automatic (such as being controlled by control system  900  with real-time monitoring, feedback and control), that provides for adjustment of the amount of liquid dose  2000  that is allowed to exit the dispensing chamber  4520 . Nozzle  4560  may be a co-axial air exhaust  4560  that further facilitates dispensing of liquid dose  2000 .  
      The dispensing system  400  uses a pump and nozzle assembly to form and dispense the dose droplet  2100 . This is advantageous due to the accuracy of the components as described above and the ability to perform real-time monitoring of their activities. Also, the dispensing system  400 , through use of nozzle  450 , provides a spherical or substantially spherical dose droplet  2100 , which reduces or prevents splashing and overspray.  
      To facilitate formation of a spherical droplet with a well-defined shape, the liquid dose  2000  can have additives included, such as, for example, a polymer, such as, for example, hydroxypropyl cellulose. The present disclosure also contemplates the use of other additives to be combined with the active agent, such as, for example, a film former to facilitate formation of film  2200  or a marker ingredient to be used with the imaging techniques described herein, such as, for example, a surrogate for chemical imaging.  
      The additive or additives, such as, for example, the polymer, enhances or facilitates the ability of the liquid dose  2000  to lock on to the tablet. The polymer or other such additive can also provide liquid dose  2000  with the desired surface tension and/or viscosity so that a single droplet is dispensed by dispensing system  400 , which facilitates control of the amount of the liquid dose and measurement of the droplet, as will be described later in greater detail. Examples of such additives include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carrageenan (kappa, iota or lambda), gelatin, polyethylene glycol, polyethylene oxide, pullulan, and/or acrylic copolymer (e.g., EUDRAGIT® grades RL, RS, E, L, S, FS30D), or any combinations thereof.  
      The dispensing system  400 , and the use of a liquid dose  2000  and dose droplet  2100  that are dispensed onto the carrier tablet  1000 , is advantageous over contemporary systems and processes in that the production facilities or sites where the machine  10  is located can centrally process, e.g., liquify, the liquid dosage. This reduces the steps of the production, such as eliminating off-site production and delivery, which decreases production time and saves on costs. Where OHC4 compounds are being used, this is especially advantageous in reducing the handling of the compounds by the workers.  
      Dispensing system  400  can alternatively have a nozzle-plate assembly  4600  (a portion of which is schematically represented in  FIGS. 2   h  through  2   j ) to form and dispense the dose droplet  2100 . The assembly  4600  has a plate  4610  with an aperture or nozzle opening  4620  therethrough. The plate  4610  is capable of movement with respect to the supply of liquid dose  2000 , as indicated by arrows  4630 . Such movement includes, but is not limited to, vibration of the plate  4610  in order to actuate the dispensing. The liquid dose  2000  is dispensed through nozzle opening  4620  when the plate  4610  is selectively moved towards the supply of the liquid dose.  
      As shown in  FIG. 2   i , the size of nozzle opening  4620  can be adjusted or changed to provide for a range of different sizes or volumes for dose droplet  2100 . The ability to accurately size very small openings in plate  4610  and the dispensing dynamics of the assembly  4600  allow for dispensing of very small amounts of liquid dose  2000 , preferably as small as one pico litre. As shown in  FIG. 2   j , a number of nozzle openings  4620  can also be used in the plate  4610  so that array dispensing can be done.  
      Nozzle-plate assembly  4600  is advantageous due to its minimization of components so that there are fewer materials in contact with the liquid dose  2000 . The dispensing operation of the assembly  4600  is reliable since there are no narrow channels and the design is insensitive to air entrapment. Dispensing through the movement of plate  4610  makes the assembly  4600  easy to load and easy to clean. Dead volume for the supply of liquid dose  2000  is minimized or eliminated due to the planar or substantially planar shape of plate  4610 .  
      The present invention further contemplates the use of other structures and methods of dispensing the liquid dose  2000  onto the carrier tablet  1000 , such as, for example, by a pad-printing device where the drug is loaded into the ink cartridge.  
      Dispensing system  400  has a dose inspection system  460  that provides real-time monitoring of each dose droplet  2100  that is to be added to the carrier tablets  1000 . In the preferred embodiment of the machine  10 , dose inspection system  460  uses high-speed imaging of the dose droplet  2100  to determine the volume of the droplet. Dose inspection system  460  has a high-speed digital camera  465  that is connected to gantry  410  and which is able to take a high-speed image  470  (shown in  FIG. 4 ) of each dose droplet  2100 . In the preferred embodiment of machine  10 , two high-speed digital cameras  465  are used, which correspond to each of the two dispensing modules  420 .  
      Referring to  FIGS. 1 through 4 , the image  470  of the dose droplet  2100  is preferably taken in-flight after the dose droplet has left the nozzle  450  but before it makes contact with carrier tablet  1000 . The machine  10  uses a laser detector to trigger the camera  465  to obtain the image  470  due to the high speed of the dose droplet  2100  (shown generally in  FIG. 2   d ). However, the present invention contemplates the use of other triggering devices and methods for triggering camera  465  and obtaining image  470 .  
      Image  470  is used by the control system  900  to calculate a volume of each of the dose droplets  2100 . The calculated volume of the dose droplet  2100 , along with the concentration obtained from flow cell  430 , is used to determine the dosage of active agent that is being dispensed onto the carrier tablet  1000 . Any dosage that does not meet tolerances will be marked with an error code by control system  900  so that the carrier tablet  1000  having that particular dose droplet  2100  can be rejected.  
      Where higher doses of active agent are required in a pharmaceutical product  3000 , dispensing module  420  may dispense a number of dose droplets  2100  or a stream of liquid dose  2000 . Dose inspection system  460  still has the ability to capture the image  470  of the stream of liquid dose  2000 , and the volume and dosage calculations can be made therefrom.  
      Dispensing system  400  has a drying system  475  that performs drying of the dose droplet  2100  on the carrier tablet  1000 . In the preferred embodiment of the machine  10 , drying system  475  has an oven  480  and drying monitors or oven sensors  482  (not shown in detail). The oven  480  provides heat and air flow to the dose droplet  2100  and carrier tablet  1000  so that the film  2200  is formed on the outer surface  1100  or substantially along the outer surface of the carrier tablet. The oven sensors  482  monitor the drying conditions of each of the dose droplets  2100  and carrier tablets  1000  to ensure that the pharmaceutical product  3000  meets the required tolerances. The heating or drying of liquid dose  2000  may evaporate excess amounts of liquid, causing the active agent to become captured in the film  2200 . The drying process of drying system  475 , as opposed to allowing the liquid dose  2000  to ‘air dry’ on the carrier tablet  1000 , can be particularly useful where reduction or elimination of certain excipients from the pharmaceutical product (via evaporation), such as, for example, a solvent like methanol, is desired.  
      For higher dosages of pharmaceutical product, such as, for example, above 5 or 10 mg, drying system  475  can dry layers of the liquid dose  2000  as they are dispensed on top of each other and/or can dry the liquid dose on opposing sides of the carrier tablet  1000 . This allows for a greater volume of liquid dose  2000  to be carried by carrier tablet  1000 .  
      Drying conditions, such as, for example, temperature, air-flow and humidity are monitored by the one or more oven sensors  482 , and a number of such sensors are used to account for any variance in conditions along the oven  480 . The data gathered by the sensors is provided to control system  900  for evaluation of the quality of the carrier tablets  1000  and dose droplets  2100  in each of the holding trays  220 .  
      In the preferred embodiment, the drying conditions are monitored for the entire holding tray  220 , and error codes can be assigned to the individual carrier tablets  1000  and dose droplets  2100  contained therein, based upon a holding tray being affected by an oven condition that does not meet the required tolerances. Alternatively, portions of trays can be monitored for drying conditions by placing more sensors  482  in the oven  480  in strategic positions. Additionally, the present invention contemplates the monitoring of other conditions or criteria related to the drying process, such as, for example, conditions that may be more significant to particular pharmaceutical product  3000 .  
      The present invention also contemplates oven  480  being an infrared (IR) oven and/or having a combination of IR, convection, conduction, and/or microwave heating. Drying system  475  can include dry sensors to detect conditions, such as, for example, the surface temperature of the carrier tablets  1000 , or IR radiation. Drying system  475  may also include a sensor for turning on the oven, such as, for example, a photo-cell triggered by holding trays  210  entering the oven  480 .  
      Dispensing system  400  has a dose confirmation system  500  that provides real-time monitoring, feedback and adjustment for the liquid dose  2000  that has been added to, and dried on, the carrier tablet  1000 . In particular, the dose confirmation system  500  monitors the positioning of the liquid dose  2000  on the carrier tablet  1000  and the amount of the liquid dose contained thereon. Preferably, dose confirmation system  500  can also monitor the active agent type and distribution of the liquid dose  2000  on the carrier tablet  1000 . Additionally, the dose confirmation system  500  can monitor for other substances, such as, for example, identifying contaminants present on the carrier tablet  1000 , as well as the amount of such other substances.  
      The data obtained by the dose confirmation system  500  is provided to the control system  900 . The control system  900  will assign error codes to individual carrier tablets  1000  and their liquid doses  2000  that do not meet the required tolerances of the pharmaceutical product  3000 .  
      In the preferred embodiment of the machine  10 , dose confirmation system  500  has a gantry  510  (similar to gantry  410  described above) with a pair of charge coupled device (CCD) cameras  520  that obtain images  525  of each of the carrier tablets  1000 . The images  525  are provided to control system  900  for a determination of the position of the liquid dose  2000  with respect to the carrier tablet  1000 .  
      Dose confirmation system  500  also has a probe  530  (shown in  FIG. 2 ) that is used for determining the amount, type and/or distribution of the liquid dose  2000  on the carrier tablet  1000 . In the preferred embodiment of machine  10 , the probe  530  uses near-infrared (NIR) chemical imaging or UV induced fluorescence chemical imaging to determine the amount of the liquid dose  2000  present on the carrier tablet  1000 .  
      Probe  530  has components that carry out NIR chemical imaging on each of the carrier tablets  1000  in holding tray  210 , such as, for example, fiber optics, focal plane array (FPA) detectors, and/or charge coupled device (CCD) detectors. Additionally, liquid crystal tunable filters can be used as wavelength selectors for the NIR chemical imaging. The use of such components, in conjunction with each other or alternatively, is facilitated by the positioning of the active agent along or near the surface of the carrier tablet  1000 .  
      The NIR chemical imaging provides good penetration into the liquid dose  2000  and upper surface  1100  of the carrier tablet  1000  for an accurate measurement of the quantity of the liquid dose. This technique is especially useful for the preferred dosing step where film  2200  is positioned on the upper surface  1100  or substantially on the upper surface of carrier tablet  1000 .  
      In the preferred embodiment of machine  10 , probe  530  uses a focal plane array detector to obtain a signal from every point in the sample area. The sample area preferably includes the entire holding tray  210  so that all of the carrier tablets  1000  are being simultaneously measured, which further improves the efficiency of the process. The focal plane detector is able to obtain simultaneous spectral information at every frequency for the sample area. Probe  530  can rapidly and non-destructively measure the liquid dose  2000  for amount, formulation and/or distribution of active agent, as well as monitor or detect other substances contained in or on the carrier tablet  1000 .  
      The present invention contemplates the use of other methods and devices for determining the presence, type, distribution and/or amount of a particular liquid dose or doses  2000  on the carrier tablet  1000 , such as, for example, spectroscopy and/or chemical imaging utilizing Raman and UV reflectance, and various other types of imaging, chemical imaging and/or spectroscopy, such as, for example, UV/visible absorption, fluorescence, laser-induced fluorescence, luminescence, photoluminescence, terahertz, and/or mid-IR. The present invention contemplates the use of various devices or components that facilitate the use of spectroscopy and/or chemical imaging for analysis of the pharmaceutical product  3000 , such as, for example, lasers (e.g., pulse lasers), beam splitters, water-vapor free environments (e.g., nitrogen shrouds), optical delays (e.g., variable optical delays), antennas and/or semi-conductors. The present invention contemplates the use of room temperature solid state detectors and/or pulsed time-gated techniques and components. The present invention contemplates the use of techniques for analysis of the pharmaceutical product  3000  that are non-ionizing, non-invasive, non-destructive, and/or require low power.  
      The present invention contemplates the use of any regions of the electromagnetic spectrum that allow for analysis of the carrier tablet  1000  and liquid dose  2000 , as well as various techniques and sources for excitation in using the particular type of spectroscopy. The present invention also contemplates the use of other techniques and components for digital imaging to allow for use of chemical imaging of the tablet  1000  and liquid dose  2000 . It should be further understood that dose confirmation system  500  also contemplates the use of surrogate detection in any of the spectral ranges.  
      The coating system  600  of machine  10  provides a coating  2300  (shown in  FIG. 12 ) over the liquid dose  2000  in order to prevent possible abrasion and the resulting loss of any active agent. The coating  2300  may be a sealant. The coating  2300  provides a uniform appearance for the pharmaceutical product  3000  by hiding the liquid dose  2000 . The coating can be chosen to closely resemble the color of the carrier tablet  1000  or be another color, such as, for example, a contrasting color to provide different commercial images. Any minor difference in color between the coating  2300  and carrier tablet  1000  is accounted for by having the perimeter of the coating align with the edge of the carrier tablet.  
      Coating system  600  preferably has a pad-printing device  610 , a coating source  620  and a coating dryer  630 . The pad-printing device  610  transfers the coating to the upper surface  1100  of the carrier tablet  1000 . The pad-printing device  610  is advantageous because of its efficient transfer of the coating to the carrier tablet without any waste, e.g., no overspray.  
      In the preferred embodiment of machine  10 , pad-printing device  610  is connected to or positions adjacent to the machine  10  to print an array of tablets with each reciprocating stroke. Pad-printing device  610  can be movably connected to a gantry  615  or other similar device to facilitate movement of the pad-printing device with respect to the holding tray  220 . The holding tray  220  continues to move as the coating  2300  is being applied by the pad-printing device  610 . However, the present invention contemplates the use of other devices and methods of positioning the pad-printing device  610  with respect to each of the tablet positions  220  so that the coating  2300  is accurately applied.  
      The pad-printing device  610  is releasably connected to the coating source  620 . In the preferred embodiment of the machine  10 , the coating source  620  is a movable container  625  that is connected to the pad-printing device  610  via removably connectable conduit  627 , so that the coating can be quickly and efficiently replaced.  
      Alternatively, a spray device or ink jet device (not shown) can be used to spray the coating upon the carrier tablet  1000 . The spray device could also be movably connected to gantry  615  to pass over each of the tablet positions  220 . The present invention contemplates the use of other devices and methods for applying a coating  2300  to the carrier tablet  1000 , which covers the liquid dose  2000 , such as, for example, an ultrasonic atomizer. The coating system  600  can use intermittent, low volume atomized sprayers to locally apply the coating  2300  over the surface of tablet  1000  where the dosage has been applied. The sprayer may use volumetric pumps to intermittently supply coating materials. A two fluid air-liquid atomization sprayer may also be used to generate a fine spray.  
      As described above with respect to dosing of the carrier tablet  1000  in layers or on opposing sides, the coating system can provide the necessary coating depending upon how the liquid dose or doses  2000  have been added to the carrier tablet, such as, for example, on both sides or between layers. This can facilitate the use of higher volumes of dosages for the pharmaceutical product  3000 , such as, for example above 5 or 10 mg.  
      Coating dryer  630  performs drying of the coating  2300  that has been applied to the carrier tablet  1000  and over the liquid dose  2000 . The coating dryer  630  preferably has an oven  640  and one or more oven sensors  650  (not shown in detail). The oven  640  provides heat and air flow to the coating  2300 . The oven sensors  650 , similar to the oven sensors  482  discussed above, monitor the drying conditions of the coatings  2300  to ensure that the pharmaceutical product  3000  meets the required tolerances.  
      The printing system  700  of machine  10  provides an identification marker on the coating  2300 . The printing system preferably has a pad-printing device  710  that transfers the marker to the coating  2300  of the carrier tablet  1000  and a pair of cameras  720  that obtain an image  730  of each of the identification markers to verify the quality of the image. Unacceptable tablets will be identified by the control system  900  for subsequent rejection by system  800 .  
      In the preferred embodiment of machine  10 , pad-printing device  710  and cameras  720  are movably connected to a gantry  735  (similar to gantries  410 ,  510  and  615 ) to facilitate movement of the pad-printing device with respect to the holding tray  210  that continues to move as the identification marker is being applied. However, the present invention contemplates the use of other devices and/or methods for positioning the pad-printing device  710  or alternative device with respect to each of the tablet positions  220  for accurate application of the identification markers, such as, for example, lasermarking, inkjet, and/or rotogravure. Each marker image  730  is provided to control system  900  for inspection and to determine if the printed identification marker meets the required tolerances of the pharmaceutical product  3000 . Also, the present invention contemplates machine  10  having an ink dryer (not shown), such as, for example, an oven, that applies heat and/or air-flow to the identification marker to dry it.  
      The acception-rejection system  800  provides a pharmaceutical product  3000  that has undergone real-time monitoring and adjustment for quality control to ensure that each of the product meets the required tolerances. Based upon the real-time monitoring being continuously performed at various stages of the process by machine  10 , control system  900  has designated each and every pharmaceutical product  3000  as either acceptable or rejected.  
      Acceptable pharmaceutical product  3000  passes through to the delivery area (not shown in detail), preferably under pressure that is selectively controlled by the control system  900 , while rejected product drops into a scrap area, preferably under the force of gravity. However, the present invention contemplates the use of other structures and methods of separating those pharmaceutical product  3000  that are designated by control system  900  as acceptable from those product that have been designated by the control system as rejected.  
      The control system  900  coordinates and synchronizes the various stages and systems of the machine  10 . In the preferred embodiment, control system  900  is a distributed process control system that has a number of microprocessors  910  that control the different systems of machine  10 . The microprocessors are preferably coordinated through a workstation  920 . However, the present invention contemplates other types of system control including central and regional control, such as, for example, a single microprocessor  910  controlling all of the systems or similar systems being controlled by one of several microprocessors  910 .  
      The microprocessors  910  and workstation  920  are in communication with each other, preferably through a network  930  using an Ethernet switch  935 , which allows for the real-time monitoring, feedback and adjustment of the process being performed by the machine  10 . The present invention contemplates the use of other structures and methods for communication, such as, for example, hardwiring. The control system  900  also has an archive microprocessor or historian  940 , which is used to centrally store the large amount of data that is compiled for each and every pharmaceutical product  3000  that is processed by the machine  10 . However, the present invention contemplates other methods of storage of the process data, such as, for example, microprocessors  910  individually storing the data that they have compiled.  
      The control system  900  preferably has a number of monitors  950  that provide displays of the data, portions of the data, summaries of the data, and/or calculations and conclusions based upon the data, so that the workers can monitor and/or adjust the process as it is occurring. More preferably, the monitors  950 , through use of the various microprocessors  910  and/or workstation  920 , can selectively display the data, portions of the data, summaries of the data, calculations based upon the data, and conclusions based upon the data. Preferably, control system  900  records data for every product  3000 , which includes preferably all, but at least most of the following: time, initial tablet status, dose droplet volume, dose droplet concentration, oven temperature, oven humidity, oven air flow, dosage location on tablet, dosage quantity and acceptability.  
      The operation of the machine  10  is shown in the flow chart of  FIG. 5 . The process  5000  is continuous between each stage, and provides a pharmaceutical product  3000  that is ready for packaging. In addition to the advantage of cost and time savings, process  5000  minimizes worker contact with the various agents, active and inactive, of the pharmaceutical product  3000 , which reduces potential contamination, as well as providing safety to the workers in dealing with potentially harmful active agents or other substances such as, for example, occupational hazard category 4 (OHC4) compounds.  
      The ability of machine  10  to minimize or eliminate worker contact with the product  3000  (including the addition of a packaging step as will be described later), provides a great advantage over contemporary processes and machines. Such contemporary processes require special safety features, such as, for example, dust containment devices and special handling by workers, where OHC4 drugs are being produced. The special safety features and special handling by workers of the contemporary machines and processes, increases the cost of production, as well as the time to produce the product. Machine  10  avoids such costs and reduces the production time, through its automated, real-time control, feedback and/or adjustment. The present invention also contemplates the use of machine  10  in a nitrogen-enriched environment in order to reduce or eliminate any oxidative degradation, which is facilitated by the lack of need for worker intervention in the process  5000 .  
       FIG. 5  shows process  5000  in combination with processes  6000  and  7000  for the manufacture of the carrier tablet  1000  and the liquid dose  2000 , respectively. Process  5000  requires the use of carrier tablets  1000  and liquid doses  2000 . However, the carrier tablets  1000  and liquid doses  2000  can be manufactured at other facilities and delivered to machine  10 . Also, other processes can be used to manufacture the carrier tablets  1000  and the liquid dose  2000  that are different from those shown in  FIG. 5 .  
      Feeding step  5100  provides an array of carrier tablets  1000  that will remain securely positioned as they proceed through machine  10  to ensure accurate dispensing of the liquid dose  2000 , coating  2300  and identification marker. The feeding step  5100  is performed by the loading, holding and conveyor systems  100  through  300  as described above, and is subject to real-time monitoring, feedback and adjustment by the control system  900 .  
      The feeding step  5100  includes adjustment of the speed of drive conveyor  310  based on a number of factors, such as, for example, the drying time required for the liquid dose  2000  or the amount of time required to dispense the dose droplets  2100 . In the preferred embodiment, the speed of drive conveyor  310  dictates the speed and positioning of all other movements in machine  10 , such as, for example, synchronization of gantries  410 ,  510  and  615  based upon the speed of the drive conveyor. However, the present invention contemplates synchronization of the systems being based off of other component&#39;s movements or other factors, which provides accuracy in the various dispensing steps of process  5000 .  
      The present invention also contemplates the speed of the conveyor system  300  being adjustable based on the real-time monitoring of the position of the liquid dose  2000  that has been dispensed on the carrier tablet  1000 . As described above, the dose confirmation system  500  obtains images  525  of each of the positions of the liquid dose  2000  on the carrier tablets  1000 . Control system  900  could adjust the speed of the drive conveyor  310  with respect to subsequent holding trays  220  based upon this data, such as, for example, where the positioning of the liquid dose  2000  is consistently off center in the same direction. Also, the feeding step  5100  includes real-time monitoring of the quality of the carrier tablet  1000 , such as, for example, a chipped or broken tablet, so that the carrier tablet can be designated as rejected, which prevents the dispensing of the dose droplet  2100  on that particular carrier tablet.  
      Dosing step  5200  is performed by dispensing system  400 , and, in particular, by the pair of dispensing modules  420 . Control system  900  provides a synchronized pulse to metered pump  425  to actuate the pressurized dispensing of the dose droplet  2100 . However, the present invention contemplates the use of other signals and techniques to actuate dispensing module  420  for dosing.  
      Calibration of the dosing step  5200  is provided by a weigh cell  455  (not shown in detail), which monitors the accuracy of the dispensing modules  420 . In operation, gantry  410  is positioned over the weigh cell  455 , and a preset number of dose droplets  2100  are dispensed onto the weigh cell for weight measurements. This data is compared to data collected from each of the images  470  of the dispensed dose droplets  2100 . The control system  900  can then calibrate the dispensing system  400  based upon volume versus weight comparisons of the preset number of dose droplets  2100 .  
      Dose inspection step  5250  is performed by the dispensing system  400  and, in particular, by the dose inspection system  460 . The dose inspection system  460  provides a quantitative measurement of the dose droplet  2100  prior to it being added to the carrier tablet  1000 , and allows for rejection of those tablets receiving droplets that do not contain the required amount of active agent.  
      To calibrate the dose inspection step  5250 , a vision reticle (not shown) and calibrated volume (not shown) are provided. The vision reticle allows for the determination of a position where the camera  465  can be triggered to capture the image  470  of the dose droplet  2100 . The calibrated volume allows for calibration of the dose inspection system  460 . In operation, gantry  410  is positioned over the vision reticle. The calibrated volume is released and detected by the dose inspection system  460 , and the control system  900  compares the calculated volume (from image  470 ) to the known calibrated volume for calibration of the dose inspection system. The calibration sequence can be set during the run periodically, such as, for example, every 15 minutes, or by the number of tablets having been processed, and/or can be set by some other standard, which is periodic or otherwise.  
      The present invention contemplates real-time adjustment of the dosing and dose inspection steps  5200  and  5250  based upon the calibration techniques described above. These calibration steps can be interposed between holding trays  220 , and control system  900  can adjust dispensing system  400 , such as, for example, adjusting the image volume calculation, based upon discrepancies between the calibrated values and the measured values. Additionally, the present invention contemplates real-time adjustment of the dosing step  5200  based upon the real-time monitoring data obtained by dose inspection step  5250 , such as, for example, adjusting the piston stroke of the pump  425  to account for dose droplets  2100  having too large or too small of a volume.  
      The high-speed video image method described above for determining the volume of dose droplets  2100 , was compared to a High Performance Liquid Chromatography method using a weight analysis as a comparator. As shown in  FIGS. 6 through 6   e , the sample of results using images  470  and the algorithms performed on the images to determine the volume, provided an accurate determination of the volume of dose droplet  2100  as it is being dispensed.  
      Alternatively, dose inspection system  460  can utilize optical profilometry for real-time monitoring and feedback control. The components utilized by dose inspection system  460  to carry out the optical profilometry are known to one skilled in the art, such as, for example, a laser and camera. The technique of optical profilometry is especially useful for larger volumes of liquid dose  2000 , such as, for example, greater than 10 microliters, where the dispensing system  400  is dispensing a stream, as opposed to the dose droplet  2100 .  
      For the optical profilometry technique, dose inspection system  460  performs a first scan of the carrier tablet  1000  prior to dispensing of the liquid dose  2000  in order to obtain a first profile of the carrier tablet. A second scan is then performed by the dose inspection system  460  to obtain a second profile of the carrier tablet  1000  with the liquid dose  2000  thereon. The difference in the first and second profiles provides the measurement of the volume of liquid dose  2000  that has been dispensed onto the carrier tablet  1000 . The present invention further contemplates the use of optical profilometry of the carrier tablet  1000  after the liquid dose  2000  has been dried on the carrier tablet. Also, the first profile may be based upon a predetermined value for the same carrier tablets  1000  to expedite the process and eliminate the need for two scans.  
      Drying step  5300  and drying air preparation step  5325  are performed by the drying system  475  and provide for drying of the dose droplet  2100  on the carrier tablet  1000  as the holding trays  220  move through oven  480 . Various drying conditions are monitored for acceptance or rejection of the holding trays  220 . The present invention contemplates the real-time monitoring of the drying conditions to be used for real-time adjustment of the drying system  475 , such as, for example, temperature, air-flow rate and/or humidity being adjusted by control system  900  based upon detection of abnormalities in these conditions.  
      Dose confirmation step  5350  is performed by the dose confirmation system  500  and provides for real-time monitoring of the position, type, distribution and amount of the liquid dose  2000  that is on the carrier tablet  1000  through use of video images  525  and near-infrared chemical imaging. A sample of results of the NIR chemical imaging method are shown in  FIGS. 7 and 7   a.    
      A unique spectrum is collected for each pixel on the focal plane array detector, which results in individual carrier tablet data having both spatially resolved spectra and wavelength dependent images. The output can be seen as a series of spatially resolved spectra (one for each point on the image) or as a series of wavelength resolved images, as shown alternatively in  FIGS. 7 and 7   a . The amount of liquid dose  2000  present on each carrier tablet  1000  can be determined by control system  900  based upon the relative size of the induced image of the liquid dose and the intensity at the individual pixels.  
      However, as described above, other methods can be interchanged with the NIR chemical imaging for the analysis of the amount of active agent. For example,  FIG. 7   b  shows an image derived from fluorescence where emissions were induced by subjecting the entire holding tray  210  to UV light excitation. A visible spectrum CCD camera was used to image the carrier tablets  1000  and each of their liquid doses  2000 . Based upon the area of the liquid doses  2000  and their gray scale intensity at individual pixels, the amount of each liquid dose can be determined by control system  900 .  FIG. 7   c  shows a luminescence image of a carrier tablet with only HPC present and no image processing, in contrast to  FIG. 7   d  which shows a luminescence image of a carrier tablet with an active agent and HPC present with image processing.  
      The present invention also contemplates the use of the real-time monitoring to provide real-time feedback and adjustment to the conveyor and dispensing systems  300  and  400 , such as, for example, adjusting the speed for better positioning of the dose droplet  2100  on the carrier tablet  1000  or adjusting the pump  425  and/or nozzle  450  to increase or decrease the volume of the dose droplet, which increases or decreases the amount of active agent that is ultimately dried on the carrier tablet.  
      The use of real-time monitoring of the dose droplet  2100  both before and after contact with the carrier tablet  1000 , also would allow for more efficient accounting for any losses occurring during the process. For example, but not limited to, if the dose confirmation step  5350  indicated that there is far less dosage present than was indicated by the dose inspection step  5250 , the dosing and drying steps  5200  and  5300  can be analyzed and adjusted to account for these losses.  
      The coating step  5400  is performed by the coating system  600  and provides a coating  2300  over the liquid dose  2000  through use of pad-printing device  610  or other dispensing device.  FIG. 5  shows process  5000  in combination with process  8000  for the manufacture of the coating. Process  5000  uses an over-coat for the coating  2300  but the coating can be manufactured at other facilities and delivered to machine  10 . Also, other processes can be used to manufacture the coating, which are different from the steps shown in process  8000 .  
      The coating drying step  5500  and drying air preparation step  5525  are performed by the coating dryer  630  and provide for drying of the coating  2300  that has been applied over the liquid dose  2000 . Similar to the real-time monitoring, feedback and adjustment described above with respect to the drying system  475  of the dispensing system  400 , the coating drying step  5500  can provide real-time control of drying of the coating  2300 .  
      The coating inspection step  5550  is performed based on the images  730  obtained by cameras  720  of the printing system  700 . Alternatively, a separate image inspection stage, similar to the components and control used by the printing system  700 , can be included along machine  10  after the holding trays  210  pass through the coating dryer  630 . The coating inspection step  5550  uses real-time monitoring of the coating  2300  applied over the liquid dose  2000  for acceptance or rejection of each of the pharmaceutical product  3000 . The present invention also contemplates the use of real-time feedback and adjustment of the coating system  600  and, in particular, the pad-printing device  610  or other dispensing device, such as, for example, adjustment to speed, positioning, quantity and/or pressure.  
      The printing step  5600  and the dispensing ink step  5625  are performed by the printing system  700  and provide the identification marker on the coating  2300  through use of another pad-printing device or other dispensing device.  
      The printing inspection step  5650  is also performed based upon the images  730  obtained by the cameras  720  of the printing system  700  and determines the accurate positioning and clarity of the identification marker. The printing inspection step  5650  uses real-time monitoring of the identification marker applied over the coating  2300  for acceptance or rejection of each of the pharmaceutical product  3000 . The present invention also contemplates the use of real-time feedback and adjustment of the printing system  700  and, in particular, the pad-printing device  710  or other dispensing device, such as, for example, adjustment to speed, positioning, quantity and/or pressure.  
      The delivery step  5700  is performed by the acception-rejection system  800  and provides a pharmaceutical product  3000  that is ready for packaging, and which has undergone real-time monitoring, feedback and adjustment to ensure that each of the product meets the required tolerances. Each and every pharmaceutical product  3000  has been designated as either acceptable or rejected, and control system  900  accepts the selected/accepted pharmaceutical product accordingly.  
      The rejection step  5800  is also performed by the acception-rejection system  800  and rejects those pharmaceutical product  3000  that do not meet the required tolerances based upon the data obtained throughout the process by the real-time monitoring, feedback and adjustment of the machine  10 .  
      Referring to  FIGS. 8 through 10 , another embodiment of a pharmaceutical manufacturing apparatus or machine of the present invention is shown and generally referred to by reference numeral  20 . The machine  20  has components that are similar to the components described above with respect to the preferred embodiment of  FIG. 1  and are similarly numbered, such as, conveyor system  300 , drug dispensing system  400  and control system  900 . Machine  20  is a scaled-down version of the preferred embodiment but still provides real-time monitoring for the process. Each of these systems  300 ,  400  and  900  are operably connected to each other to efficiently and ergonomically provide pharmaceutical product  3000  that have each undergone real-time monitoring, and, preferably, real-time feedback and adjustment.  
      Holding trays  210  are manually placed on drive conveyor  310  where the carrier tablets  1000  begin their descent through machine  20 . Each holding tray  210  is identified through use of the bar code  230  on the tray and a scanner  235 . The holding trays  210  continue to move along machine  20  and pass through to the dispensing system  400  where a dispensing module  420 , which is mounted to gantry  410 , dispenses dose droplets  2100  on each of the carrier tablets  1000 . Camera  465  takes an image of each dose droplet being dispensed and, in conjunction with concentration data obtained from flow cell  430 , the real-time monitoring of the amount of active agent being dispensed occurs.  
      After passing through oven  480 , where the liquid dose  2000  is dried into a film  2200  on the outer surface  1100  or substantially along the outer surface of the carrier tablet  1000 , each of the carrier tablets undergoes real-time monitoring of the position and amount of the liquid dose. Camera  520  (shown in  FIG. 9 ), which is mounted on gantry  510 , obtains an image  525  of each of the carrier tablets  1000  and liquid doses  2000  thereon. The images  525  are processed by control system  900  for the location and quantity of the dose.  
      Under NIR or UV induced fluorescence, camera  520  captures the image  525  of the deposition spot left after dosing and drying. Image analysis software uses gray scale to tabulate the number of pixels and relative intensity of the pixel to develop an image of the dried spot left behind. High doses will give either a greater area of coverage or a higher intensity of gray scale. Based on this information, the dose on the tablet is determined.  
      The holding tray  210  is then manually removed from the drive conveyor  310 . Data has been compiled for each pharmaceutical product  3000  regarding droplet dosage, dose position, quantity of dose, and drying conditions. This data is used by control system  900  to provide a designation for each of the pharmaceuticals as either acceptable or rejected. The machine  20  uses separate scanners  235  at different stages of the machine for identification of the individual carrier tablets  1000 .  
      A second alternative embodiment of the pharmaceutical manufacturing apparatus of the present invention is shown in  FIG. 8   a  and is generally represented by reference numeral  20 ′. Similar to the embodiment described above with respect to  FIGS. 8 through 10 , machine  20 ′ is a scaled down version of the preferred embodiment of machine  10  shown in  FIG. 1 . Machine  20 ′ has many features similar to machines  10  and  20 , and such features are similarly numbered, such as, conveyor system  300 , and drug dispensing system  400 . Machine  20 ′ exemplifies the modularity of the present invention as it includes the features of machine  20  and additionally has gantry  510 , which is readily available for connection with dose confirmation system  500 .  
      Referring now to  FIGS. 8   b  through  8   o , there is shown a schematic illustration of an alternative exemplary embodiment for a spectroscopic detection system or device, which is generally represented by reference numeral  8020 . The spectroscopic detection system  20  generally comprises at least one radiation transmission system  8022  and a first control system  8024 . Radiation transmission system  8022  is adapted to provide or transmit incident radiation (e.g., incident radiation pulse) to at least one pharmaceutical sample  8010  and detect the emission radiation emitted from the sample  8010 . As illustrated in  FIG. 8   b , the first control system  24  preferably includes a light source  8026  for providing the desired wavelength of light or incident radiation to the radiation transmission system (or light probe)  8022  via excitation line  8023   a , an analyzer  8028  for analyzing the emission radiation detected by the radiation transmission system  8022 , which is communicated to the analyzer  8028  via collection line  23   b , and storage or memory system  8027  for storing emission characteristics of selected (or desired) actives for subsequent comparison with detected emission radiation from the sample(s)  8010 . Preferably, the excitation and collection lines  8023   a ,  8023   b  are contained within a single optical line (e.g., fiber optic cable).  
      According to this alternative embodiment, the light source  8026  is adapted to generate and provide at least one incident radiation pulse. More preferably, the light source  8026  is adapted to generate and provide a plurality of incident radiation pulses. As discussed in detail below, the spectroscopic detection system  8020  further includes second control (or synchronizing) system  8029  preferably in communication with the first control system  8024  (and, hence, the light source  8026 , analyzer  8028  and memory system  8027 ) and transport system via line  8023   d  for (i) positioning a respective sample  8010  proximate the light probe  8022  and (ii) synchronizing the movement of the samples  8010  on the transport system  8030  with at least the incident radiation generating system, more preferably, the incident radiation transmission to and detection of the emission radiation from the samples  8010  (see  FIG. 8   c ).  
      As illustrated in  FIG. 8   b , the second control system  8029  is preferably a sub-system or component of the first control system  8024 . Alternatively, the second control system  8029  is a separate component. Radiation transmission system  8022  can be various types that are employed to effectuate the transmission of light to the pharmaceutical sample(s)  8010  and receipt of emission radiation therefrom, such as, for example, a conventional light probe (e.g., an n-around-1 fiber light probe). Preferably, the incident radiation provided by the light probe  8022  comprises light (or pulse thereof) in the ultraviolet-visible spectral range. The light thus preferably has a wavelength in the range of approximately 200-800 nm. In one alternative embodiment, the light has a wavelength in the range of approximately 225-600 nm. In a further alternative embodiment, the light has a wavelength in the range of approximately 300-450 nm. The wavelength of the light is preferably active specific, i.e., based on the spectral or reflectance characteristics of the selected active agent.  
      Although the spectroscopic detection system  8020  illustrated in  FIG. 8   b  shows one light probe  8022  and associated excitation and collection lines  8023   a ,  8023   b , it is to be understood that a plurality of light probes and associated lines can readily be employed within the scope of this alternative embodiment. As discussed above, the emission radiation emitted by a pharmaceutical sample (or each of a plurality of pharmaceutical samples) is detected by the radiation transmission system or light probe  8022  and at least a first signal indicative of a respective pharmaceutical sample emission characteristics is communicated to the analyzer  8028 . The emission radiation is then compared to the stored emission characteristics of selected actives to determine at least the presence and identity of an active contained in or on a respective sample or the absence of an active in or on a respective sample. The concentration of a detected active can also be determined through known formulations, such as the formulation disclosed in Massart, et al.,  Chemomertrics: a Textbook , Data Handling in Science and Technology, Vol. 2 (1988), which is incorporated by reference herein.  
      Referring now to  FIG. 8   d , there is shown an alternative embodiment of a transport system generally designated by reference numeral  8030  that is usable with the spectroscopic detection system  8020 . As illustrated in  FIG. 8   d , the transport system  8030  includes a sample table  8032 , a position table  8040  and a base  8050 .  
      Referring now to  FIGS. 8   e  through  8   g , the sample table  8032  includes at least one, and more preferably a plurality of, recessed sample receptacles (or holders)  8034  on the top surface with each receptacle  8034  being adapted to receive a respective pharmaceutical sample  8010 . Referring to  FIGS. 8   h  and  8   i , the sample table  8032  further includes at least two substantially parallel “T-shaped” slots  8036  on the bottom surface that are adapted to slideably receive the position table tracks  8042  (see  FIG. 8   d ).  
      According to this alternative embodiment, the sample table  8032  can comprise various sizes to accommodate the desired number of receptacles  8034 . By way of illustration, in one alternative embodiment, the sample table  8032  has a length of approximately 16 mm a width of approximately 9 mm and includes 200 receptacles  8034 . The sample table  8032  is preferably constructed of an inert material, such as Teflon&gt;, stainless steel and coated aluminum, to substantially reduce the possibility of interference with the transmission of light to and emission of light from the samples  8010  contained in the receptacles  8034 . In an alternative embodiment, the sample table  8032  comprises a two-piece member, with a light-weight base portion (e.g., aluminum) and a top receptacle portion (having the receptacles  8034  formed on the top surface) constructed of an inert material that is secured on the base portion.  
      Referring now to  FIGS. 8   d  and  8   j , there is shown the position table  8040  of the transport system  8030 . As illustrated in  FIG. 8   j , the position table  8040  includes at least two “T-shaped” tracks  8042  that preferably extend across the top surface of the position table  8040 . According to this alternative embodiment, the position table tracks  8042  are configured and positioned for slideable entry into and through the sample table slots  8036 .  
      Referring now to  FIG. 8   k , the position table  8040  similarly includes two substantially parallel “T-shaped” slots on the bottom surface that are adapted to slideably `receive the base tracks  8052  (see  FIGS. 8   d ,  8   l  and  8   m ). The position table  8040  and base  8050  can be constructed out of various light-weight materials, such as aluminum or ABS. Preferably, the position table  8040  and base  8050  are constructed out of aluminum.  
      Referring now to  FIGS. 8   d  and  8   n , according to the invention, slideable engagement of position table tracks  8042  in sample table slots  8036  effectuates substantially linear movement of the sample table  8032  in the directions denoted by arrows X and X′ (i.e., sample path “SP 1 ”). Slideable engagement of base tracks  8052  in position table slots  8044  effectuates substantially linear movement of the position table  8040  in the directions denoted by arrows Y and Y′ (i.e., sample path “SP 2 ”). As will be appreciated by one having ordinary skill in the art, various conventional system can be employed within the scope of the invention to provide the noted movement of the transport system  8030  and, hence, samples  8010 . In a preferred alternative embodiment, a pair of motorized shafts or screws  8060   a ,  8060   b  are provided.  
      As illustrated in  FIG. 8   d , the first shaft  8060   a  is preferably in communication with the sample table  8032  and provides motive forces in the X′ and X directions. The second shaft  8060   d  is preferably in communication with the position table  8040  and provides motive forces in the Y′ and Y directions. As will further be appreciated by one having ordinary skill in the art, various alternative transport systems can be employed within the scope of the invention. Such systems include a conventional conveyor, which would provide a single sample path. As indicated above, the spectroscopic detection system  8020  is further adapted to be in synchrony with the transport system  8030  of the invention. In a preferred alternative embodiment, the detection system  8020  includes second control system  8029  that is in communication with the first control system  8024  and transport system  8030 . The second control system  8029  is designed and adapted to at least perform the following functions: (i) control the positioning of a sample or samples  8010  by the transport system  8030 , (ii) position a respective sample  8010  proximate the light probe  8022  (i.e., illumination position), and (iii) synchronize the movement of the sample or samples  8010  by the transport system  8030  with at least the incident radiation generating system (i.e., light source  8026 ) of the invention, more preferably, the illumination of and detection of emission radiation from each sample  8010  as it traverses a respective sample path (i.e., SP 1 , SP 2 ). The noted synchronized sample transport, illumination, detection and analysis is preferably accomplished at a minimum rate (or speed) in the range of 1-5 samples/sec., more preferably, approximately 1 sample/sec. Thus, the method and system of the invention provides high speed, accurate, in-situ analysis of pharmaceutical formulations, and, in particular, drug candidate samples that is unparalleled in the art.  
      Referring now to  FIG. 8   o , the spectroscopic system  8020  preferably includes a display system to visually display the sample I.D., system and test parameters and, most importantly, the results achieved by virtue of the spectroscopic system and method described above, e.g., the presence, identity and concentration of the active present in a sample. As illustrated in  FIG. 8   o , in one alternative embodiment, the display system comprises at least one monitor  8065  that is in communication with the second control system  8029  and, hence, first control system  8024  via line  8023   c . In a further alternative embodiment, the display system includes at least one computer system or PC  8070  that includes an associated monitor  8072 . As will be appreciated by one having ordinary skill in the art, the computer system  8070  can further be adapted and programmed to provide direct operator control of the first and/or second control system  8024 ,  8029 . In yet a further alternative embodiment, the display system includes at least one monitor  8065  and at least one computer system  8070 .  
      The method for in-situ determination of the presence of an active agent in a pharmaceutical sample in accordance with one alternative embodiment of the invention thus comprises providing at least one pharmaceutical sample, moving the pharmaceutical sample along at least one sample path, generating at least one incident radiation pulse having a wavelength in the range of approximately 200-800 nm, illuminating the pharmaceutical sample with the radiation pulse when the sample is moved proximate the probe  8022  (i.e., illumination position), detecting the emission radiation emitted from the pharmaceutical sample, and comparing the detected emission radiation with stored emission characteristics of selected actives to determine at least the presence or absence of an active.  
      In a further alternative embodiment, the method for in-situ determination of the presence of an active agent in pharmaceutical samples comprises providing a plurality of pharmaceutical samples, moving the pharmaceutical samples along at least one sample path, generating a plurality of incident radiation pulses, each of the radiation pulses having a wavelength in the range of 200-800 nm, illuminating each of the pharmaceutical samples when moved to an illumination position with at least a respective one of the incident radiation pulses, detecting the emission radiation emitted from each of the pharmaceutical samples, and comparing the emission radiation emitted from each of the pharmaceutical samples with stored emission radiation characteristics of pre-determined actives to determine the presence or absence of the active. In an additional alternative embodiment, the noted method includes the step of synchronizing at least the step of moving the pharmaceutical samples with the step of generating the incident radiation pulses.  
      Referring to  FIGS. 11 and 12 , a first embodiment of the carrier tablet  1000  and the resulting pharmaceutical product  3000 , after being processed by machine  10 , are shown. The carrier tablet  1000  preferably has a recess or reservoir  1150  disposed centrally along outer surface  1100 . Reservoir  1150  provides a basin for the dose droplet  2100  to land after being dispensed to avoid spillage. The reservoir  1150  has a volume that is sufficient to hold the liquid dose  2000 . Depending on the viscosity of the liquid dose  2000 , the volume of the reservoir  1150  may be less than the volume of the liquid dose (where the viscosity allows the liquid dose to curve above the open end of the reservoir) or may be equal or slightly more than the dose volume.  
      The reservoir  1150  is preferably smoothly concave to minimize or avoid splashing. However, the present invention contemplates the use of other shapes, sizes and positions for reservoir  1150  to facilitate the dose droplet being added to the carrier tablet  1000 . The present invention also contemplates the outer surface  1100  not having any reservoir where the liquid dose  2000  has a high viscosity or there is strong surface tension that prevents the dose from sliding off of the carrier tablet  1000 .  
      The carrier tablets  1000  preferably have reservoirs  1150  formed in both outer surface  1100  and the opposing outer surface  1200 . This avoids having to provide the proper orientation of the carrier tablet  1000  during the loading stage. Carrier tablets  1000  can also be pre-coated to prevent absorption so that the film  2200  is maintained on outer surface  1100  or substantially along outer surface  1100 . However, for certain liquid doses  2000  and carrier tablets  1000 , this may be unnecessary, where there is no absorption by the carrier tablet.  
      The preferred embodiment of pharmaceutical product  3000  provides the liquid dose on outer surface  1100  or substantially along the outer surface. This prevents the active agent from damaging the structure of the carrier tablet  1000 . This also facilitates various methods of real-time monitoring, such as, for example, NIR chemical imaging that has the ability to analyze through some depth but not through the entire carrier tablet. However, the present invention contemplates dispensing the liquid dose  2000  into the matrix of the carrier tablet  1000 , where the tablet absorbs the dose but is not de-stabilized, such as an orally disintegrating tablet that is frequently uncoated and has a lesser hardness than that of a conventionally compressed tablet. For active agents that will not damage the structure of the carrier tablet  1000 , such as, for example, dissolving of portions of the tablet, this type of dispensing is sufficient. The present invention further contemplates a combination of absorption of the active agent into the matrix of the carrier tablet  1000 , while also forming a film on the outer surface of the carrier tablet.  
      Referring to  FIGS. 13 and 14 , a second embodiment of a carrier tablet  9000  and the resulting pharmaceutical product  3010 , after being processed by machine  10 , are shown. The carrier tablet  9000  preferably has a recess or reservoir  9150  disposed centrally along outer surface  9100 . Reservoir  9150  provides a basin for the dose droplet  2100  to land after being dispensed to avoid spillage. Additionally, a second reservoir (not shown) can be used to surround reservoir  9150 , which provides a basin for the coating to land after being dispensed to avoid spillage and to provide a more uniform appearance.  
      It should be understood that alternative sizes and shapes for carrier tablets  1000  and  9000  can also be used. For example, but not limited to, machines  10 ,  20  and  20 ′ could dispense liquid dose  2000  into gelatin, Hydroxy Propyl Methyl Cellulose (HPMC) or injection molded polymer capsule shells, or any combinations thereof, where the shell is used to hold the dose.  
      It should further be understood that some of the components and/or systems described with respect to machines  10 ,  20  and  20 ′ may not need to be utilized for certain pharmaceutical product. For example, but not limited to, pharmaceutical products that are vitamins or cosmetics may not require the same rigorous quality control for all of the criteria as compared to more powerful active agents. In such instances, control system  900  will not apply any unnecessary real-time monitoring activities. Additionally, control system  900  will synchronizes the other systems based upon the lack of use of certain systems, which will further maximize the efficiency of the process, such as, for example, where drying of the carrier tablet  1000  and liquid dose  2000  is minimal or not required, the other activities can be greatly sped up.  
      The present invention contemplates machines  10 ,  20  and  20 ′, and the various components and systems therein, being modular. This will allow machines  10 ,  20  and  20 ′ to carry out only the necessary activities for a particular pharmaceutical product  3000  by removing selected unnecessary components, and will provide time saving, such as, for example, avoiding passing holding trays  220  through the coating dryer oven  630  where no coating is being applied.  
      The present invention contemplates the interchangeability of different components to perform the various activities of machines  10 ,  20  and  20 ′, such as, for example, probe  53   b  that performs NIR chemical imaging being interchangeable with other probes that perform other types of analysis, such as, for example, spectroscopy and chemical imaging such as, for example, utilizing Raman, UV reflectance, fluorescence, and/or terahertz techniques. Machines  10 ,  20  and  20 ′ can utilize the type of analysis, and hence the components that perform that analysis, which are most efficient and accurate for a particular pharmaceutical product  3000 . The present invention also contemplates control system  900  indicating which types of analysis and their corresponding components are to be used for a particular pharmaceutical product  3000 .  
      The present invention further contemplates process  5000  including a packaging step so that the end result is a product  3000  that is ready for shipping, especially where real-time release of pharmaceutical product  3000  is utilized. The design and modularity of machines  10 ,  20  and  20 ′ facilitates the addition of a packaging step to process  5000 .  
      Machines  10 ,  20  and  20 ′ also provide the ability to change production to a different pharmaceutical product  3000  in a fraction of the time that it takes to make a similar adjustment to a contemporary machine. The cleaning of the machines  10 ,  20  and  20 ′ for a change of production to a different pharmaceutical product  3000  requires only the cleaning of the dispensing module  420 , which can be quickly disassembled. Dispensing modules  420  are relatively low-cost which allows for their replacement rather than a time-consuming repair.  
      Machines  10 ,  20  and  20 ′ and process  5000  improve efficiency in manufacturing the pharmaceutical product  3000  based upon the manufacturing steps as well as the quality control steps. The continuity of process  5000  quickly and efficiently provides the product  3000  that are directly ready for packaging, without the need for any quality control testing, e.g., wet chemistry, being performed on them. Also, machines  10 ,  20  and  20 ′ provide the process  5000  that can be run continuously without the need for stopping as in contemporary devices and techniques.  
      The real-time monitoring, feedback and adjustment of the present invention avoids unnecessary manufacturing steps (e.g., dispensing on rejected tablets) and provides quality control based on the individual properties of each of the pharmaceutical tablets  3000 . The present invention is cost effective because it only discards the defective product  3000  identified by control system  900 , rather than discarding all of the product in a batch that has a significant number of defective tablets, as by contemporary methods of product sampling.  
      Process  5000  is particularly efficient at the production of low dosage pharmaceuticals, e.g., less than 5 mg of active agent. Process  5000  provides for the depositing of precise amounts of the active agent and is thus particularly useful at the lower dosages, e.g., 1 μg to 1000 μg. Machines  10 ,  20  and  20 ′ and process  5000  can produce pharmaceuticals with higher amounts of dosages, e.g., greater than 5 mg, as well as pharmaceutical-like product, such as, for example, vitamins.  
      The dispensing performed by process  5000  results in a dosage of active agent for the product with a content uniformity for the batch that is preferably less than 5% relative standard deviation (RSD), more preferably less than 3% RSD, and most preferably less than 2% RSD. The accuracy in dispensing of the active agent by process  5000  is over any range of dosage. The advantage of process  5000 , and the resulting accuracy of the dispensing, is especially evident at lower dosages compared to contemporary manufacturing processes.  
      The present invention contemplates the use of coatings and/or additives in combination with the liquid dose  2000  for the purpose of controlling the rate of release of the pharmaceutical product along the Gastro Intestinal (GI) track. As described above, where a plurality of active agents are dispensed onto carrier tablet  1000 , such as, for example by layering or on opposing sides of carrier tablet  1000 , the release of the different active agents can be controlled to occur at desired areas along the GI track through use of the coatings and/or additives.  
      The present invention contemplates the use of individual systems or combinations of systems of machines  10 ,  20  and  20 ′ in combination with other devices, to provide one or more of the steps described in process  5000 . For example, but not limited to, dispensing module  420  (including pump  425 , flow cell  430  and dispensing head  435 ) and dose inspection system  460  can be operably connected to a blister filling machine (not shown).  
      The combination of dispensing module  420  and dose inspection system  460  with the blister filling machine would allow for tablets that are held in the thermoformed pockets of the blister package to receive the liquid dose  2000  from the dispensing module. Similar to the real-time monitoring, feedback and control described above with respect to machines  10 ,  20  and  20 ′, the positioning of dispensing module  420  with respect to the blister package, and, in particular, each of the tablets, would be adjusted to provide for accurate dispensing.  
      The combination of dispensing module  420 , dose inspection system  460  and the blister filling machine would further provide for quality control assessment of each and every tablet. If one or more of the tablets of a blister package were found to not meet the required tolerances, then the entire blister package would be rejected. Based upon the accuracy of dispensing module  420 , which will provide a very low rejection rate of tablets, this would still be a commercially viable process. Alternatively, any tablet that was rejectable would be removed from the blister package and replaced by another tablet that was taken from a reservoir of acceptable tablets.  
      It should be further understood by one of ordinary skill in the art that the degree of real-time monitoring and/or feedback can be varied depending upon the particular product being manufactured and/or based upon other factors. For example, but not limited to, the machine  10 ,  20  and  20 ′ may only utilize the high-speed imaging for detection of whether the dose droplet  2100  has accurately been dispensed upon carrier substrate  1000 . Preferably, the volume calculation of dose inspection system  460  is also utilized to calculate the amount of liquid dose  2000  in the dose droplet  2100 . However, the use of contemporary quality control techniques is also contemplated, such as batch sampling. Also, the present invention contemplates the use of contemporary quality control techniques, such as, for example, batch sampling, in parallel with the real-time monitoring and/or feedback described herein for machines  10 ,  20  and  20 ′.  
      It should be further understood by one of ordinary skill in the art that the various devices, techniques and/or systems described herein for machines  10 ,  20  and  20 ′ can be utilized by themselves or in combination with one or more of the other systems of machines  10 ,  20  and  20 ′ or in combination with contemporary devices for manufacturing pharmaceutical and pharmaceutical-like product. For example, but not limited to, the high-speed imaging and volume calculation of dose inspection system  460  may be followed by a contemporary batch sampling technique for quality control of the resulting pharmaceutical product  3000 .  
      The video imaging and volume calculation of dose inspection system  460  provides versatile real-time monitoring and feedback control for the pharmaceutical product  3000 . This type of quality control is not dependent on the particular formulation of the active agent in the liquid dose  2000 , as opposed to some forms of chemical imaging which have such dependency.  
      The present invention contemplates the use of other techniques for real-time monitoring and/or feedback control for machines  10 ,  20  and  20 ′ including both contact and non-contact methods. Alternative non-contact monitoring techniques include measurement of change in the capacitance before and after dispensing, measurement of electrical field produced by liquid dose  2000  due to magnetics, and micro-electro-mechanical-systems, such as, for example, utilizing piezo-resistive pressure sensors. An alternative contact monitoring technique includes measurement of the conductance of liquid dose  2000 . The present invention contemplates these alternative contact and non-contact techniques being used instead of either or both of the dose inspection system  460  and the dose confirmation system  600 , as well as in combination with either or both of the systems, where such alternative techniques are able to appropriately monitor the pharmaceutical product being processed, as desired.  
      It should also be noted that the terms “first”, “second”, “third”, “fourth”, “upper”, “lower”, and the like, are used herein to modify various elements. These modifiers do not imply a spatial, sequential, or hierarchical order to the modified elements unless specifically stated.  
      While the present invention has been described with reference to one or more exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the present invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the scope thereof. Therefore, it is intended that the present invention not be limited to the particular embodiment(s) disclosed as the best mode contemplated, but that the invention will include all embodiments falling within the scope of the appended claims.