System and method for simulation, modeling and scheduling of equipment maintenance and calibration in biopharmaceutical batch process manufacturing facilities

A method and computer program product for simulating, modeling and scheduling equipment maintenance and calibration procedures in a biopharmaceutical production facility is described herein. The method and computer program product includes the steps of identifying maintenance, and maintenance and calibration data associated with biopharmaceutical production process equipment. After the maintenance and calibration data are identified, biopharmaceutical production process equipment is used to generate a table of equipment and maintenance and calibration data. After the table of equipment and data is generated, the table is compared with a procedure time line to determine the schedule of calibration and maintenance for the equipment in the biopharmaceutical production process.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates generally to the design of large scale batch
 manufacturing facilities, and specifically to the design of
 biopharmaceutical drug manufacturing processes.
 2. Related Art
 Biopharmaceutical plants produce biopharmaceutical products through
 biological methods. Typical biopharmaceutical synthesis methods are
 mammalian cell culture, microbial fermentation and insect cell culture.
 Occasionally biopharmaceutical products are produced from natural animal
 or plant sources or by a synthetic technique called solid phase synthesis.
 Mammalian cell culture, microbial fermentation and insect cell culture
 involve the growth of living cells and the extraction of biopharmaceutical
 products from the cells or the medium surrounding the cells. Solid phase
 synthesis and crude tissue extraction are processes by which
 biopharmaceutical are synthesized from chemicals or extracted from natural
 plant or animal tissues, respectively.
 The process for producing biopharmaceutical is complex. In addition to
 basic synthesis, additional processing steps of separation, purification,
 conditioning and formulation are required to produce the end product
 biopharmaceutical. Each of these processing steps includes additional unit
 operations. For example, the step of purification may include the step of
 Product Adsorption Chromatography, which may further include the unit
 operations of High Pressure Liquid Chromatography (HPLC), Medium Pressure
 Liquid Chromatography (MPLC), Low Pressure Liquid Chromatography (LPLC),
 etc. The production of biopharmaceutical is complex because of the number,
 complexity and combinations of synthesis methods and processing steps
 possible. Consequently, the design of a biopharmaceutical plant is
 expensive.
 Tens of millions of dollars can be misspent during the design and
 construction phases of biopharmaceutical plants due to inadequacies in the
 design process. Errors and inefficiencies are introduced in the initial
 design of the biopharmaceutical production process because no effective
 tools for modeling and simulating a biopharmaceutical production process
 exists. The inadequacies in the initial process design carry through to
 all phases of the biopharmaceutical plant design and construction. Errors
 in the basic production process design propagate through all of the design
 and construction phases, resulting in increased cost due to change orders
 late in the facility development project. For example, detailed piping and
 instrumentation diagrams (P&IDs) normally cost thousands of dollars per
 diagram. Problems in the biopharmaceutical production process design
 frequently necessitate the re-working of these detailed P&IDs. This adds
 substantially to the overall cost of design and construction of a
 biopharmaceutical plant.
 There are generally three phases of biopharmaceutical plants which coincide
 with the different levels of drug approval by the FDA. A Clinical Phase
 I/II biopharmaceutical plant produces enough biopharmaceutical product to
 support both phase I and phase II clinical testing of the product which
 may involve up to a few hundred patients. A Clinical Phase III
 biopharmaceutical plant produces enough biopharmaceutical product to
 support two to three-thousand patients during phase III clinical testing.
 A Clinical Phase III plant will also produce enough of the
 biopharmaceutical drug to support an initial commercial offering upon the
 licensing of the drug by the FDA for commercial sale. The successive
 phases represent successively larger biopharmaceutical facilities to
 support full scale commercial production after product licensing. Often
 the production process design is repeated for each phase, resulting in
 increased costs to each phase of plant development.
 The design, architecture and engineering of biopharmaceutical plants is a
 several hundred million dollars a year industry because of the complex
 nature of biopharmaceutical production. Design of biopharmaceutical plants
 occurs in discrete phases. The first phase is the conceptual design phase.
 The first step in the conceptual design phase is identifying the
 high-level steps of the process that will produce the desired
 biopharmaceutical. Examples of high-level steps are synthesis, separation,
 purification and conditioning. After the high-level process steps have
 been identified, the unit operations associated with each of the
 high-level steps are identified. Unit operations are discrete process
 steps that make up the high-level process steps. In a microbial
 fermentation process, for example, the high-level step of synthesis may
 include the unit operations of inoculum preparation, flask growth, seed
 fermentation and production fermentation.
 The unit operation level production process is typically designed by hand
 and is prone to errors and inefficiencies. Often, in the conceptual design
 phase, the specifications for the final production process are not
 complete. Therefore some of the equipment design parameters, unit
 operation yields and actual production rates for the various unit
 operations must be estimated. These factors introduce errors into the
 initial design base of the production process. Additionally, since the
 production process is designed by hand, attempting to optimize the process
 for efficiency and production of biopharmaceutical products is
 impractically time consuming.
 Scale calculations for each of the unit operations are performed to
 determine the size and capacity of the equipment necessary to produce the
 desired amount of product per batch. Included in the scale calculations is
 the number of batches per year needed to produce the required amount of
 biopharmaceutical product. A batch is a single run of the
 biopharmaceutical process that produces the product. Increasing the size
 and capacity of the equipment increases the amount of product produced per
 batch. The batch cycle time is the amount of time required to produce one
 batch of product. The amount of product produced in a given amount of
 time, therefore, is dependent upon the amount produced per batch, and the
 batch cycle time. The scale calculations are usually executed by hand to
 determine the size and capacity of the equipment that will be required in
 each of the unit operations. Since the scale calculations are developed
 from the original conceptual design parameters, they are also subject to
 the same errors inherent in the initial conceptual design base.
 Typically a process flow diagram is generated after the scale calculations
 for the unit operations have been performed. The process flow diagram
 graphically illustrates the process equipment such as tanks and pumps
 necessary to accommodate the process for a given batch scale. The process
 flow diagram illustrates the different streams of product and materials
 through the different unit operations. Generally associated with the
 process flow diagram is a material balance table which shows the
 quantities of materials consumed and produced in each step of the
 biopharmaceutical production process. The material balance table typically
 includes rate information of consumption of raw materials and production
 of product. The process flow diagram and material balance table provides
 much of the information necessary to develop a preliminary equipment list.
 The preliminary equipment list shows the equipment necessary to carry out
 all of the unit operations in the manufacturing procedure. Since the
 process flow diagram, material balance table and preliminary equipment
 list are determined from the original conceptual design parameters, they
 are subject to the same errors inherent in the initial conceptual design
 base.
 A preliminary facility layout for the plant is developed from the process
 flow diagram, material balance table and preliminary equipment list. The
 preliminary facility layout usually begins with a bubble or block diagram
 of the plant that illustrates the adjacencies of rooms housing different
 high-level steps, as well as a space program which dimensions out the
 space and square footage of the building. From this information a
 preliminary equipment layout for the plant is prepared. The preliminary
 equipment layout attempts to show all the rooms in the plant, including
 corridors, staircases, etc. Mechanical, electrical and plumbing engineers
 estimate the mechanical, electrical and plumbing needs of the facility
 based on the facility design layout and the utility requirements of the
 manufacturing equipment. Since the preliminary facility layout is
 developed from the original conceptual design parameters, they are subject
 to the same errors inherent in the initial conceptual design base.
 Typically the next phase of biopharmaceutical plant design is preliminary
 piping and instrumentation diagram (P&ID) design. Preliminary P&IDs are
 based on the process flow diagram from the conceptual design phase. Often
 the calculations on the process design are re-run and incorporated into
 the preliminary P&ID. The preliminary P&IDs incorporate the information
 from the material balance table with the preliminary equipment list to
 show the basic piping and instrumentation required to run the
 manufacturing process.
 Detailed design is the next phase of biopharmaceutical plant design. Plans
 and specifications which allow vendors and contractors to bid on portions
 of the biopharmaceutical plant are developed during the detailed design.
 Detailed P&IDs are developed which schematically represent every detail of
 the process systems for the biopharmaceutical plant. The detailed P&IDs
 include for example, the size and components of process piping,
 mechanical, electrical and plumbing systems; all tanks, instrumentation,
 controls and hardware. A bill of materials and detailed specification
 sheets on all of the equipment and systems are developed from the P&IDs.
 Detailed facility architecture diagrams are developed that coincide with
 the detailed P&IDs and equipment specifications. The detailed P&IDs and
 facility construction diagrams allow builders and engineering companies to
 bid on the biopharmaceutical plant project. Since the preliminary and
 detailed P&IDs are developed from the original conceptual design
 parameters, they are subject to the same errors inherent in the initial
 conceptual design base. Reworking the preliminary and detailed P&IDs due
 to errors in the conceptual design phase can cost thousands of dollars per
 diagram.
 The inability to accurately model and simulate the biopharmaceutical
 production process drives inaccurate initial design. Often, these
 inaccuracies result in changes to the design and construction diagrams at
 the plant construction site, or repair and reconstruction of the plant
 during the construction phase resulting in millions of dollars in
 additional cost.
 Once the biopharmaceutical facility has been built, and is operational, the
 production equipment requires periodic service. Equipment maintenance and
 instrument calibration is necessary to sustain the biopharmaceutical
 production process. The types and frequency of maintenance and calibration
 required are a function of the particular equipment used in the facility,
 as well as the frequency and nature of use. The equipment involved in the
 production process, solution preparation process, and equipment
 preparation all require regular maintenance during sustained operation.
 Often, maintenance frequency and cost are not considered in the design of
 a biopharmaceutical production facility. Maintenance costs, however, are a
 significant fraction of the cost of operating the biopharmaceutical
 facility and producing the biopharmaceutical product. Equipment
 maintenance is typically scheduled, planned and managed manually which
 results in inefficiency and extra costs.
 The manual scheduling systems typically employed for planning equipment
 calibration and maintenance are generally inefficient and tedious. There
 may be several thousand maintenance and calibration points in a
 manufacturing plant all requiring different types and frequencies of
 maintenance and calibration as a function of their service in
 manufacturing operations. A maintenance or calibration error in an
 instrument can cause a critical step in a manufacturing operation to fail
 and result in loss of product.
 What is needed, therefore, is an advanced scheduling capability to
 accurately predict when various instruments and equipment require
 maintenance and calibration based on their cumulative service hours in
 order to more adequately insure integrity of the manufacturing processes.
 SUMMARY OF THE INVENTION
 The present invention satisfies the above-stated needs by providing a
 method and computer program product for simulating, modeling and
 scheduling equipment maintenance and calibration in the biopharmaceutical
 production process. The method and computer program product directly and
 more accurately links maintenance and calibration scheduling to cumulative
 equipment service hours than previously possible. The result will be more
 efficient planning and scheduling of equipment maintenance and calibration
 activities and enhanced integrity of manufacturing operations. The method
 and computer program product includes the steps of identifying maintenance
 and calibration data associated with biopharmaceutical production process
 equipment. After the maintenance and calibration data is identified,
 biopharmaceutical production process equipment data is used to generate a
 table of equipment and maintenance and calibration data. After the table
 of equipment maintenance and calibration data is generated, the table is
 compared with a procedure time line to determine the schedule of
 calibration and maintenance for the equipment in the biopharmaceutical
 production process.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 1.0 Biopharmaceutical Batch Process Simulator
 FIG. 1 illustrates a high-level flow diagram of the preferred embodiment.
 The process begins by determining the necessary reactor vessel capacity at
 step 102. The reactor vessel is the container in which the crude product
 is first synthesized. For example, in mammalian cell culture processes,
 the reactor vessel houses the mammalian cells suspended in growth media.
 Next, the unit operation sequence for production of the biopharmaceutical
 product is determined at step 104. The unit operation sequence is the
 series of unit operations that are required to produce the
 biopharmaceutical product. Each unit operation is an individual step in
 the biopharmaceutical manufacturing process with an associated set of
 manufacturing equipment. The unit operation list is the list of unit
 operations that make up the unit operation sequence and their associated
 sequence information. The unit operation sequence information is the
 information that defines the scheduling cycles for each of the unit
 operations in the unit operation list. Scheduling cycles are iterations
 ((the default being one (1)) of unit operations in the unit operation
 sequence. Together, the unit operation list and the unit operation
 sequence information define the unit operation sequence. The desired
 biopharmaceutical product dictates the particular unit operations and
 their order in the biopharmaceutical production process. Some examples of
 unit operations are: inoculum preparation, initial seeding of the reactor
 vessel, solids harvest by centrifugation, high-pressure homogenization,
 dilution, etc.
 Scheduling cycles and cycle offset duration for each of the unit operations
 in the biopharmaceutical production process are determined at step 106.
 Scheduling cycles are iterations of unit operations in the unit operation
 sequence, and occur in three levels. Additionally, each level of
 scheduling cycle has an associated offset duration that dictates the time
 period between the beginnings of successive scheduling cycles. "Cycles per
 unit operation" is the first level of scheduling cycles. Cycles per unit
 operation are defined as the number of iterations a unit operation is
 repeated in a process by itself before proceeding to the next unit
 operation. For example, the harvest and feed unit operation in a mammalian
 cell culture process has multiple cycles per unit operation. Product-rich
 media is drawn from the reactor vessel and nutrient-rich media is fed into
 the reactor vessel multiple times during one harvest and feed unit
 operation. The multiple draws of product-rich reactor media are pooled for
 processing in the next unit operation.
 The second level of scheduling cycles is "cycles per batch." Cycles per
 batch are defined as the number of iterations a set of consecutive unit
 operations are repeated as a group before proceeding to the next unit
 operation after the set of consecutive unit operations. The set of
 consecutive unit operations repeated as a group are also referred to as a
 subprocess. For example, the set of unit operations including inoculum
 preparation, flask growth, seed fermentation, production fermentation,
 heat exchange, and continuous centrifugation/whole-cell harvest in a
 microbial fermentation process are often cycled together. Running through
 each of the six steps results in a single harvest from the microbial
 fermentation reactor vessel. Multiple harvests from a reactor vessel may
 be needed to achieve a batch of sufficient quantity. Each additional
 harvest is pooled with the previous harvest, resulting in a single batch
 of cell culture for the process.
 The third level of scheduling cycles is "cycles per process." Cycles per
 process are defined as the number of iterations a batch cycle is repeated
 for a process that employs continuous or semi-continuous product
 synthesis. In such a case, a single biopharmaceutical production process
 may result in multiple batches of product. For example, in a mammalian
 cell-culture process a single cell culture is typically in continuous
 production for 60-90 days. During this period multiple harvests of crude
 product are collected and pooled on a batch basis to be processed into the
 end product biopharmaceutical. The pooling of multiple harvests into a
 batch of material will occur several times during the cell culture period
 resulting in multiple batch cycles per process.
 In step 108, a process parameters table master list is referenced to obtain
 all operational parameters for each unit operation in the unit operation
 list. The process parameters table contains a list of all unit operations
 and operational parameters necessary to simulate a particular unit
 operation. Examples of operational parameters are the solutions involved
 in a particular unit operation, temperature, pressure, duration,
 agitation, scaling volume, etc. Additionally, the process parameters table
 supplies all of the individual tasks and task durations involved in a
 particular unit operation. For example, the unit operation of inoculum
 preparation includes the individual tasks of setup, pre-incubation,
 incubation, and cleanup. Examples of unit operations for biopharmaceutical
 manufacturing and their associated operational parameters are included in
 this application as FIGS. 65A-65G.
 A block flow diagram is generated at step 110 after unit operation list has
 obtained the operational parameters from the process parameters table at
 step 108. The block flow diagram illustrates each unit operation in the
 manufacturing process as a block with inputs for both incoming product and
 new material, as well as outputs for both processed product and waste. The
 block flow diagram is a simple yet convenient tool for quantifying
 material flows through the process in a way that allows the sizing of many
 key pieces of equipment relative to a given process scale.
 The information in each block of the block flow diagram is generated from
 the parameters and sizing ratios from the process parameters table in the
 unit operation list, and block flow diagram calculation sets. A
 calculation set is a set of algebraic equations. The parameters and
 calculation sets are used to calculate the quantities of material inputs,
 product and waste outputs required for that unit operation based on the
 quantity of product material being received from the previous unit
 operation. Likewise, a given block flow diagram block calculates the
 quantity of product to be transferred to the next unit operation block in
 the manufacturing procedure. These calculations take into account the unit
 operation scheduling cycles identified at step 106, as further explained
 below.
 A process time line is generated at step 112 after the block flow diagram
 is generated at step 110. The process time line is a very useful feature
 of the present invention. The process time line is generated from the unit
 operation list, the tasks associated with each of the unit operations, the
 scheduling cycles for each of the unit operations in the process, the
 process parameters from the master process parameters table and the volume
 of the material as calculated from the block flow diagram. The process
 time line is a relative time line in hours and minutes from the start date
 of the production process. The relative time is converted into days and
 hours to provide a time line for the beginning and ending times of each
 unit operation and its associated tasks for the entire biopharmaceutical
 drug production process.
 The process time line is a very powerful tool for process design. The
 process time line can be used to accurately size pumps, filters and heat
 exchangers used in unit operations, by calculating the flow rate from the
 known transfer time and the volume of the material to be transferred,
 filtered or cooled. The process time line accurately predicts loads for
 labor, solution preparation, equipment cleaning, reagent, process
 utilities, preventative maintenance, quality control testing, etc.
 FIG. 2 further illustrates step 102 of determining the necessary reactor
 vessel capacity. The amount of biopharmaceutical product to be produced in
 a given amount of time is determined in step 202. Normally, the amount of
 biopharmaceutical product required is expressed in terms of mass produced
 per year. The number of reactor vessel runs for a particular
 biopharmaceutical product per year is determined at step 204. Factors
 considered when determining the number of reactor vessel cycles for a
 particular biopharmaceutical product are, for example, the number of
 biopharmaceutical products produced in the reactor vessel (i.e., the
 reactor vessel is shared to produce different products), the reaction time
 for each cycle of the reactor vessel and the percentage of up-time for the
 reactor vessel over the year.
 The yield of each batch or reactor cycle is calculated at step 206. The
 yield from each batch or a reactor cycle is process-dependent and is
 usually expressed in grams of crude product per liter of broth. Given the
 required amount of biopharmaceutical product per year from step 202, the
 number of reactor cycles available to produce the required
 biopharmaceutical product from step 204, and the yield of each reactor
 cycle from step 206, the necessary reactor volume to produce the required
 amount of biopharmaceutical product is calculated at step 208.
 FIG. 3 illustrates a unit operation list for an exemplary microbial
 fermentation biopharmaceutical production process. The far left-hand
 column, column 302, lists the unit operation sequence numbers for each of
 the unit operations in the process. The exemplary microbial fermentation
 unit operation list includes 23 unit operations. The unit operation
 sequence number defines the order in which the unit operations occur. For
 example, unit operation sequence number 1, inoculum preparation, occurs
 first, before unit operation sequence number 2, flask growth. Column 304
 shows the unit operation identifier codes associated with each of the unit
 operations in the unit operation list (see step 108). The unit operation
 identifier codes are used to bring operational parameters from the process
 parameters table into the unit operation list. For example, heat exchange,
 unit operation list numbers 5, 8 and 10, has a unit operation identifier
 code 51.
 As described above with reference to FIG. 1, after the unit operation
 sequence for a particular biopharmaceutical production process has been
 determined at step 104, the scheduling cycles associated with each unit
 operation is determined at step 106. Columns 306, 310 and 318 list the
 number of scheduling cycles for the microbial fermentation process of FIG.
 3. Scheduling cycles are iterations of unit operations in the unit
 operation sequence, and occur in three levels. Additionally, each level of
 scheduling cycle has an associated offset duration that dictates the time
 period between the beginnings of successive scheduling cycles, shown in
 columns 308, 316 and 324.
 Column 306 lists the number of cycles per unit operation for each of the
 unit operations in the microbial fermentation unit operation sequence. In
 the exemplary microbial fermentation unit operation sequence, each of the
 unit operations has only one cycle per unit operation. Again, cycles per
 unit operation define the number of iterations a unit operation is
 repeated in a process by itself before proceeding to the next unit
 operation.
 Column 308 lists the cycle offset duration in hours for the cycles per unit
 operation. Since each of the unit operations in the microbial fermentation
 example of FIG. 3 has only one cycle per unit operation, there is no cycle
 offset duration for any of the unit operations. Cycle offset duration
 defines the time period between the beginnings of successive scheduling
 cycles.
 Column 310 lists the cycles per batch for each of the unit operations in
 the microbial fermentation unit operation sequence. Unit operation
 sequence numbers 1-6 are defined as having three cycles per batch. Cycles
 per batch defines the number of iterations a set of consecutive unit
 operations are repeated as a group before proceeding to the next unit
 operation. In FIG. 3, for example, the set of unit operations 1-6, as
 defined in unit operation start column 312 and unit operation end column
 314, cycle together as a group (e.g., the sequence of unit operations for
 the exemplary microbial fermentation process is 1, 2, 3, 4, 5, 6, 1, 2, 3,
 4 ,5, 6, 1, 2, 3, 4, 5, 6 and 7). Unit operations 1-6 cycle together as a
 group three times before the process continues to unit operation 7, as
 defined in column 310.
 After unit operation sequence numbers 1-6 have cycled consecutively three
 times, the microbial fermentation production process continues at unit
 operation sequence number 7, resuspension of cell paste. After unit
 operation sequence number 7, the process continues with three cycles per
 batch of unit operation sequence numbers 8-10. The unit operations of heat
 exchange, cell disruption and heat exchange are cycled consecutively three
 times, as defined in columns 310, 312 and 314. After unit operation
 sequence numbers 8-10 have cycled three times, the microbial fermentation
 production process continues at resuspension/surfactant, unit operation
 sequence number 11.
 Unit operation sequence numbers 11 and 12 cycle together two times, as
 defined by columns 310, 312 and 314. After unit operation sequence numbers
 11 and 12 have been cycled two times, the microbial fermentation
 production process continues without cycling from unit operation sequence
 number 13 through unit operation sequence number 23 to conclude the
 microbial fermentation production process.
 Columns 326-332 of FIG. 3 represent the step wise recover (SWR) and overall
 recovery (OAR) percentages of the product and total proteins. SWR is the
 recovery of protein for the individual unit operation for which it is
 listed. OAR is the recovery of protein for the overall process up to and
 including the unit operation for which it is listed. The product recovery
 columns represent the recovery of the desired product protein from the
 solution in the process. The protein recovery columns represent the
 recovery of contaminant proteins from the solution which result in higher
 purity of the product solution.
 FIG. 4 illustrates a unit operation list for an exemplary mammalian cell
 culture production process. Column 402 lists unit operation sequence
 numbers 1-19. Unit operation sequence numbers 1-19 define the order in
 which the unit operations of the mammalian cell culture production process
 occur. The most notable differences between the microbial fermentation
 process of FIG. 3 and the mammalian cell culture process of FIG. 4 are the
 multiple cycles per unit operation of unit operation sequence number 8 and
 the multiple cycles per process of unit operation sequence numbers 8-18.
 Unit operation sequence number 8 of FIG. 4 illustrates the concept of
 multiple cycles per unit operation. Unit operation sequence number 8 is
 the unit operation of harvesting product rich growth media from and
 feeding fresh growth media into the mammalian cell reactor vessel. In most
 mammalian cell culture processes, the product is secreted by the cells
 into the surrounding growth media in the reactor vessel. To harvest the
 product, some of the product rich growth media is harvested from the
 reactor vessel to be processed to remove the product, and an equal amount
 of fresh growth media is fed into the reactor vessel to sustain production
 in the reactor vessel. The process of harvesting and feeding the reactor
 vessel can continue for many weeks for a single biopharmaceutical
 production process. Unit operation sequence number 8 is repeated seven
 times, or 7 cycles per unit operation (e.g., the unit operation sequence
 is 7, 8, 8, 8, 8, 8, 8, 8, 9). Note that the offset duration for unit
 operation sequence number 8 is 24 hours. The offset duration defines the
 time period between the cycles per unit operation. In the example of FIG.
 4, unit operation sequence number 8 is repeated 7 times (7 cycles per unit
 operation) and each cycle is separated from the next by 24 hours, or one
 day. This corresponds to unit operation sequence number 8 having a
 duration of one week, with a harvest/feed step occurring each day.
 FIG. 4 also illustrates the feature of multiple cycles per process. Cycles
 per process is defined as the number of iterations a batch cycle is
 repeated in a given process that employs continuous or semi-continuous
 product synthesis. Each batch cycle results in a batch of product. A
 single biopharmaceutical production process, therefore, may result in
 multiple batches of product. In the mammalian cell culture process example
 of FIG. 4, unit operation sequence numbers 8-18 are repeated together as a
 group eight times (column 418). Each of these cycles of unit operation
 sequence numbers 8-18 produce one batch of product (columns 420-422). The
 offset between each cycle of unit operation sequence numbers 8-18 is 168
 hours, or one week (column 424).
 In the example of FIG. 4, unit operation sequence numbers 8-18 proceed as
 follows: the reactor vessel is harvested and fed once each day for seven
 days; the results of the harvest/feed operation are pooled in unit
 operation sequence number 9 at the end of the seven days; unit operations
 9-18 are then executed to process the pooled harvested growth media from
 unit operation sequence number 8. Unit operation sequence numbers 8-18 are
 cycled sequentially once each week to process an additional seven day
 batch of harvested growth media from unit operation sequence number 8. At
 the end of eight weeks, the mammalian cell culture process is completed.
 FIG. 5 further illustrates step 108, cross referencing the unit operation
 sequence with the master process parameters table. The operational
 parameters in the process parameters table are those parameters necessary
 to simulate a particular unit operation. The parameters from the process
 parameters table define the key operational parameters and equipment
 sizing ratios for each unit operation in the unit operation sequence. The
 values for these parameters and ratios are variables which can be easily
 manipulated and ordered to model and evaluate alternative design scenarios
 for a given process scale. Examples of the process parameters associated
 with each unit operation are listed in FIGS. 65A-65G. It should be noted,
 however, that the list of unit operations, parameters, values, and scaling
 ratios is not exhaustive. One of ordinary skill in the art could expand
 the process parameters table to encompass additional unit operations and
 production processes for other batch process industries such as chemical
 pharmaceutical, specialty chemical, food, beverage and cosmetics. Such
 expansion would allow the present invention to simulate and schedule
 additional batch production processes for other such batch processes.
 FIG. 5 illustrates the files necessary to cross-reference the unit
 operation list with the process parameters table in step 108. Exemplary
 unit operation list 502 for the biopharmaceutical production process and
 process parameters table 504 are input into processing step 506. Step 506
 cross-references the unit operation list and process parameters table
 based on unit operation identification code (see FIG. 3). The parameters
 are copied from the process parameters table 504 into the unit operation
 list 502 to generate unit operation list 508.
 FIG. 6 further illustrates exemplary process parameters table, 504. The
 operational parameters in the process parameters table are those
 parameters necessary to simulate a particular unit operation. The unit
 operation identification codes of process parameters table 504 are used in
 the cross-reference step 506 to assign the parameters from the process
 parameters table 504 to the unit operation list 502. Examples of
 operational parameters are the solutions involved in a particular unit
 operation, temperature, pressure, duration, agitation, scaling volume,
 etc. Additionally, the process parameters table defines all of the
 individual tasks and task durations involved in each unit operation. It
 should be noted, however, one of ordinary skill in the art could expand
 the process parameters table to encompass additional unit operations and
 production processes for other batch process industries such as chemical
 pharmaceutical, specialty chemical, food, beverage and cosmetics. Such
 expansion would allow the present invention to simulate and schedule
 additional batch production processes for other such batch processes.
 FIG. 7 further illustrates step 110, generating a block flow diagram. A
 block flow diagram depicts each unit operation in the biopharmaceutical
 production process as a block with inputs for both incoming product and
 new material, as well as outputs for both processed product and waste. The
 material that flows through each of the unit operation blocks is
 quantified by calculation sets in each of the block flow diagram blocks. A
 unit operation block in a block flow diagram is a graphical representation
 of a unit operation. A calculation set is a set of algebraic equations
 describing a unit operation. Some examples of outputs of the calculation
 sets are: required process materials for that unit operation, equipment
 performance specifications and process data outputs to be used for the
 next unit operation. Some examples of inputs to the calculation sets are:
 product quantity (mass) or volume (liters) from a previous unit operation,
 other parameters and/or multipliers derived from the process parameters
 table, as well as the design cycles defined in the unit operation list.
 Block flow diagram 708 is generated from unit operation list 508 and block
 flow diagram calculation set 704. Block flow diagram calculation set 704
 is an exhaustive list of unit operation identifier codes and the
 calculation sets associated with each unit operation identifier. Unit
 operation list 508 and block flow diagram calculation set 704 are linked
 together based on unit operation identifier code.
 Step 706 calculates the block flow diagram material flow requirements and
 basic equipment sizing requirements from unit operation list 508 which
 includes all of the associated operational parameters from the process
 parameters table, and the block flow diagram calculation set 704. Block
 flow diagram 708 allows the sizing of many key pieces of equipment
 relative to a given process scale. Since the material flow quantities into
 and out of each unit operation is determined at step 706, the capacity of
 many equipment items involved in each unit operation can be determined.
 The block flow diagram also manages important information in the unit
 operation list 502 such as the percent recovery, percent purity and
 purification factor of the product in each unit operation. This
 information helps identify the steps in the process that may need
 optimization.
 The following is an example calculation set for a tangential flow
 micro-filtration (TFMF) system unit operation. Tangential flow
 micro-filtration is an important process technology in biopharmaceutical
 manufacturing. This technology significantly extends the life of the
 filtration media and reduces the replacement cost of expensive filters.
 TFMF generically requires the same steps to prepare the membrane for each
 use as well as for storage after use. The design parameters for each unit
 operation such as TFMF have been developed around these generic design
 requirements.
 Generic Parameters (Variables) from the Process Parameters Table

Equipment Design Type Plate & Frame
 Membrane Porosity 0.2 micron
 Membrane Flux rate 125 Liters/square meter/hour
 Process Time 2 Hours
 Redounded/Filtrate Rate 20 to 1
 Flush volume 21.5 Liters/square meter
 Prime volume 21.5 Liters/square meter
 Wash Volume 0.5% of Process Volume
 Regenerate Volume 10.8 Liters/square meter
 Storage Volume 215 Liters/square meter
 % Recovery of Product 95%
 % Recovery of Total Protein 80%
 Clean In Place (CIP) Yes
 Steam In Place (CIP) Yes
 Input Values from Previous Unit Operation

Product Volume 1,000 Liters
 Product Quantity 5 Kg
 Total Protein Quantity 3.0 Kg
 The calculation set for this unit operation first takes the incoming
 process volume and uses it as a basis of sizing the filtration membrane
 for the filtration system based on the above flux rate and required
 processing time.
EQU 1,000 Liters /125 L/SM/Hr / 2 Hours=4.0 SM of 0.2 micron membrane
 After calculating the square meter (SM) of membrane required by this unit
 operation, the volumes of each of the support solutions can be calculated
 based on the above volume ratios.

Flush volume 21.5 Liters/SM .times. 4.0 SM = 86 Liters
 Prime volume 21.5 Liters/SM .times. 4.0 SM = 86 Liters
 Wash Volume 5% of 1,000 Liters = 50 Liters
 Regenerate 21.5 Liters/SM .times. 4.0 SM = 86 Liters
 Storage 10.8 Liters/SM .times. 4.0 SM = 42 Liters
 The flow rate of the filtrate is calculated from the volume to be filtered
 and the required process time.
EQU 1,000 Liters / 2 Hours=8.3 Liters/minute
 The flow rate of the retentate is calculated based on the above
 retentate/filtrate ratio.
EQU 8.3 Liters per minute.times.20 =167 Liters/minute
 Based on the input of the process volume to this unit operation and the
 above parameters, the equipment size, the filtration apparatus, the
 retentate pump, the support linkage and associated systems can be
 designed.
 In addition, the input values for the quantity of product and contaminant
 protein received from the previous unit operation together with the
 recovery factors listed in the parameters allow the calculation of the
 cumulative recovery of product through this step, as well the percent
 purity of the product and the product purification factor for this step.
 This information is helpful for identifying steps in the manufacturing
 process which require optimization.
 FIG. 8 illustrates an exemplary block flow diagram for the first five unit
 operations of the microbial fermentation process unit operation list of
 FIG. 3. Unit operations 1 through 5 are shown as blocks 802, 804, 806, 808
 and 810. The input solutions to each of the steps are shown as arrows
 tagged with solution identifier information from the unit operation list
 508. The process streams to which these solutions are added at each unit
 operation are also shown as arrows tagged with process stream identifier
 information. Working from the initial process stream characteristics
 (P-101) in unit operation 1, inoculum prep, the volumes of input materials
 (solutions) and subsequent process streams in each of the unit operations
 is determined using scale-up ratios which are included in the information
 from the unit operation list 508 for each respective unit operation. For
 example, the volume of solutions and process streams flowing into and out
 of each of unit operation blocks 802-810 in FIG. 8 is determined by the
 initial starting characteristics of the process stream P-101 and the
 volume of its associated input material S-101 in the first unit operation,
 block 802 and the scale up ratio in each of the successive unit
 operations, blocks 804-810. The solutions involved in each of unit
 operation blocks 802-810 are likewise part of the information for each
 respective unit operation in the unit operation list 508.
 FIG. 9 further illustrates step 112, generating the process time line. The
 process time line is generated (steps 904-906) from unit operation list
 508 and block flow diagram calculation set 704. Unit operation list 508
 contains enough input information to generate a detailed process time line
 which includes the start and stop times for most of the tasks associated
 with each unit operation. The durations of some unit operation tasks are
 not scale dependent. The durations of other unit operation tasks are,
 however, scale dependent. In the latter case, as a process is scaled up,
 the amount of time required to complete a unit operation task increases.
 In such cases, where duration of a unit operation task is scale dependent,
 block flow diagram calculation set 704 is required to calculate the
 quantity of material handled by the unit operation task. After the
 quantity of material handled by a unit operation task is determined, its
 duration can be determined. Examples of scale dependent task durations are
 the time required to pump solutions from one storage tank to another, the
 amount of time required to heat or cool solutions in a heat exchanger, the
 amount of time required to filter product or contaminants from solution.
 FIG. 10 is an example of a high-level process time line for a microbial
 fermentation process. The unit operation sequence of the process time line
 of FIG. 10 corresponds to the unit operation list of FIG. 3. The
 high-level process time line shown in FIG. 10 illustrates two process
 cycles of the microbial fermentation unit operation sequence, labeled
 "First Process Cycle" and "Second Process Cycle." A process cycle is a
 complete run of the biopharmaceutical production process, as defined by
 the unit operation sequence for the process.
 The first two columns of the process time line of FIG. 10 identify the unit
 operation sequence number and unit operation description of the unit
 operation being performed, respectively. The first three sets of unit
 operations correspond to the three cycles per batch of unit operation
 sequence numbers 1-6 of FIG. 3. Three cycles of unit operations 1-6 are
 performed and the results are pooled into unit operation 7, pool harvests.
 The two columns to the right of the duration column identify the week and
 day that the particular unit operation is occurring in the first process
 cycle.
 The day and the week each unit operation is performed is calculated from
 the start time of the process, as well as the cumulative duration of each
 of the previous unit operations. In the example of FIG. 10, Sunday is
 defined as the first day of the week. In the example of FIG. 10, the
 process sequence begins at unit operation 1, inoculum prep, on Friday of
 the first week. After unit operation 1 has completed (24 hours later,
 since unit operation 1 has a 24 hour duration) unit operation 2 is
 performed on Saturday. The begin and end times for each successive unit
 operation are calculated from the duration of the unit operation and end
 time of the previous unit operation. Note that FIG. 10 is calculated to
 the day and week only for the purposes of explanation. Usually the process
 time line is determined for each of the tasks associated with a unit
 operation to the minute.
 As illustrated in FIG. 10, unit operation 7 occurs on Monday of the third
 week in the first process cycle. The third column from the left is the
 duration of each of the unit operations. After the three cycles of unit
 operations 1 through 6 have been pooled in unit operation 7, the process
 continues at unit operations 8 through 10, heat exchange, cell disruption
 and heat exchange. Each of unit operations 8 through 10 are cycled three
 times and the associated scheduling information is contained in column to
 the right of the unit operation duration. Since each cycle of unit
 operations 8 through 10 have a duration of 0.5 hours, as shown in column
 3, each cycle occurs on Monday of the third week in the process.
 FIG. 11 illustrates the final unit operations of the process time line for
 the microbial fermentation process. After 3 cycles of unit operations 8
 through 10 have been completed, unit operation sequence numbers 11 and 12
 cycle together two times on Monday, week 3 of the first process cycle.
 After unit operation sequence numbers 11 and 12 have been cycled twice,
 the microbial fermentation production process continues without cycling
 from unit operation sequence number 13 through unit operation sequence
 number 22 to conclude the microbial fermentation production process. The
 durations and associated start times are listed for each of the unit
 operations 13-22.
 FIGS. 12A-12H illustrate the preferred embodiment of a detailed process
 time line. The unit operation sequence of the process time line of FIGS.
 12A-12H correspond to the unit operation list of FIG. 3. The process time
 line of FIGS. 12A-12H illustrates a single process cycle of the microbial
 fermentation unit operation sequence. The individual tasks associated with
 each unit operation are included after the unit operation. For example, in
 FIG. 12A, unit operation 1A, inoculum prep, consists of the individual
 tasks of set up, pre-incubation, incubation, and clean up. Columns 11-14
 show the start date and time and finish date and time for each of the
 tasks in each unit operation. Since setup and clean up are not part of the
 critical path of the process, they do not directly affect the start and
 end times of following unit operations. The start and finish date and
 times for the set up and clean up operations of each of the unit
 operations are valuable because they ensure that the equipment will be
 available for each unit operation if the process time line is followed.
 The process time line of FIGS. 12A-12H includes examples of unit operation
 task duration calculations. Row 20, column 15 of FIG. 12A, which
 corresponds to the harvest task of unit operation 3A, seed fermentation,
 is an example of a duration calculation. As stated above, the duration of
 some unit operations is process scale dependent (i.e., the duration is
 dependent upon the volume processed). The harvest task in the seed
 fermentation unit operation is an example of a task whose duration is
 process scale dependent. In column 15, the calculations column,
 information listed for the harvest task is 50 liters, 1.7 liters/minute
 (LPM), and 0.5 hours. Fifty liters represents the volume of material that
 is harvested during a harvest task. 1.7 liters/minute represents the rate
 at which the solution is harvested. Given the volume to be harvested and
 the flow rate of the harvest, the duration of the harvest task is
 calculated to be 0.5 hours. Each task in a unit operation that is volume
 dependent has its duration calculated in order to generate the process
 time line of FIGS. 12A-12H.
 The process time line of FIGS. 12A-12H can be resolved to minutes and
 seconds, if necessary. The accuracy of the process time line allows the
 precise planning and scheduling of many aspects of the batch manufacturing
 process. The process time line scheduling information can be used to
 schedule manufacturing resources such as labor, reagents, reusables,
 disposables, etc., required directly by the manufacturing process.
 Pre-process support activities such as solution preparation, and equipment
 prep and sterilization, required to support the core process, including
 the labor, reagents, etc. can be scheduled, cost forecasted and provided
 for. Post-process support activities such as product formulation, aseptic
 fill, freeze drying, vial capping, vial labeling and packaging required to
 ship the purified product in a form ready for use may be added to the
 process time line and managed. Based on the process time line, labor,
 reagents, etc., required to support these post-process support functions
 can be acquired and managed. One of the most important aspects of the
 present invention is the determination of process utility loads such as
 USP Purified Water, Water For Injection, Pure Steam, etc., for all of the
 manufacturing equipment. The process time line can be used to determine
 the peak utility loading, and utility requirements for the facility.
 Building utility loads such as building steam, heating, ventilation, air
 conditioning, plumbing, etc., for all manufacturing equipment, process
 areas and facility equipment can be determined based on the process time
 line and the equipment associated with each of the unit operations. The
 process time line can be used to measure the time that the equipment has
 been in service to schedule preventative maintenance of all plant
 equipment, Quality Assurance activities including instrument calibration,
 automated batch documentation, etc. and Quality Control activities
 including process system maintenance, raw material testing, in process
 testing and final product testing, etc.
 2.0 Solution Preparation Scheduling Module
 The preferred embodiment of the present invention is a computer based
 system and method for the simulation, modeling and scheduling of batch
 process solution preparation. The preferred embodiment is based on a
 method for generating scheduling information which accurately defines the
 complex manufacturing operations of solution preparation in batch
 manufacturing processes. This scheduling capability system allows the
 definition of manufacturing costs and systems in a more detailed and
 accurate manner than previously possible. As a result, this invention
 allows the rapid and accurate evaluation of numerous batch manufacturing
 alternatives in order to arrive at an optimal process design early in a
 facility development project. In so doing the invention minimizes project
 cost over runs which result from inaccuracies that can carry forward from
 the early stages of design into construction. The invention also allows
 the accurate scheduling of solution preparation activities in an operating
 manufacturing plant, including the scheduling of resources required by
 solution preparation such as labor, reagents, disposables, reuseables,
 utilities, equipment maintenance & calibration, etc.
 The object of the solution preparation scheduling module is to assign each
 solution to a solution preparation vessel and to generate a solution
 preparation schedule for each solution preparation vessel. Scheduling
 solution preparation in each solution preparation vessel allows the
 biopharmaceutical production process designer to manage, predict and
 optimize solution preparation vessel inventory, equipment cost, utility
 requirements, clean and preparation and other solution preparation
 associated activities.
 FIG. 13 is a flow chart providing an overview of the process for scheduling
 and simulating solution preparation in a biopharmaceutical production
 process. Step 1302 determines the solution preparation time for each
 solution preparation vessel. A solution preparation vessel is a vessel
 used for the preparation of solution used in the biopharmaceutical
 production process. In the preferred embodiment, each type of solution
 preparation vessel used in the biopharmaceutical production process has an
 associated solution preparation time. The solution preparation time is the
 amount of time it takes to prepare solution in the solution preparation
 vessel. Preparation of one solution preparation vessel's volume of
 solution is called a solution preparation cycle. Each solution preparation
 vessel has associated solution preparation parameters. Solution
 preparation parameters describe the amount of time necessary to complete
 various steps in the solution preparation process.
 Step 1304 assigns the solutions in the biopharmaceutical production process
 to particular solution preparation vessels. Solutions are assigned to
 particular vessels in order to schedule and determine the load on the
 solution preparation vessels. Step 1304 includes the procedure of
 determining the total volume of each solution needed for the
 biopharmaceutical production process and assigning it to a preparation
 vessel of the appropriate size. Large volume solutions can be prepared in
 smaller multiple solution preparation cycles and pooled to yield a higher
 volume batch of solution. Conversely, smaller volume solutions can be
 batch prepared in larger preparation volumes to accommodate multiple
 process cycles provided the shelf life of these solutions allow longer
 storage times.
 Step 1306 determines the calculated start date and the next preparation
 date of each solution. The calculated start date for the preparation of a
 solution is the date which solution preparation should begin in order to
 have the solution ready for use in the biopharmaceutical process. The
 calculated start date takes into account the amount of time necessary to
 prepare the solution, and other lead time factors necessary for
 preparation of solution. The next preparation date is the earliest date
 that a solution will be prepared after its calculated start date. The next
 preparation date is determined by adding the periodicity of solution
 preparation to the calculated start date. The periodicity of solution
 preparation is how often each solution must be prepared in order to
 sustain the biopharmaceutical production process.
 Step 1308 determines the earliest solution preparation date for each
 solution preparation vessel for a given process cycle. Since each solution
 has been assigned to a solution preparation vessel, and the calculated
 start dates for each solution have been determined, step 1308 determines
 the earliest calculated start date for each solution preparation vessel.
 The earliest calculated start date associated with a solution preparation
 vessel is the date which the first solution is prepared in the vessel for
 a given process cycle. The earliest calculated start date associated with
 a solution preparation vessel identifies the point in the process cycle by
 which the preparation vessel must be available.
 Step 1310 determines the latest next preparation date for each solution
 preparation vessel. The latest next preparation date for each solution
 preparation vessel is the date that a solution preparation vessel is last
 used for solution preparation to support a given process cycle. Based on
 the solution to solution preparation vessel assignments determined in step
 1304, the earliest calculated start date for each solution and the next
 preparation dates for each of the solutions determined in step 1306, step
 1310 determines the latest next preparation date for each solution
 preparation vessel. The earliest calculated start date and the latest next
 preparation date associated with a solution preparation vessel define the
 usage boundaries of the solution preparation vessel in the process cycle.
 The loading of a solution prep vessel can be evaluated during the time
 between the earliest calculated start date and the latest next preparation
 date. In the case where the usage boundary is set by a solution which is
 batch prepared to accommodate multiple process cycles, the usage boundary
 of a tank includes these multiple process cycles. Therefore the loading on
 a solution preparation vessel in this instance will also account for
 solutions from multiple process cycles.
 The duration of time between the first biopharmaceutical production process
 activity related to a given process and the last biopharmaceutical
 production process activity related to that process may be called a
 manufacturing cycle (i.e., multiple process cycles define a manufacturing
 cycle). In the case where an activity, such as the preparation of a
 solution, accommodates multiple process cycles, a manufacturing cycle
 consists of multiple process cycles. In the case where all the activities
 associated with a process only accommodate one process cycle a
 manufacturing cycle consists of only one process cycle. Therefore
 manufacturing cycles may consist of one or more process cycles with their
 related support activities.
 Step 1311 calculates the use duration for each solution preparation vessel.
 The use duration for each solution preparation vessel is the time that a
 solution preparation vessel is occupied with the preparation of solution
 for a manufacturing cycle. For example, when multiple solutions are
 assigned to a single solution preparation vessel, the use duration for the
 solution preparation vessel is determined based on the earliest calculated
 start date and the latest next preparation date for all of the solutions
 assigned to the solution preparation vessel. The total number of hours the
 solution preparation vessel is occupied can be calculated from the use
 duration (days) and the number of shift hours per day for the particular
 manufacturing cycle (e.g., single shift operation would normally be 8
 hours per day).
 Step 1312 calculates the cumulative solution preparation time for each
 solution preparation vessel. The cumulative solution preparation time is
 the amount of time a solution preparation vessel is occupied with the
 preparation of solutions in a biopharmaceutical manufacturing cycle. Step
 1312 calculates the cumulative solution preparation time for each solution
 preparation vessel based on:
 1) the solutions assigned to a particular vessel;
 2) the prep vessel use duration;
 3) the duration of a process cycle;
 4) the number of preps of a solution per process cycle; and
 5) solution preparation times.
 For example, if five solutions are to be prepared in a particular solution
 preparation vessel each requiring two preparations per process cycle,
 process cycle durations of seven days, solution preparation times of three
 hours, during a use duration of fourteen days, the cumulative solution
 preparation time for the solution preparation vessel would be sixty hours
 over a two week period.
 Step 1314 determines the percent utilization of each solution preparation
 vessel. The percent utilization of each solution preparation vessel is the
 fraction of the use duration that the solution preparation vessel is
 actually engaged in the preparation of solution, or the cumulative
 solution preparation time. The percent utilization is determined based on
 the use duration, cumulative solution preparation time and the number of
 hours per solution prep shift for the process cycle. For example, if the
 use duration for a solution preparation vessel is fourteen days, and there
 are eight shift hours per day, then the solution preparation vessel has a
 total availability of one hundred twelve hours. If, as calculated above,
 the cumulative solution preparation time for the solution preparation
 vessel is sixty hours, then the percent utilization of the solution
 preparation vessel is approximately fifty-four percent. The percent
 utilization of each solution preparation vessel is determined in step 1314
 so that the biopharmaceutical production process planner is able to gauge
 the level of utilization of the solution preparation equipment and make
 any adjustments in the solution preparation equipment pool or production
 cycles.
 Step 1316 generates the initial shift schedule for each solution
 preparation vessel. The initial shift schedule is a daily schedule of
 solutions to be prepared in a particular solution preparation vessel. Step
 1316 generates the initial shift schedule based on the calculated start
 date for each solution, the periodicity of solution preparation for each
 solution and the solution to solution preparation vessel assignment.
 Step 1318 back schedules solution preparation procedures that do not fit in
 the shift schedule and checks for system capacity problems. Back
 scheduling is the process of rescheduling solution preparation cycles for
 previous days or time slots. The initial shift schedule is generated
 regardless of the number of hours a solution preparation vessel is
 occupied for a particular day. For example, the initial shift schedule may
 have a particular solution preparation vessel scheduled for fourteen hours
 of solution preparation. In a biopharmaceutical production process that
 operates sixteen hours a day, all of the solutions scheduled for the
 solution preparation vessel can be accommodated. If, however, the
 biopharmaceutical production process operates only eight hours a day, not
 all of the required solutions may be prepared on the scheduled date. Step
 1318 back schedules to earlier days those solution preparation cycles that
 cannot be completed on the initially scheduled day. The scheduling of a
 back scheduled solution preparation cycle into an available shift is
 performed according to the priority of the oldest back scheduled date for
 all available back scheduled solutions. The end result of step 1318 is to
 generate a final shift schedule for each prep vessel which assigns the
 appropriate solutions to that vessel and schedules out the preparation of
 each solution according to shift capacity, the duration of each prep
 assigned to that shift.
 Step 1320 generates a time line for the operation of each solution prep
 vessel and its associated equipment according to the shift assignments in
 the final shift schedule and the durations associated with each solution
 prep step in the solution prep procedure table. Based on this time line
 resources requirements for labor, reagents, disposables, reusables,
 utilities, maintenance, etc., can be accurately scheduled.
 FIG. 14 further illustrates step 1302, determining the solution preparation
 time for each solution preparation vessel. Step 1302 begins at step 1420
 determining the setup time for a solution preparation vessel. Step 1420
 compares a list of solution preparation vessels 1402 that are available
 for use in the biopharmaceutical production process and their associated
 solution preparation vessel identifiers with a master list of solution
 preparation vessel identifiers and their associated set up times 1410.
 Solution identifiers and solution preparation vessel identifiers are keys
 or tags that identify individual solution preparation vessel and solution
 types. Examples of solution preparation vessel set up times are
 illustrated in FIG. 15, column 1410. List of solution preparation vessels
 1402 includes the minimum/maximum working volumes for each vessel, as well
 as the particular tasks associated with the solution preparation vessel
 and any process equipment necessary to complete solution preparation. The
 solution preparation tasks and equipment may be included in the total
 solution preparation time 1428 for use in equipment preparation and
 scheduling.
 Next, step 1408 determines the water collection time for each preparation
 vessel. The water collection time is the amount of time necessary to fill
 the maximum working volume 1406 of the solution preparation vessel at the
 water collection rate 1404. Water collection rate 1404 is the rate at
 which the solution preparation vessel can be filled. Different solution
 preparation vessels have different water collection rates, depending on
 their specific water collection hardware. Step 1408 estimates the water
 collection time for each solution preparation vessel based on its maximum
 working volume 1410 and the water collection rate 1404. In the preferred
 embodiment, the volume of water to be collected is assumed to be the
 preparation vessel maximum working volume 1406. In alternative
 embodiments, the volume of water to be collected can be the actual volume
 of solution prepared in the solution preparation cycle. Examples of water
 collection rate 1404, maximum working volume 1406 and water collection
 time 1502 are illustrated in FIG. 15, columns 1404, 1406 and 1502,
 respectively.
 Step 1414 defines the weigh and mix times associated with each solution
 preparation vessel. Weigh and mix time 1416 is the time required to weigh,
 mix and adjust the components of a solution. Preparation vessel
 identifiers 1402 are matched with the associated preparation vessel weigh
 and mix time 1416. The weigh and mix time 1416 associated with each
 solution preparation vessel in the biopharmaceutical process is thereby
 assigned to the associated solution preparation vessel identifier 1402.
 The default weigh and mix time variables can be manipulated by the process
 designer. Examples of weigh and mix time 1416 are illustrated in FIG. 15,
 column 1416.
 Next, step 1418 determines the time required to filter the solution in a
 preparation vessel. The time required to filter the solution in a
 preparation vessel is the amount of time post-preparation filtering and
 transfer of the prepared solution out of the solution preparation vessel
 requires. Step 1418 calculates the time required to filter the solution in
 a preparation vessel based on preparation vessel identifier 1402,
 preparation vessel maximum working volume 1406, filtration flux rate 1424
 and surface area of filtration media 1412. In the preferred embodiment,
 the volume of solution to be filtered is assumed to be the preparation
 vessel maximum working volume 1406. In alternative embodiments, the volume
 of solution to be filtered can be the actual volume of solution prepared
 in the solution preparation cycle. The surface area of the filtration
 media 1412 is the area of the filtration media used to filter the solution
 as it is transferred out of the solution preparation vessel. Filtration
 flux rate 1424 is the rate per unit area that the solution is can be
 filtered through the filtration media. Examples of filtration flux rate
 1424 and surface area of filtration media 1412 are illustrated in FIG. 15,
 columns 1424 and 1412, respectively.
 Step 1426 calculates the adjusted filtration time. The adjusted filtration
 time is the filtration time as determined in step 1418 multiplied by the
 filtration delay factor 1430. Filtration delay factor 1430 is based on the
 additional filtration time typically required to manipulate solution
 storage vessels on a fill line. Step 1426 calculates the adjusted
 filtration time by multiplying the filtration time calculated in step 1418
 by the filtration delay factor 1430. FIG. 15, column 1430 shows exemplary
 values for filtration delay factor 1430.
 Step 1432 determines clean in place and steam in place durations associated
 with each solution preparation vessel. Clean in place duration 1422 and
 steam in place duration 1434 are the durations of the cleaning procedures
 necessary to prepare a solution preparation vessel for use in the next
 solution preparation cycle. Step 1432 matches preparation vessel
 identifiers 1402 with clean in place duration 1422 and steam in place
 duration 1434 to determine the clean in place duration 1422 and steam in
 place duration 1434 times associated with each of the solution preparation
 vessel used in the biopharmaceutical production process. FIG. 15, columns
 1422 and 1434 illustrate exemplary values for clean in place duration 1422
 and steam in place duration 1434, respectively.
 Step 1436 calculates total solution preparation time 1428 for each
 preparation vessel by summing the time values calculated in steps 1420,
 1408, 1414, 1418, 1426 and 1432. Total solution preparation time 1428
 represents the amount of time required to prepare the maximum working
 volume 1406 of solution in a particular solution preparation vessel. It
 should be noted, however, that one of ordinary skill could expand the
 calculation of total solution preparation time 1428 to include additional
 steps, factors or parameters other than those described herein. Such
 expansion would allow the present invention to calculate the total
 solution preparation time 1428 for a solution preparation vessel more
 accurately, or to include additional factors in the calculation. In
 addition, the calculation of total solution preparation time 1428 for a
 solution preparation vessel could also be adjusted to accommodate solution
 preparation working volumes which are less than the maximum solution
 preparation working volumes for a given solution prep vessel. Column 1428
 of FIG. 15 provides exemplary values for total solution preparation time
 1428.
 FIG. 15 shows an exemplary list of solution preparation parameters.
 Examples of such parameters are minimum working volume 1402, maximum
 working volume 1406, set up time 1410, water collection rate 1404, water
 collection time 1502, weigh and mix time 1416, square area of filter media
 1412, volume per unit of filter area per hour 1424 and post-solution
 preparation and cleaning procedure duration 1422, 1434.
 Minimum working volume 1402 and maximum working volume 1406 are the minimum
 and maximum volumes of solution a solution preparation vessel can prepare.
 Set up time 1410 is the amount of time necessary to prepare a solution
 preparation vessel for the solution preparation process. Water collection
 time 1404 is the time necessary to fill the solution preparation vessel
 with the maximum working volume 1406 of water. Weigh and mix time 1416 is
 the time necessary to weigh and mix the ingredients of a solution in a
 particular solution preparation vessel. Square area of filter medium 1412
 is the area of the filter associated with a particular solution
 preparation vessel. Volume per unit of filter area per hour 1424 is the
 flux rate per unit of filter area associated with a particular solution
 preparation vessel. Post solution preparation and cleaning procedure
 duration 1422 and 1434 are the times associated with preparing the
 solution preparation vessel after the preparation of a batch of solution.
 FIG. 16 further illustrates step 1304, assigning the solutions required by
 the biopharmaceutical production process to particular solution
 preparation vessels. In order to schedule solution preparation cycles,
 each solution must be assigned to a solution preparation vessel. Step 1304
 begins with step 1602. Step 1602 sets the preparation cycles per batch for
 a solution to be prepared. Preparation cycles per batch 1608 are the
 number of times a solution is prepared in a solution preparation vessel to
 support one product batch cycle. For example, if one-hundred and fifty
 liters of solution 101 is required to make a batch of product in a
 biopharmaceutical production process and the solution is to be prepared in
 a fifty liter solution preparation vessel, solution 101 may be prepared in
 three preparation cycles per batch of fifty liters each, yielding a 150
 liter batch of solution 101. Alternatively, solution 101 may be prepared
 in four preparation cycles per batch of thirty-seven and one-half liters
 each in a solution preparation vessel of at least thirty-seven and
 one-half liters. In the preferred embodiment, preparation cycles per batch
 1608 of solution is initially set by the designer. Preparation cycles per
 batch 1608 will affect values throughout the solution preparation
 scheduling module and the solution preparation procedure as a whole. The
 number of preparation cycles per batch 1608 for each solution will dictate
 the size of a solution preparation vessel and the time required to prepare
 a batch of solution.
 Step 1606 determines the number of days per solution preparation cycle 1610
 for each of the solutions involved in the biopharmaceutical production
 process. The number of days per solution preparation cycle 1610 is
 determined from preparation cycles per batch 1608 and days per batch cycle
 1604. The batch cycle time is the amount of time required to produce one
 batch of product. Days per batch cycle 1604 is the number of days between
 successive batches of product. The number of days per preparation cycle
 1610 is the number of days between the beginnings of each solution
 preparation. Dividing the number of days per batch cycle by the
 preparation cycles per batch 1608 yields the number of days per
 preparation cycle 1610. For example, if one-hundred and fifty (150) liters
 of solution per batch of product is to be prepared in a solution
 preparation vessel with a working volume of fifty liters, the preparation
 cycles per batch 1608 is three. If one batch of biopharmaceutical product
 is produced every 6 days, the days per batch cycle 1604 is six. Given that
 there are three preparation cycles per batch for a particular solution,
 and there are six days per batch cycle, the number of days per preparation
 cycle 1610 is determined to be two. That is, there are two days between
 the beginnings of each fifty liter preparation cycle of solution.
 Decision step 1612 checks the shelf life of the solution against the number
 of days per preparation cycle 1610. In the preparation of solutions, it is
 possible that the number of days per preparation cycle 1610 may exceed the
 shelf life of the solution. In such a situation, it is possible to have
 "stale" solution available for use in the biopharmaceutical production
 process because it has been held to long. If decision step 1612 determines
 that number of days per preparation cycle 1610 is greater than the shelf
 life, step 1304 continues at step 1602 where the number of preparation
 cycles per batch 1608 is adjusted (preferably increased). Adjusting the
 preparation cycles per batch 1608 of the solution will allow the solution
 preparation process designer to decrease the number of days per
 preparation cycle 1610 as determined in step 1606. If decision step 1612
 determines that the number of days per preparation cycle 1610 is less than
 the shelf life of the instant solution, step 1304 continues at step 1616.
 Step 1616 calculates the liters per preparation cycle of solution 1620 for
 each solution. Liters per preparation cycle of solution 1620 is calculated
 by dividing the total liters per batch for each solution 1618 by the
 number of preparation cycles per batch 1608 as determined in step 1602.
 Total liters per batch for each solution 1618 is the quantity of each
 solution type needed to produce a batch of product in the
 biopharmaceutical production process and is stored in the material balance
 table.
 Step 1624 determines the solution preparation vessel type for the
 preparation of each solution. Step 1624 assigns each solution to a
 solution preparation vessel in step 1624, generating preparation vessel to
 solution assignment list 1626. Step 1624 assigns each solution to a
 solution preparation vessel based on the number of liters per preparation
 cycle of solution 1620 and preparation vessel identifier and associated
 volume list 1402. Solution preparation vessels are chosen from preparation
 vessel identifier and associated volume list 1402 in order to place liters
 per preparation cycle of solution 1620 within the minimum working volume
 1402 and the maximum working volume 1406 range of a solution preparation
 vessel. Preparation vessel to solution assignment list 1626 is a list of
 solutions to be prepared in the biopharmaceutical production process, and
 their associated solution preparation vessel.
 FIG. 17 illustrates exemplary values of data for the present invention.
 Column 1618 illustrates exemplary values for the total liters per batch
 for each solution 1618. Column 1608 illustrates exemplary values for
 number of preparation cycles per batch 1608. In the instant example, all
 of the solutions as shown in column 1608 are prepared in one preparation
 cycle per batch. Column 1604 illustrates exemplary values for days per
 batch cycle 1604. Column 1610 illustrates exemplary values of number of
 days per preparation cycle 1610 as determined in step 1606. In the instant
 example, since the number of preparation cycles per batch 1608 of solution
 is equal to one for all of the solutions in the solution production
 process, the number of days per preparation cycle 1610 equals the number
 of days per batch cycle 1604. Column 1614 illustrates exemplary values of
 shelf life of solution 1614. Column 1706 illustrates exemplary values for
 the outcome of decision step 1612 where number of days per preparation
 cycle 1610 is compared to shelf life of solution 1614. Column 1618 of FIG.
 17 illustrates exemplary values for total number of liters per batch for
 each solution 1618. Since the number of preparation cycles per batch 1608
 for each of the solutions is one in the instant example, the number of
 liters per preparation cycle of solution 1620 is equal to total liters per
 batch for each solution 1618.
 Columns 1708-1728 of FIGS. 17 and 18 illustrate an exemplary solution to
 solution preparation vessel assignment list 1626. The tank identifiers run
 along the top of column 1708-1728 and the solution identifiers run along
 the vertical axis on the far left hand side of the tables in FIGS. 17 and
 18. In FIG. 18, exemplary solution preparation vessel identifiers are
 placed in the columns horizontally opposed from the solution identifiers
 indicating that the preparation vessel is assigned to that solution.
 FIG. 18 illustrates exemplary preparation vessel to solution assignment
 list 1626. Columns 1626 illustrates preparation vessel to solution
 assignments. Column 1722 illustrates solution preparation vessel #108 is
 associated with solutions S-0107, S-0108, S-0112, S-0115, S-0117, and
 S-0120. Similarly, column 1724 illustrates solution preparation vessel
 #109 is associated with solutions S-0116, S-0118, and S-0119. Column 1726
 illustrates solution preparation vessel #110 is associated with solutions
 S-0106 and S-0114. Column 1728 illustrates solution preparation vessel
 #111 is associated with solutions S-0101 and S-0113.
 FIG. 20 further illustrates step 1306, determining the calculated start
 date for preparation of each solution 2010 and the next preparation date
 for each solution 2022. The next preparation date 2022 is based on the
 calculated start date 2010 and the number of days per solution preparation
 cycle 1610. Step 1306 begins at step 2004, determining the calculated
 start date for the preparation of each solution ("calculated start date")
 2010. Calculated start date 2010 is the date by which the preparation of a
 solution should begin in order to prepare the solution in time for use in
 the biopharmaceutical production process. The calculated start date 2010
 is determined by calculating back from the earliest date a solution is
 needed 2006 in the biopharmaceutical production process and the "lead
 time" needed to prepare and test a batch of solution before use. In the
 preferred embodiment, the back calculated values are the total solution
 preparation time for a solution preparation vessel 1428, the number of
 back days to allow for a failed lot of solution 2002 and the number of
 hold days for solution quality assurance and quality control (QA/QC)
 testing 2008. If a batch of solution fails QA/QC testing, the solution
 will have to be prepared again, and this lead time is expressed as the
 number of back days to allow for a failed lot of solution 2002. The
 earliest date a solution is required 2006 comes directly from the process
 time line via the material balance table. The material balance is a list
 of solution formulation reagents and calculation sets, each of which is
 associated with a unit operation. The material balance table includes the
 volumes of all the process streams in the block flow diagram 704 and their
 constituent solution components according to the formulation of the
 solution. The material balance table also identifies the time that a
 solution is required in the manufacturing process according to the task
 scheduling data in the process time line 906.
 After the calculated start date for solution preparation 2010 is
 determined, it is assigned to the associated solution and prep vessel
 solution assignment list 1626 resulting in a calculated start date 2010
 for the preparation of each solution and its associated solution
 preparation vessel.
 Step 2018 calculates the next solution preparation date for each solution
 after the calculated start date 2010 has been determined for each solution
 by selecting the greater of days for batch or days for preparation. Step
 2018 calculates the next solution preparation date for each solution by.
 The next solution date is calculated in step 2018 by adding the number of
 days per preparation cycle 1610 to the calculated start date for
 preparation of each solution assigned to a preparation vessel 2010.
 FIG. 24 further illustrates step 1308, determining the earliest solution
 preparation start date for each solution preparation vessel in a process
 cycle. Step 1308 begins by determining and assigning the calculated
 solution preparation start dates 2010 to each solution preparation vessel
 in step 2402. Solution preparation vessel ("prep vessel") to solution
 assignment list 1626 and calculated solution preparation start date for
 all solutions 2010 are cross-referenced to generate calculated and
 assigned solution prep start dates to prep vessels 2404. Step 2406
 generates the earliest solution preparation start date for each solution
 preparation vessel ("earliest start date") 2408. Calculated and assigned
 solution prep start dates to prep vessels 2404 is processed in step 2406
 to determine the earliest solution preparation start date associated with
 each preparation vessel. Step 2406 results the earliest preparation start
 dates assigned to each preparation vessel 2408. This list provides the
 solution preparation vessels necessary for the biopharmaceutical
 production process, as well as the earliest date each solution preparation
 vessel is needed for preparation of solution in the process cycle.
 FIG. 25 further illustrates step 1310, determining the latest solution
 preparation start date for each solution preparation vessel. Step 1310
 begins by determining and assigning the next solution preparation dates to
 each solution preparation vessel at step 2502. A next solution preparation
 date is the date that a solution preparation vessel will be needed for the
 preparation of solution next after the earliest start date 2408. The
 solution preparation vessel to solution assignment list 1626 and next
 solution preparation date for each solution 2022, as determined in step
 2018, are matched to generate a list of next solution preparation dates to
 each preparation vessel at step 2502. Next, step 2504 determines the
 latest next solution preparation start date associated with each
 preparation vessel 2506. The latest next solution preparation start dates
 are those dates associated with preparation vessels which signify the last
 preparation of solution procedure to occur in a particular solution
 preparation vessel during a process cycle.
 FIG. 26 further illustrates step 1311, calculating solution preparation
 vessel utilization time for each solution preparation vessel 2604.
 Solution preparation vessel utilization time 2604 for each preparation
 vessel is that time during which the vessel is occupied with the
 preparation of solution(s) for a particular manufacturing cycle. Solution
 preparation vessel utilization time 2604 is the duration between the
 earliest preparation start date 2408 and the end of latest next solution
 preparation cycle. The end of latest next solution preparation cycle is
 calculated by adding the total solution preparation time for a solution
 preparation vessel 1428 to the latest next solution preparation start date
 for each solution preparation vessel 2506, which results in the date when
 the solution preparation vessel has completed preparing solution in a
 process cycle. Solution preparation vessel utilization time for each
 solution preparation vessel 2604 is determined by comparing the earliest
 solution preparation start date 2408 with the sum of the latest next
 solution preparation start date 2506 and the total solution preparation
 time for each solution preparation vessel 1428.
 FIG. 27 further illustrates step 1312, calculating the cumulative solution
 preparation time for each solution preparation vessel 2708. Cumulative
 solution preparation time for each solution preparation vessel 2708 is the
 amount of time that each preparation vessel is actually occupied with the
 preparation of solution. Essentially, cumulative solution preparation time
 is the product of the total solution preparation time for a solution
 preparation vessel 1428 and the number of solution preparation cycles that
 the solution preparation vessel is used for in the manufacturing cycle.
 For example, if the total solution preparation time for a solution
 preparation vessel is six hours per cycle, and the solution preparation
 vessel is used in the preparation of six cycles of solution, the
 cumulative solution preparation time 2708 is thirty-six hours.
 Step 1312 begins by assigning a solution preparation total time for each
 solution preparation vessel to each preparation vessel at step 2702. Total
 solution preparation time for each preparation vessel 1428 from step 1302
 is matched to preparation vessel to solution assignment list 1626. The
 lists of preparation vessels, the solutions associated therewith and their
 total solution preparation times are input into step 2704. Step 2704
 determines the cumulative solution preparation time for each solution by
 multiplying the total solution preparation time 1428 for the solution
 preparation vessel by a solution's respective number of preparation cycles
 per batch 1608. Step 2704 results in the amount of time each solution
 preparation vessel is occupied with the preparation each particular
 solution. Step 2706 determines the cumulative solution preparation time
 for each solution preparation vessel 2708 by summing the amount of time
 each solution preparation vessel is actually occupied with the preparation
 of solution. Steps 2704 and 2706 result in the list of cumulative solution
 preparation times for each preparation vessel 2708.
 FIG. 28 further illustrates step 1314, determining the percentage
 utilization of each solution preparation vessel. The percentage
 utilization of a solution preparation vessel is the ratio of the
 cumulative total solution preparation time for each solution preparation
 vessel 2708 to the total time that a solution preparation vessel is
 available for solution preparation 2802 expressed as a percentage.
 Determining the percentage utilization of each solution preparation vessel
 2808 allows the process designer to tailor the preparation cycles per
 batch 1602 of each solution to maximize the utilization of the solution
 preparation equipment, thereby minimizing cost and maximizing efficiency.
 Step 1314 begins by calculating the total number of hours a solution
 preparation vessel is available at step 2802. The total number of hours a
 preparation vessel is available is the product of the solution preparation
 vessel utilization time 2604, as determined in step 2602, and the hours
 per solution preparation shift 2804. The hours per solution preparation
 shift 2804 is provided from in the original process design parameters for
 the biopharmaceutical production process. For example, if the process is
 designed as a two shift process, the plant would normally run sixteen
 hours a day, and the number of hours per solution prep shift 2804 would be
 sixteen.
 Step 2802 multiplies the solution preparation vessel utilization time 2604
 by the hours per solution preparation shift per day 2804. Step 2802
 results in the number of raw hours that a solution preparation vessel is
 available to the biopharmaceutical production process. For example, if the
 solution preparation vessel utilization time 2604 is six days, and the
 biopharmaceutical production process is run one shift a day (eight hours),
 the number of hours the solution preparation vessel is available for use
 in the biopharmaceutical production process is forty-eight. Forty-eight is
 the maximum number of hours that the solution preparation vessel is
 available for use. If such a solution preparation vessel is actually
 occupied with the preparation of solution for twenty-four hours, the
 percentage utilization of the solution preparation vessel during its
 period of availability 2808 would be fifty percent.
 Step 2806 calculates the percentage utilization of each solution
 preparation vessel. The percentage utilization 2808 is determined by
 comparing the total number hours a solution preparation vessel is
 available as calculated in step 2802 with the cumulative total solution
 preparation time for each solution preparation vessel 2708. By dividing
 cumulative total solution preparation time for each solution preparation
 vessel 2708 by the total number of hours a preparation vessel is available
 as calculated in step 2802, percentage utilization of each preparation
 vessel during its period of availability 2808 is calculated, as explained
 in the example above.
 FIG. 29 further illustrates step 1316, generating the initial shift
 schedule 2910. The initial shift schedule 2910 is a table of dates
 scheduling the preparation of solutions for use in the biopharmaceutical
 production process. Initial shift schedules 2910 are generated for each of
 the solution preparation vessels. An initial shift schedule for a solution
 preparation vessel contains the solutions to be prepared and their
 associated preparation dates, as well as the days per prep cycle. FIG. 31
 is an example of an initial shift schedule. Step 1316 begins with step
 2902, generating a time-line starting from the earliest start prep date of
 all the solutions required by the biopharmaceutical production process at
 step 2902. In the preferred embodiment, the time-line is incremented one
 day at a time, out to a date predetermined by the system designer. In
 alternative embodiments, the time-line and shift schedule are incremented
 or delimited in whichever time intervals are most convenient.
 Step 2904 determines and matches solution preparation dates for each
 solution 2404 with the dates in the shift schedule time-line from step
 2902. Matched solution preparation dates to solution preparation vessels
 2404 are entered into the shift schedule time-lines for each of the
 solution preparation vessels. Starting from the calculated start date
 2404, step 2904 enters successive preparation start dates for each
 solution associated with a preparation vessel based on the number of days
 per preparation cycle 1610. For example, if a particular solution assigned
 to solution preparation vessel has two days per preparation cycle, the
 solution is scheduled for preparation in its solution preparation vessel
 every two days after its calculated start date 2010. Step 2904 results in
 a list of solutions and associated preparation dates for each solution
 preparation vessel 2906.
 Step 2908 enters the total number of solution preparation hours for each
 solution into each initial shift schedule time-line. The result is the
 number of preparation hours each day associated with every solution
 preparation in the initial shift schedule. Step 2908 matches solution
 preparation times for each solution preparation vessel 1428 with the dates
 assigned in each of the shift schedule time-lines to generate the initial
 shift schedule 2910. The total number of hours each solution preparation
 vessel is occupied with the preparation of solution each day can then be
 determined by adding the number of solution preparation hours associated
 with each day on an initial shift schedule time-line 2910. In the
 preferred embodiment, the number of hours of solution preparation per day
 per solution preparation vessel is essentially the product of the number
 of solution preparation cycles and the total solution preparation time for
 the solution preparation vessel 1428. For example, if a solution
 preparation vessel has a total solution preparation time for the solution
 preparation vessel 1428 of five hours, and is scheduled for four solution
 preparation cycles, the solution preparation vessel is scheduled for
 twenty hours of solution preparation that day. Step 2910 results in the
 initial shift schedule with solution identifiers and their solution
 preparation times assigned to their respective shifts 2910.
 FIG. 31 is an example of an initial shift schedule for solution preparation
 vessel 101. Exemplary solution identifiers are shown in column 3102.
 Column 3102 illustrates exemplary solution identifiers for the solutions
 used in the biopharmaceutical production process. Solution identifiers
 3102 with date entries in corresponding An exemplary value for hours per
 solution prep shift is given in box 2804. Exemplary values for number of
 days per preparation cycle is given in column 1610. Exemplary values of
 solution prep dates of each solution is given in column 2906.
 FIG. 30 further illustrates step 1318, back scheduling solution preparation
 in the initial shift schedule. Solution preparation is initially scheduled
 in steps 1302-1316 without considering the possibility of scheduling
 conflict. Back scheduling solution preparation is done in order to avoid
 conflicts in the solution preparation process. Scheduling conflicts result
 from scheduling more solution preparation cycles for a solution
 preparation vessel than can be accommodated in the amount of time
 available. For example, a scheduling conflict will occur if a particular
 solution preparation vessel is scheduled for twenty hours of solution
 preparation on one sixteen hour day. The present invention back schedules
 those solution preparation cycles that do not fit into their scheduled
 shift or day. For example, if a solution preparation vessel is scheduled
 for three solution preparation cycles of three hours each, the solution
 preparation vessel is scheduled for nine hours of preparation activity. If
 the production facility runs on an eight hour day, not all of the
 solutions can be prepared as scheduled. The present invention back
 schedules one of the solution preparation cycles, leaving six hours of
 solution preparation to be completed in one day. The back scheduled
 solution preparation cycle is rescheduled to the first previous available
 shift so that the solution is prepared in time for use in the
 biopharmaceutical production process as scheduled in the process time
 line. After step 1318 is completed, the solution preparation time line is
 in proper form for use as a solution preparation and scheduling and
 management tool.
 Step 1318 begins at step 3002, successively summing the solution
 preparation times for each of the days or shifts in the initial shift
 schedule 2910. the solution preparation times are summed in order to
 determine the total solution preparation time for each solution
 preparation vessel on each shift. For the purpose of summing the solution
 preparation times, a shift is the number of hours in one biopharmaceutical
 production process day (e.g., eight hours for a single shift plant,
 sixteen hours for a double shift plant, etc.). Step 2002 results in a list
 for each solution preparation vessel of summed solution preparation times
 for each shift 3004. Summed solution preparation times 3004 are compared
 with the available shift hours/day 2804 in step 3006. If the sum of the
 scheduled solution preparation times 3004 exceeds the number of shift
 hours available 2804, solutions are marked as "back scheduled" and are
 rescheduled for the first previously available shift. From the previous
 example, one of the three hour solution preparation cycles is to be
 rescheduled for the first previously available shift, leaving six hours of
 solution preparation in the eight hour shift. If the originally scheduled
 day for the nine hours of solution preparation was Wednesday, the three
 hour solution preparation would be back scheduled to Tuesday. After a
 solution that doesn't fit into the current day has been back scheduled, it
 is removed from the current day schedule.
 If step 3006 determines that the number of shift hours 2804 available
 exceeds the sum of the scheduled solution preparation times 3004, step
 3010 determines if any solution is scheduled for preparation on the
 current shift. If step 3010 determines that a solution is scheduled for
 preparation in the current shift, step 3012 leaves the solution scheduled
 for preparation in the shift schedule.
 If step 3010 determines that no solutions are assigned to the solution
 preparation vessel for the shift that is being evaluated, step 1318
 continues to step 3014. Step 3014 determines if any solutions have been
 back scheduled to the current shift for preparation for a later shift. If
 no solution preparation cycles have been back scheduled to the current
 shift, the process continues to step 3002 where the next shift is analyzed
 for back scheduling. If step 3014 determines that solution preparation
 cycles have been back scheduled, the process continues at step 3016. Step
 3016 checks the original scheduling date on the back scheduled solution
 preparation cycle to determine if the back scheduled date is earlier than
 the original scheduling date minus the periodicity of the back scheduled
 solution. For example, if the solution has been successively back
 scheduled for four days (i.e., the preparation cycle of the solution had
 to be scheduled back four days in order to fit into a shift), and its
 periodicity was two days, the back scheduled prep would be potentially
 interfering the previously scheduled prep of the same solution thereby
 indicating a shift schedule capacity error.
 If step 3016 determines that the solution is back scheduled beyond its
 periodicity, an alarm is raised indicating that a system capacity issue
 exists at step 3020. If step 3016 determines that the back scheduled
 solution preparation cycle not earlier than its orbitally scheduled date
 minus its periodicity, the solution preparation cycle is scheduled for the
 current shift at step 3018.
 FIG. 32 further illustrates step 1320, generating solution preparation
 schedule 3210. Solution preparation schedule 3210 schedules each task
 associated with solution preparation for the biopharmaceutical process
 based on the back-scheduled shift schedule 3202 and the solution
 preparation procedure 3212. Solution preparation schedules 3210 are
 generated for each solution preparation vessel that has an assigned
 solution. Back-scheduled initial shift schedule 3202, as generated in Step
 1318, contains the solution preparation vessel to solution preparation
 assignment for each of the shifts in the initial shift schedule 2910. Step
 1320 is performed for each of the shifts in the initial shift schedule
 2910, thereby scheduling all of the solution preparation tasks for each
 solution preparation vessel on each shift.
 Step 1320 begins at Step 3206, determining the number of solution
 preparation that are scheduled for the current shift in the back-scheduled
 initial shift schedule 3202. If no solutions are scheduled for
 preparation, step 1320 continues to step 3204 which moves to the next
 shift in the back-scheduled initial shift schedule 3202. If there are
 solution preparations scheduled for the current shift, step 1320 continues
 to step 3208. Step 3208 generates the solution preparation schedule 3210
 from the solution preparation procedure data 3212 for each solution
 preparation scheduled in the shift. For example, if two solutions are
 scheduled to be prepared in solution preparation vessel 101, each task in
 each solution preparation procedure is scheduled out in solution
 preparation schedule 3210. An exemplary solution preparation procedure
 3212 is illustrated in FIG. 14 (steps 1420, 1408, 1414, 1418, 1426, 1432,
 and 1436).
 FIG. 15 illustrates exemplary solution preparation procedure data, as
 described above, used to generate solution preparation schedule 3210. Step
 3208 schedules out each task for each solution preparation assigned to the
 current shift. After step 3208, and if there are additional shifts in the
 back-scheduled initial shift schedule 3202, step 1320 continues at step
 3204 proceeding to the next shift in back-scheduled initial shift schedule
 3202. Step 1320 repeats to schedule all of the solution preparations in
 the back-scheduled initial shift schedule. Step 1320 results in,
 therefore, solution preparation schedule 3210 which is a time line, by
 shift, for each solution preparation task for each solution preparation
 assigned to a solution preparation vessel.
 3.0 Equipment Preparation Scheduling Module
 The object of the equipment preparation module is to simulate, schedule and
 model equipment preparation and loading in the biopharmaceutical
 production process. Equipment used in the biopharmaceutical production
 becomes soiled and must be cleaned, wrapped and sterilized in order to be
 used again. The process of cleaning, wrapping and sterilizing is known as
 equipment preparation. A piece of equipment that has been used in the
 biopharmaceutical production process and requires preparation before it
 can be used again is called a soiled process component. Equipment
 preparation is performed in order to sustain the biopharmaceutical
 production process.
 Current methods for the design equipment preparation procedures typically
 fall short of accurately defining the relatively complex procedures that
 are executed in an equipment prep area. As a result the equipment and work
 areas associated with equipment prep are usually inefficiently designed.
 Since the cleaning and sterilizing (prep) equipment associated with
 equipment prep activities are capital and utility intensive, an improved
 method for accurately modeling and optimizing these areas of a
 biopharmaceutical production facility is needed. The preferred embodiment
 provides a computer simulation method for the design and scheduling of
 equipment prep operations which is more accurate and efficient than
 conventional design methods.
 FIG. 33 is a flowchart illustrating an overview of the process for
 scheduling and simulating equipment preparation in a biopharmaceutical
 production process. Step 3302 generates a preparation equipment protocol
 table. A preparation equipment protocol is a protocol for the operation of
 a piece of preparation equipment. Preparation equipment protocols usually
 include a plurality of equipment preparation tasks. A preparation task is
 a step in the equipment preparation process. For example, in a glassware
 dryer, a task may be loading the dryer, preheating the dryer, drying the
 glassware, unloading the dryer, etc. A preparation equipment protocol
 table is a set of standard preparation equipment protocols to clean soiled
 process components. Preparation equipment protocols are usually developed
 through experimentation and quality assurance testing. The preparation
 equipment protocols that prepare the soiled process components for reuse
 most effectively and to the required levels of cleanliness become the
 preparation equipment protocols.
 Preparation equipment protocols are associated with specific pieces of
 preparation equipment. Examples of preparation equipment are bench sinks,
 wash stations, glassware washers, glassware dryers, carboy washers, carboy
 dryers, autoclaves, steam sterilizers, etc. Furthermore, there may be
 multiple preparation equipment protocols per piece of preparation
 equipment. For example, there may be four preparation protocols associated
 with each type of bench sink, each having different combinations of bench
 sink cleaning tasks and durations. Although the preferred embodiment
 describes a finite set of preparation equipment, soiled process components
 and preparation equipment protocols, one of ordinary skill could easily
 expand the process described herein to any preparation equipment or soiled
 process components.
 Step 3304 generates an equipment preparation procedure table. An equipment
 preparation procedure is a standard procedure comprising a plurality of
 preparation equipment protocols by which a soiled process component is
 cleaned and sterilized for reuse in the biopharmaceutical production
 process. For example, an equipment preparation procedure for a carboy may
 include the preparation equipment protocols of bench sink rinsing, bench
 sink cleaning, carboy washing, carboy drying, wrapping and sterilization
 in an autoclave. Different types of soiled process components require
 different combinations of preparation equipment protocols in order to be
 readied for reuse in the biopharmaceutical production process, thereby
 defining different equipment preparation procedures. As with preparation
 equipment protocols, equipment preparation procedures are determined
 through experimentation, quality assurance and quality control. Each type
 of equipment used in the biopharmaceutical production process has an
 associated equipment preparation procedure.
 An equipment preparation procedure table is a list of preparation equipment
 protocols and their associated information that define an equipment
 preparation procedure for each of the soiled process component types. In a
 preferred embodiment, there are equipment preparation categories for each
 piece of soiled process components. Instead of an equipment preparation
 procedure associated with each type of soiled process component, there is
 a an equipment preparation procedure associated with each equipment
 preparation category. Preparation equipment protocols associated with each
 of the different equipment preparation categories are placed together in a
 table format to provide the preparation procedures for each piece of
 soiled process components assigned to an equipment preparation category.
 Step 3306 generates the equipment dimension table. Equipment dimensions are
 the length, height and depth of a piece of process equipment requiring
 cleaning and sterilization (e.g., beaker, flask, carboy, stainless steel
 fittings, etc.). The equipment dimension table defines the dimensions of
 all process equipment potentially requiring cleaning after use in the
 biopharmaceutical production process. The equipment dimension table is
 determined directly from the list of equipment used in the
 biopharmaceutical production process. The equipment dimension list
 provides a means for determining the volume of the equipment to be cleaned
 in the biopharmaceutical production process, thereby allowing the
 calculation of the capacity of the preparation equipment.
 Step 3308 generates a master list of equipment that may require
 preparation. Each unit operation in the biopharmaceutical production
 process is associated with preparation equipment. Step 3308 generates a
 master list of equipment associated with the biopharmaceutical production
 process and solution preparation process. In the preferred embodiment, the
 preparation equipment associated with each unit operation for both the
 biopharmaceutical production process and solution preparation process is
 defined when the unit operations for these activities are defined. As
 described above, the process equipment associated with unit operations of
 a biopharmaceutical production process are incorporated into a production
 process time line. Likewise the activities associated with each step of
 solution preparation is identified in step 1302 and incorporated into
 total solution preparation time for the solution preparation vessels 1428.
 Step 3310 generates the equipment preparation load table. The equipment
 preparation load table includes data describing when particular soiled
 process components from the equipment dimension table are available for
 preparation. For example, some information comes from the finish times for
 the tasks in process time line 906 that define when the soiled process
 components from the biopharmaceutical production process will be available
 for cleaning. Step 3310 generates the equipment preparation load table by
 comparing the process time line schedule with the equipment preparation
 master list.
 Step 3312 generates the equipment preparation load summary table. The
 equipment preparation load summary table is the sum of all equipment
 preparation load tables from each of the biopharmaceutical production
 processes active in the biopharmaceutical facility. For example, a
 facility may be producing multiple biopharmaceutical products in multiple
 processes. In such a case, the preparation equipment handles equipment
 preparation for multiple biopharmaceutical production processes. Likewise,
 a facility may have multiple solution preparation suites. In such a case,
 the preparation equipment handles equipment preparation for multiple
 solution prep suites. Step 3312 generates the equipment preparation load
 summary table for the sum of all biopharmaceutical production processes by
 combining the equipment preparation load tables for all of the
 biopharmaceutical production processes.
 Step 3314 estimates the preparation equipment capacity. The capacity of the
 preparation equipment is determined in order to provide sufficient
 capacity to handle the load of soiled process components in the
 biopharmaceutical facility. Preparation capacity is the flow rate of
 soiled process components that the preparation equipment can accommodate.
 Preparation capacity is estimated based on the flow rate of equipment from
 the preparation load summary table. The rate at which soiled process
 components are generated in the biopharmaceutical production facility is a
 good estimate of the capacity of the preparation equipment.
 Step 3316 determines the equipment preparation time line. The equipment
 preparation time line includes scheduling each soiled process component
 through each piece of preparation equipment in each of the equipment
 preparation procedures. Functional specifications for the preparation
 equipment and the utility load requirements for the preparation equipment
 can be generated from the equipment preparation time line. Functional
 specifications describe a piece of equipment with particularity. For
 example, functional specifications for a pump include pump type, flow
 rate, maximum and minimum input and output pressures, input and output
 fitting sizes, electrical requirement, temperature range and type and
 frequency of required maintenance.
 FIG. 34 further illustrates step 3302, generating the preparation equipment
 protocol table. Step 3302 begins with step 3404, generating the
 preparation equipment protocol identifiers 3408. Preparation equipment
 protocol identifiers 3408 are keys or codes which identify each
 preparation equipment protocol. Preparation equipment protocol identifiers
 3408 allow each preparation equipment protocol to be identified in the
 equipment preparation module and are used to generate the preparation
 equipment protocol table. Step 3404 assigns unique preparation equipment
 identifiers 3408 to each of the preparation equipment protocols 3402.
 Preparation equipment protocol table 3402 also includes the task and
 duration information associated with each preparation equipment protocol.
 Next, step 3406 generates preparation equipment protocol table 3410.
 Preparation equipment protocol table 3410 is generated by assigning
 preparation equipment protocol identifiers 3408 to each preparation
 equipment protocol in preparation equipment protocol table 3402.
 FIGS. 36A-36H are exemplary preparation equipment protocol tables 3410.
 Column 3408 in FIGS. 36A-36H illustrate exemplary preparation equipment
 protocol identifiers 3408. Preparation equipment protocol table 3410
 contains information describing each preparation protocol. Preparation
 equipment protocol identifiers BS-1 through BS-5 identify individual bench
 sink preparation protocols. For example, FIG. 36A illustrates protocol
 task durations for the bench sink preparation equipment. Protocol task
 duration is the amount of time associated with a task in a preparation
 equipment protocol. For example, protocol BS-1 in FIG. 36A has a loading
 task duration of 5 minutes. Bench sink protocol BS-1, therefore, includes
 the step of loading the bench sink, which requires 5 minutes. Protocol
 task durations of prewash rinse with non-potable hot water (NPHW), prewash
 rinse with non-potable cold water (NPCW), detergent wash with reagent,
 post wash rinse with NPHW and NPCW, final rinse and hold dry are
 illustrated in FIG. 36A. Columns 3602 and 3604 are examples of protocol
 parameters. Protocol parameters are data elements that describe particular
 facets of a preparation equipment protocol. In the example of FIG. 36A,
 protocol parameters detergent wash reagent and grams of reagent per cubic
 foot are used to describe the detergent in the bench sink wash process.
 FIG. 36B illustrates an exemplary preparation equipment protocol table for
 a wash station. Column 3408 of FIG. 36B illustrates exemplary preparation
 equipment protocol identifiers 3408 for a wash station. FIG. 36C
 illustrates an exemplary preparation equipment protocol table for a
 glassware washer. Column 3408 in FIG. 36C illustrates exemplary
 preparation equipment protocol identifiers 3408 for a glassware washer.
 FIG. 36D illustrates an exemplary preparation equipment protocol table
 3410 for a glassware dryer. Column 3408 in FIG. 36D illustrates exemplary
 preparation equipment protocol identifiers 3408 for a glassware dryer.
 FIG. 36D illustrates exemplary task durations for tasks associated with
 the glassware dryer protocols. Some examples of task durations are loading
 3618, heat up 3620, drying 3624, cooling 3626 and unloading 3628, as shown
 by their respective columns. Column 3622 illustrates the drying
 temperature protocol parameter. FIG. 36E illustrates an exemplary
 preparation equipment protocol table 3410 for a carboy washer. FIG. 36F
 illustrates an exemplary preparation equipment protocol table 3410 for a
 carboy dryer.
 FIG. 36G illustrates an exemplary preparation equipment protocol table for
 a steam sterilizer. Due to the multiple protocol parameters and task
 durations associated with steam sterilizer preparation equipment
 protocols, the preparation equipment protocol table of FIG. 36G is
 two-dimensional. Row 3608 illustrates exemplary preparation equipment
 protocol identifiers 3408 forth steam sterilizer. The steam sterilizer
 preparation equipment protocol table 3410 includes multiple protocol tasks
 1-33 as illustrated in column 3606. Each of the tasks in the steam
 sterilizer protocol has associated protocol parameters and protocol
 durations as illustrated in columns 3608,3610,3612,3614 and 3616. Row 32
 in column 3606 of FIG. 36G illustrates exemplary values for the total time
 in minutes required for each of the different steam sterilizer protocols
 (protocol identifiers SS-1, SS-2 and SS-3). FIG. 36H illustrates an
 exemplary preparation equipment protocol table 3410 for a dry heat
 stabilizer.
 FIG. 35 further illustrates step 3304 generating equipment preparation
 procedure table 3512. Equipment preparation procedure table 3512 includes
 data associated with each equipment preparation procedure, including the
 sequence of preparation equipment protocols and their individual durations
 as well as their cumulative duration over the entire procedure. Step 3304
 begins at step 3506, generating equipment preparation procedure
 identifiers 3510. Equipment preparation procedure identifiers are tags or
 codes which identify equipment preparation procedures. FIGS. 37A and 37B
 illustrate an exemplary equipment preparation procedure table 3512. Row
 3702 illustrates exemplary equipment preparation procedure identifiers
 3510. EPC-1, EPC-2, EPC-3, EPC-4, EPC-5, EPC-6 and EPC-7 are examples of
 codes which identify equipment preparation procedures.
 Step 3508 generates equipment preparation procedure table 3512. Step 3508
 generates equipment preparation procedure table 3512 from preparation
 equipment protocol tables 3502, equipment preparation procedures 3504 and
 equipment preparation procedure identifiers 3510. Equipment preparation
 procedures 3504 provides the list of preparation equipment protocols that
 identify a particular equipment preparation procedure and equipment
 assignment. FIG. 37A, for example, shows equipment preparation procedure
 EPC-1 includes (as shown in column EPC-1) preparation equipment protocols
 BS-1, BS-3, GD-1, and SS-1 in FIG. 37B. Equipment preparation procedures
 3504 also include the equipment assignments for each of the equipment
 preparation procedures. Equipment assignments define the soiled process
 components associated with, or prepared by, each equipment preparation
 procedure. For example, a particular equipment preparation procedure may
 only be used to clean carboys. Step 3508 compares the preparation
 equipment protocols in the equipment preparation procedures 3504 with the
 preparation equipment protocol tables 3502. The protocol durations and
 protocol parameters provide the information in equipment preparation
 procedures table 3512. Equipment preparation procedure identifiers 3510
 are assigned to each individual equipment preparation procedure in
 equipment preparation procedure table 3512.
 FIGS. 37A and 37B illustrate exemplary equipment preparation procedure
 tables 3512. Row 3702 illustrates exemplary equipment preparation
 procedure identifiers EPC-1, EPC-2, EPC-3, EPC-4, EPC-5, EPC-6, and EPC-7.
 Equipment preparation procedure identifiers 3510 identify equipment
 preparation procedures for different categories of equipment. Exemplary
 equipment preparation procedure identifier EPC-5 includes the preparation
 equipment protocols of wash station (WS-1), carboy washer (CW-1), carboy
 dryer (CD-1), and steam sterilization autoclave 1 (SS-2). Associated with
 each of the preparation equipment protocols are task durations. Column
 3704 illustrates task durations for equipment preparation procedure EPC-5.
 The task durations for each of the preparation equipment protocols are
 totaled to yield the equipment preparation procedure duration for EPC-5.
 Cumulative totals for the equipment preparation procedure duration are
 given in column 3706, rows 8, 15, 24, 31, 38, 45, 52, 66, 75 and 82. The
 cumulative durations are the sum of all the previous preparation equipment
 protocol durations in the equipment preparation procedure.
 FIG. 38 further illustrates step 3306, generating equipment dimension table
 3816. Step 3306 begins at step 3806, generating the master equipment
 dimension list 3808. Step 3806 uses the list of equipment requiring
 preparation 3802 and the equipment dimensions list 3804 to generate master
 equipment list 3806 which defines the dimensions of all process equipment
 that may cleaned by the equipment preparation procedure. List of equipment
 requiring preparation 3802 is a complete list of all the equipment used in
 the biopharmaceutical production process. List of equipment requiring
 preparation 3802 may be generated from the unit operations that define the
 process time line 906 or solution preparation schedule. Alternatively,
 list of equipment requiring preparation 3802 may be provided by the system
 designer as the equipment used in the biopharmaceutical production process
 by design. List 3802 identifies those pieces of equipment that will need
 to be prepared in order to complete the biopharmaceutical production
 process. Equipment dimensions list 3804 is a master list of equipment
 dimensions for all of the equipment available for use in the
 biopharmaceutical production process. Often, equipment dimensions list
 3804 will be provided by the vender or manufacturer of the process
 equipment. List of equipment requiring preparation 3802 is compared to the
 equipment dimensions list 3804 in order to assign the equipment dimensions
 to the equipment used in the biopharmaceutical production process,
 resulting in master equipment dimension list 3808.
 Next, step 3812 generates the equipment dimension table with segregated
 equipment preparation procedure identifiers. Step 3812 segregates the
 equipment dimension list into equipment preparation procedures as defined
 in the equipment preparation procedures and equipment assignment list
 3504. The master equipment dimension list 3808 is segregated based on the
 equipment preparation procedure identifiers 3510 in order to generate
 equipment dimension table 3816 according to equipment preparation
 procedure identifiers. The resultant equipment dimension table 3816
 includes a list of specific process equipment and their associated
 equipment preparation procedure identifiers. Each particular equipment
 preparation procedure (e.g., EPC-1, EPC-2, EPC-3, etc.) is assigned to
 particular equipment types. Equipment dimension table 3816 also includes
 the dimensions of equipment to be prepared.
 FIG. 39 illustrates an exemplary equipment dimension table 3816. Row 3902
 illustrates exemplary equipment preparation procedure identifiers 3510.
 Rows 3904 identify the dimensions of each particular type of equipment
 involved in the equipment preparation process. Rows 3904 illustrates
 exemplary values for the dimensions of soiled process components to be
 cleaned in the equipment preparation procedure. Row 1 of rows 3904
 illustrates exemplary values for the right-to-left dimension (R/L) in
 inches. Row 2 of rows 3904 illustrates exemplary values for the
 front-to-back dimension (F/B) in inches. Row 3 of rows 3904 illustrates
 exemplary values for top-to-bottom dimensions (T/B) in inches. Row 5 of
 rows 3904 illustrates exemplary values for volume in cubic inches (CI).
 Row 6 of rows 3904 illustrates exemplary values for volume in cubic feet
 (CF). CI and CF- are computed directly from the rectilinear dimensional
 values in rows 1-3 of rows 3904.
 Column 3906 illustrates exemplary dimensional values for siphon tube
 equipment in equipment preparation procedure EPC-1. Column 3908
 illustrates exemplary dimensional values for instruments including
 pressure indicators (PI), optical density probe and pH probe. Column 3910
 illustrates exemplary dimensional values for fittings including tees,
 elbows, crosses, reducers, hose barbs and clamps. Column 3912 illustrates
 exemplary dimensional values for small and medium plasticware. Column 3914
 illustrates exemplary dimensional values for silicone and butyl rubber
 stoppers. Column 3916 illustrates exemplary dimensional values for small
 and large flexible tubing. Column 3918 illustrates exemplary dimensional
 values for small and medium glassware. Column 3920 illustrates exemplary
 dimensional values for one, twenty and forty-five liter polypropelene
 carboys. Column 3922 illustrates exemplary dimensional values for ten,
 twenty and forty-five liter borosilicate glass carboys.
 FIG. 40 further illustrates step 3308, generating equipment preparation
 master list 4004. Equipment preparation master list 4004 includes the
 process equipment that may be soiled by unit operation tasks and the
 solution preparation procedure tasks in the biopharmaceutical production
 process. As described above, each task in unit operation master list 508
 has associated process equipment. The process equipment associated with
 each unit operation task is added to the equipment preparation master list
 4004 in step 4002. Step 4002 uses unit operation master list 508 to
 generate a master list of equipment that may require preparation after use
 in the biopharmaceutical production process. Each piece of equipment has
 an associated dimension as defined in equipment dimension table 3816. Step
 4002 compares unit operation master list 508 with equipment dimension
 table 3816 to assign the equipment dimensions to the equipment in unit
 operation master list 508 when generating equipment preparation master
 list 4004. Step 4002 compares solution preparation task list 4006 with
 equipment dimension table 3816 to assign the equipment dimensions to the
 solution preparation task list 4006 when generating equipment preparation
 master list 4004. After step 4002, equipment preparation master list 4004
 contains the list of process equipment used in the biopharmaceutical
 production process that may become soiled process components requiring
 cleaning by the equipment preparation procedures.
 FIG. 41 further illustrates step 3310, generating equipment preparation
 load table 4104. Equipment preparation load table 4104 includes data
 indicating when soiled process components from the equipment preparation
 master list 4004 will be available from the biopharmaceutical production
 process. Step 4102 generates equipment preparation load table 4104 by
 combining solution preparation schedule 3210 and process time line 906
 with equipment preparation master list 4004. Cumulative flow of equipment
 out of the biopharmaceutical production process as represented by solution
 preparation schedule 3210 and process time line 906 is compared with
 equipment preparation master list 4004 in order to provide the equipment
 dimensional information in equipment preparation load table 4104.
 Equipment preparation load table 4104 includes soiled process components,
 the schedule for when the soiled process components are available for
 equipment preparation procedures, the dimensional information associated
 with each soiled process component and which task in the biopharmaceutical
 production process or solution preparation process generated the soiled
 process components. Equipment preparation load table 4104 represents the
 volumetric flow rate of equipment out of the biopharmaceutical production
 process that needs to be prepared for later use in order to sustain
 continuous biopharmaceutical production.
 FIGS. 42A-42E illustrate an exemplary equipment preparation load table
 4104. Column 4202 illustrates exemplary task titles. Task titles 4202 may
 originate from solution preparation procedure tasks or the titles of tasks
 in unit operations. Column 4204 illustrates exemplary task end times. The
 values in columns 4204 represent the date and time various soiled process
 components will be available for cleaning and preparation in equipment
 preparation procedures. Columns 4206-4216 of FIGS. 42A and 42B illustrate
 exemplary values for soiled process components available for preparation
 in equipment preparation procedures. In each of the columns, each of the
 soiled process components contains the number and cubic footage with which
 it is associated. FIGS. 42C-42D illustrate additional tasks in the
 biopharmaceutical production process. As before, columns 4218-4228 of
 FIGS. 42C-42D illustrate exemplary values for soiled process components
 available for preparation in equipment preparation procedures.
 FIG. 43 further illustrates step 3312, generating equipment preparation
 load summary table 4304. Equipment preparation load table 4104 defines
 when soiled process components from the equipment preparation master list
 4004 will be available from all biopharmaceutical production processes
 active in the biopharmaceutical facility. Because single equipment
 preparation facilities may be shared across multiple biopharmaceutical
 production processes, the equipment load tables 4104 are combined to
 create equipment preparation load summary table 4304. Equipment
 preparation load summary table 4304 allows the scheduling and simulation
 of equipment preparation procedures for the entire biopharmaceutical
 production facility.
 FIG. 44 further illustrates step 3314, determining the capacities of the
 preparation equipment 4416. Step 3314 begins with step 4404, generating an
 initial equipment preparation schedule 4408. An initial equipment
 preparation schedule 4408 is generated for each equipment preparation
 procedure (EPC-1, EPC-2, EPC-3, etc.). As stated above, each equipment
 preparation procedure is associated with specific soiled process
 components. The initial equipment preparation schedule 4408 begins prior
 to the earliest date that soiled process components are available, as
 provided by the equipment preparation load summary table 4304.
 The initial equipment preparation schedule 4408 is an initial schedule for
 the arrival of soiled process components at each piece of preparation
 equipment. Since the duration of each task in each of the equipment
 preparation procedures is known, the time at which soiled process
 components arrive at various preparation equipment is calculated directly
 by adding the duration of each task from the preparation equipment
 protocol table 3410 to the equipment preparation load summary table 4304.
 The time at which each soiled process component arrives at a particular
 step in a preparation equipment protocol is the sum of previous equipment
 preparation procedure tasks and the time which the soiled process
 component became available, as indicated in the equipment preparation load
 summary table 4304. Scheduling the soiled process components that arrive
 at each piece of preparation equipment allows the peak loading on the
 preparation equipment to be determined. The peak loading of the
 preparation equipment can then be used to determine the size and capacity
 of the preparation equipment.
 Step 4412 compares the peak cubic footage load, as determined in step 4410,
 with the cubic footage of the largest soiled process component from the
 equipment dimension table 3816. Step 4412 selects the larger of the peak
 cubic foot load and the cubic footage of the largest equipment item from
 the equipment dimension table.
 Step 4414 uses the larger peak CF value as determined in step 4412 to
 generate the capacities for the preparation equipment 4416. Capacities for
 the preparation equipment 4416 will need to be high enough to handle the
 peak cubic footage of soiled process components that need to be prepared
 in the equipment preparation procedure. The capacities determined instep
 4414 and stored in table 4416, therefore, are the maximum capacities for
 the preparation equipment. Once the necessary capacity for the preparation
 equipment has been determined, an equipment prep time line can be
 generated.
 FIG. 46 further illustrates step 3316, generating the equipment preparation
 time lines 4610. Equipment preparation time lines 4610 include scheduling
 information for each soiled process component through each piece of
 preparation equipment in equipment preparation procedures. Equipment
 preparation time line 4610 includes the schedule of operation for each
 piece of preparation equipment. Equipment preparation time lines 4610 also
 include scheduling information for each particular facet of preparation
 equipment operation including resource loads for labor, utilities,
 disposables, reusables, maintenance, calibration, etc. Together with the
 capacity data determined in step 4414, equipment preparation time line
 4610 allows the determination of functional specifications for preparation
 equipment to which cost and other data can be matched.
 Step 3316 begins with step 4606, generating the final equipment preparation
 shift schedules for each piece of preparation equipment. As stated above,
 after the preparation equipment capacities have been determined in step
 3314, the maximum load capacities for the preparation equipment 4602 are
 known. Capacities for preparation equipment 4416 define the maximum load
 capacities for preparation equipment 4602. Minimum load capacity for
 preparation equipment 4604 is a value set by the biopharmaceutical
 production process designer in order to maximize efficiency or for the
 validation of equipment preparation procedure. For example, a
 biopharmaceutical production process designer may determine that
 sterilizer equipment should not be operated at less than fifty percent of
 its load capacity. The sterilizer equipment, therefore, would be operated
 only when sufficient volume of soiled process components have been
 accumulated. Step 4606 generates the final equipment preparation shift
 schedules for each piece of equipment based on the maximum load capacities
 for preparation equipment 4602, the minimum load capacities for
 preparation equipment 4604, and equipment preparation procedure table
 3512. The final equipment preparation shift schedules include the load
 cycling through the preparation equipment dictated by the minimum load
 capacities 4604 and the maximum load capacities 4602. Maximum load
 capacities 4602 and minimum load capacities 4604 define when each
 particular protocol in the equipment preparation procedure table 3512 is
 executed. The final equipment preparation shift schedules contain accurate
 scheduling of the operation of each Step 4608 generates the equipment
 preparation time lines 4610. The equipment preparation time lines 4608
 differ from the final equipment preparation shift schedules, as determined
 in step 4606, by providing detailed scheduling of the tasks associated the
 prep equipment protocols in equipment prep procedure table 3512. Equipment
 preparation time lines 4610 are generated by comparing equipment
 preparation procedure table 3512 with the final equipment preparation
 shift schedules for each piece of preparation equipment. Equipment
 preparation time lines 4610 contain the time data for specific tasks and
 operation of preparation equipment.
 FIG. 47 illustrates the process of generating preparation equipment
 functional specifications 4706. Preparation equipment functional
 specifications list 4706 contains functional specifications and costs
 associated with each piece of preparation equipment used in the equipment
 preparation procedure. Maximum load capacities for preparation equipment
 4602 is used with equipment preparation time lines 4610 to provide the
 necessary specifications for the preparation equipment in the preparation
 equipment procedure. Step 4704 compares the specifications of maximum load
 capacities 4602 and equipment preparation time lines 4610 to determine
 which preparation equipment units from master equipment and cost list 4702
 are required for the equipment preparation procedures. Master equipment
 and cost list 4702 contains the functional specifications of all of the
 available preparation equipment and their associated costs. Preparation
 equipment is selected from master equipment and cost list 4702 based on
 functional specification matching with equipment preparation time lines
 4610 and maximum load capacities for the preparation equipment 4602. The
 result of step 4704 is preparation equipment list with functional
 specifications and cost 4706, which is a subset of master equipment and
 cost list 4702. Preparation equipment list with functional specifications
 and costs 4706 provides a means to more accurately match required
 preparation equipment with detailed cost and other data such as loads for
 utilities maintenance, calibration, quality assurance and quality control
 testing, etc.
 FIG. 48 illustrates a process of generating preparation equipment utility
 time line 4810. The preparation equipment utility time line 4810 provides
 the utility requirements for the equipment preparation process. The
 preparation equipment utility time line 4810 includes the utility
 requirements for each piece of preparation equipment and the associated
 date and time for the requirements. The preparation equipment utility time
 line 4810 allows the calculation of utility costs associated with each
 piece of preparation equipment and allows a biopharmaceutical facilities
 designer to determine the necessary utility supply to the preparation
 equipment. The process of generating preparation equipment utility time
 line 4810 begins with step 4804, generating the preparation equipment
 utility table. The preparation equipment utility table includes a list of
 the preparation equipment functional specifications from preparation
 equipment list 4706 matched with the utility data for each piece of
 preparation equipment as given by preparation equipment utility data 4802.
 Preparation equipment utility data 4802 includes the requirements for each
 piece preparation equipment during each task in a preparation equipment
 protocol. Examples of utility data are electrical power requirements,
 potable and nonpotable hot and cold water requirements, waste water
 requirements, steam requirements, etc. Step 4804 generates preparation
 equipment utility table 4806 by matching the data from equipment
 preparation equipment list 4706 with preparation equipment utility data
 4802 on a preparation equipment by preparation equipment basis.
 Step 4808 generates preparation equipment utility time line 4810. Step 4808
 matches the data in preparation equipment utility table 4806 with
 equipment preparation time line 4610 to generate preparation equipment
 utility time line 4810. Preparation equipment utility time line 4810
 schedules out the utility requirements for each piece of preparation
 equipment on a for each task in the preparation equipment protocols. Each
 of the tasks in equipment preparation time line 4610 is matched to the
 data in preparation equipment utility table 4806. Based on equipment
 preparation time line 4610 and the utility requirements for each piece of
 preparation equipment as described in preparation equipment utility table
 4806, the utility requirements for each of preparation equipment is
 scheduled out in preparation equipment utility time line 4810. The utility
 time line 4810 when combined with the utility time lines from other
 manufacturing operations such as biopharmaceutical production, solution
 preparation, etc. provides peak loading data for the accurate sizing of
 utilities. The detailed data of the equipment time lines allows for the
 identification and optimization of utility peak loads and cost through the
 analysis of well documented operations schedules.
 4.0 Equipment Maintenance Scheduling Module
 Equipment maintenance in a biopharmaceutical production facility is
 necessary to sustain the biopharmaceutical production process. The types
 and frequency of maintenance required is a function of the particular
 equipment used in the facility, as well as the frequency and nature of
 use. The equipment involved in the production process, solution
 preparation process, and equipment preparation all require regular
 maintenance during sustained operation. Often, maintenance frequency and
 cost are not considered in the design of a biopharmaceutical production
 facility. Maintenance costs, however, are a significant fraction of the
 cost of operating the biopharmaceutical facility and producing the
 biopharmaceutical product. Since maintenance is a significant cost of
 operating a biopharmaceutical production facility, a method and computer
 program product for scheduling and modeling the maintenance of process
 equipment, solution preparation equipment and preparation equipment would
 allow the biopharmaceutical facility designer to predict and minimize the
 cost of maintenance. Additionally, scheduling and modeling maintenance of
 a biopharmaceutical production process would allow for more complete
 modeling of a biopharmaceutical production facility.
 Modeling and scheduling biopharmaceutical production facility maintenance
 is based on the functional specifications and usage of the
 biopharmaceutical production process equipment. Each piece of equipment
 has associated maintenance parameters. For example, a particular pump may
 require a new drive belt, seals and lubrication after a predetermined
 number of hours of operation. Filtration media in filters must be changed
 after a predetermined number of hours of use. Given equipment functional
 specifications, equipment maintenance requirements and production
 schedules for biopharmaceutical production process equipment, equipment
 maintenance can be modeled and scheduled.
 FIG. 49 illustrates the process of generating process equipment maintenance
 table 4906. Process equipment maintenance table 4906 includes maintenance
 procedures, maintenance duration (i.e., the amount of time required to
 perform the maintenance), reusables (i.e., those maintenance items that
 must be replaced periodically), disposables (i.e., those maintenance items
 that must be replaced after every use), the maintenance period (i.e., the
 amount of use before the equipment must be serviced), and the number of
 hours required to complete the maintenance tasks for the equipment.
 Step 4904 generates process equipment maintenance tables 4906 from the
 process equipment list and functional specifications 4908 and process
 equipment maintenance data 4902. Process equipment list 4908 is generated
 from unit operation list 508. Unit operation list 508 includes the process
 equipment associated with each task in a unit operation. The process
 equipment list 4908, therefore, includes a list of process equipment from
 unit operation list 508. Process equipment list 4908 also includes
 functional specifications associated with each piece of process equipment
 in process equipment list 4908. Functional specifications describe a piece
 of equipment with particularity. For example, functional specifications
 for a pump include pump type, flow rate, maximum and minimum input and
 output pressures, input and output fitting sizes, electrical requirement,
 temperature range and type and frequency of required maintenance.
 Functional specifications associated with each piece of process equipment
 are determined from the block flow diagram 704, process time line 906 and
 equipment data sheets. Equipment data sheets, usually vendor or
 manufacturer provided, are equipment specifications that provide the
 capacity and functional specifications for equipment available for use in
 the biopharmaceutical production processes. Each unit operation has
 associated process equipment. The functional specifications of the
 equipment, however, are rate- and time-dependent. Block flow diagram 704
 defines the volume of solution and biopharmaceutical product handled by
 each unit operation. The process time line 906 defines the rate at which
 solutions and biopharmaceutical product are handled in each unit
 operation. The volume and rate information from the block flow diagram and
 process time line, therefore, define the operational parameters of the
 process equipment. The functional specifications of the process equipment
 are determined directly by matching the volume and rate parameters for the
 equipment with the volume and rate parameters in equipment data sheets.
 The functional specifications of the equipment from the equipment data
 sheet are then added to the process equipment list to form process
 equipment list with functional specifications 4908.
 Step 4904 generates process equipment maintenance table 4906 from process
 equipment list with functional specifications 4908 and process equipment
 maintenance data 4902. Process equipment maintenance data 4902 includes
 functional specifications for each piece of process equipment and their
 associated maintenance information. Process equipment maintenance data
 4902 includes replaceables, reusables, labor, cycle life and the cost of
 the associated maintenance item. Some examples of replaceables and
 reusables are: filters, gaskets, bearings, seals, belts, crank-shafts,
 lubricants and thermal media. Associated with each maintenance item is the
 number and identifier for the item, the quantity, the cycle life (i.e.,
 the amount of time or use before replacement), and the cost per cycle.
 Also included in process equipment maintenance data 4902 is the amount of
 labor associated with each maintenance item and the number of dollars per
 cycle for the labor.
 Step 4904 matches process equipment list with functional specifications
 4908 with process equipment maintenance data 4902, to generate process
 equipment maintenance table 4906. Process equipment list with functional
 specifications 4908 is matched with process equipment maintenance data
 4902 based on a comparison of functional specifications in the process
 equipment list 4908 and the process equipment maintenance data 4902. Step
 4904 copies the process equipment maintenance data 4902 for each piece of
 process equipment in the process equipment list 4908, thereby creating
 process equipment maintenance table 4906.
 FIGS. 64A-64AB illustrate an exemplary process equipment maintenance table
 4906. Column 6402 illustrates exemplary unit operations and their
 associated process equipment, as determined from process equipment list
 4908. FIGS. 64A-64E illustrate the process equipment maintenance data for
 unit operations 1-6, as illustrated in column 6402.
 Column 6404 of FIG. 64A illustrates exemplary maintenance data values for
 the filter maintenance items. Included in column 6404 are item number,
 quantity, cycle life of the filter materials, unit cost of the filter
 materials, dollars per cycle of the filter material, the labor of hours
 required to service the filter media, and the dollars per cycle for the
 labor. Item number identifies the stock number or part number of the item
 used in the maintenance procedure. Cycle life of the materials identifies
 the useful life the maintenance item. Quantity identifies the quantity of
 the maintenance item used in the maintenance procedure. Unit cost is the
 per unit cost of the maintenance item. Dollars per cycle is the quotient
 of the cost of the maintenance items and the cycle life of the maintenance
 items.
 Column 6406 illustrates exemplary maintenance data for gasket maintenance
 items. Column 6408 of FIGS. 64A and 64B illustrates exemplary maintenance
 data for bearing maintenance items. Column 6410 of FIG. 64B illustrates
 exemplary maintenance data for seal maintenance items. Column 6412 of
 FIGS. 64B and 64D illustrate exemplary maintenance data for belt
 maintenance items. Column 6416 of FIG. 64C illustrates exemplary
 maintenance data for crank shaft maintenance items. Column 6418 of FIGS.
 64C and 64D illustrates exemplary maintenance data for lubricant
 maintenance items. Column 6420 of FIG. 64D illustrates exemplary
 maintenance data for thermal media maintenance items. FIGS. 64E-64AB
 illustrate the same maintenance items as described in column 6404-6420, as
 associated with unit operations 7-22.
 FIG. 50 illustrates the process of generating the process equipment
 maintenance time line 5004. Process equipment maintenance time line 5004
 is a schedule maintenance items or procedures for process equipment in the
 biopharmaceutical production process. Step 5002 generates process
 equipment maintenance time line 5004 by applying the equipment scheduling
 data from the process equipment time line 906 data to the process
 equipment maintenance table 4906. Step 5002 calculates the accumulated
 usage time for each piece of equipment and schedules maintenance on the
 equipment at the times specified by the process equipment maintenance
 table 4906. Process equipment maintenance time line 5004 includes process
 equipment maintenance data from process maintenance data 4906 and the
 specific time and date when each piece of process equipment should be
 serviced. Step 5002, therefore, determines the number of unit operations
 or process cycles required to attain the cycle life rating on the
 maintenance item in order to trigger the maintenance processes.
 FIG. 51 illustrates the process of generating solution preparation
 equipment maintenance table 5106. Solution preparation equipment
 maintenance table 5106 includes maintenance procedures, maintenance
 duration (i.e., the amount of time required to perform the maintenance),
 reusables (i.e., those maintenance items that must be replaced
 periodically), disposables (i.e., those maintenance items that must be
 replaced after every use), the maintenance period (i.e., the amount of use
 before the equipment must be serviced), and the number of hours required
 to complete the maintenance tasks for the equipment.
 Step 5104 generates solution preparation equipment maintenance table 5106
 from the solution preparation equipment list and functional specifications
 5108 and solution preparation equipment maintenance data 5102. Solution
 preparation equipment list 5108 is generated from preparation vessel
 identifier and associated volume list 1402. Preparation vessel identifier
 and associated volume list 1402 includes the solution preparation
 equipment associated with each solution preparation vessel. The solution
 preparation equipment list 5108, therefore, includes a list of solution
 preparation equipment from preparation vessel identifier and associated
 volume list 1402. Solution preparation equipment list 5108 also includes
 functional specifications associated with each piece of solution
 preparation equipment in solution preparation equipment list 4809. The
 functional specifications for each solution preparation vessel and its
 associated solution preparation equipment are included in preparation
 vessel identifier and associated volume list 1402 when it is defined.
 Step 5104 generates solution preparation equipment maintenance table 5106
 from solution preparation equipment list with functional specifications
 5108 and solution preparation equipment maintenance data 5102. Solution
 preparation equipment maintenance data 5102 includes functional
 specifications for each piece of solution preparation equipment and their
 associated maintenance information. Solution preparation equipment
 maintenance data 5102 includes replaceables, reusables, labor, cycle life
 and the cost of the associated maintenance item. Some examples of
 replaceables and reusables are: filters, gaskets, bearings, seals, belts,
 crank-shafts, lubricants and thermal media. Associated with each
 maintenance item is the number and identifier for the item, the quantity,
 the cycle life (i.e., the amount of time or use before replacement), and
 the cost per cycle. Also included in solution preparation equipment
 maintenance data 5102 are the amount of labor associated with each
 maintenance item and the number of dollars per cycle for the labor.
 Step 5104 matches solution preparation equipment list with functional
 specifications 5108 with solution preparation equipment maintenance data
 5102, to generate solution preparation equipment maintenance table 5106.
 Solution preparation equipment list with functional specifications 5108 is
 matched with solution preparation equipment maintenance data 5102 based on
 a comparison of functional specifications in the solution preparation
 equipment list 5108 and the solution preparation equipment maintenance
 data 5102. Step 5104 copies the solution preparation equipment maintenance
 data 5102 for each piece of solution preparation equipment in the solution
 preparation equipment list 5108, thereby creating solution preparation
 equipment maintenance table 5106.
 FIG. 52 illustrates the process of generating the solution preparation
 equipment maintenance time line 5204. Solution preparation equipment
 maintenance time line 5204 is a schedule maintenance items or procedures
 for solution preparation equipment in the biopharmaceutical production
 process. Step 5202 generates process equipment maintenance time line 5204
 by applying the equipment scheduling data from the solution preparation
 equipment time line 3210 data to the solution preparation equipment
 maintenance table 5106. Step 5202 calculates the accumulated usage time
 for each piece of equipment and schedules maintenance on the equipment at
 the times specified by the solution preparation equipment maintenance
 table 5106. Solution preparation equipment maintenance time line 5204
 includes solution preparation equipment maintenance data from process
 maintenance data 5106 and the specific time and date when each piece of
 solution preparation equipment should be serviced. Step 5202, therefore,
 determines the number of unit operations or process cycles required to
 attain the cycle life rating on the maintenance item in order to trigger
 the maintenance processes.
 FIG. 53 illustrates the process of generating preparation equipment
 maintenance table 5306. Preparation equipment maintenance table 5306
 includes maintenance procedures, maintenance duration (i.e., the amount of
 time required to perform the maintenance), reusables (i.e., those
 maintenance items that must be replaced periodically), disposables (i.e.,
 those maintenance items that must be replaced after every use), the
 maintenance period (i.e., the amount of use before the equipment must be
 serviced), and the number of hours required to complete the maintenance
 tasks for the equipment.
 Step 5304 generates preparation equipment maintenance table 5306 from
 preparation equipment list with functional specifications 4706 and
 preparation equipment maintenance data 5302. Preparation equipment list
 4706 also includes functional specifications associated with each piece of
 preparation equipment as determined in step 3314. Preparation equipment
 maintenance data 5302 includes functional specifications for each piece of
 preparation equipment and their associated maintenance information.
 Preparation equipment maintenance data 5302 includes replaceables,
 reusables, labor, cycle life and the cost of the associated maintenance
 item.
 Step 5304 matches preparation equipment list with functional specifications
 4706 with preparation equipment maintenance data 5302, to generate
 preparation equipment maintenance table 5306. Preparation equipment list
 with functional specifications 4706 is matched with preparation equipment
 maintenance data 5302 based on a comparison of functional specifications
 in the preparation equipment list 4706 and the preparation equipment
 maintenance data 5302. Step 5304 copies the preparation equipment
 maintenance data 5302 for each piece of preparation equipment in the
 preparation equipment list 4706, thereby creating preparation equipment
 maintenance table 5306.
 FIG. 54 illustrates the process of generating the preparation equipment
 maintenance time line 5404. Preparation equipment maintenance time line
 5404 is a schedule maintenance items or procedures for preparation
 equipment in the biopharmaceutical production process. Step 5402 generates
 process equipment maintenance time line 5404 by applying the equipment
 scheduling data from the preparation equipment time line 4610 data to the
 preparation equipment maintenance table 5306. Step 5402 calculates the
 accumulated usage time for each piece of equipment and schedules
 maintenance on the equipment at the times specified by the preparation
 equipment maintenance table 5306. Preparation equipment maintenance time
 line 5404 includes preparation equipment maintenance data from process
 maintenance data 5306 and the specific time and date when each piece of
 preparation equipment should be serviced. Step 5402, therefore, determines
 the number of unit operations or process cycles required to attain the
 cycle life rating on the maintenance item in order to trigger the
 maintenance processes.
 5.0 Equipment Calibration Module
 Equipment calibration in a biopharmaceutical production facility is
 necessary to sustain the biopharmaceutical production process. Equipment
 calibration is essential to the accurate measurement and control of all
 key manufacturing operations. Instruments such as pressure indicators,
 temperature indicators, flow meters, load cells etc. are at the core of
 most manufacturing systems. The reliability of these instruments and the
 processes they serve is dependent on punctual and consistent calibration
 programs. The types and frequency of calibration required is a function of
 the particular equipment used in the facility, as well as the frequency
 and nature of use. The equipment involved in the production process,
 solution preparation process and equipment preparation all require regular
 calibration during sustained operation. Often, calibration frequency and
 cost are not considered in the design of a biopharmaceutical production
 facility. Calibration costs and scheduling, however, are a significant
 fraction of the cost of operating the biopharmaceutical facility and
 producing the biopharmaceutical product. Since calibration is a
 significant cost of operating a biopharmaceutical production facility, a
 method and computer program product for scheduling and modeling the
 calibration of process equipment, solution preparation equipment and
 preparation equipment would allow the biopharmaceutical facility designer
 to predict and minimize the cost of equipment calibration. Additionally,
 scheduling and modeling equipment calibration of a biopharmaceutical
 production process would allow for more reliable calibration programs to
 insure the adequate and consistent performance of all manufacturing
 systems.
 Modeling and scheduling biopharmaceutical production equipment calibration
 is based on the functional specifications and usage of the
 biopharmaceutical production process equipment. Each piece of equipment
 has associated calibration points. These calibration points typically
 include pressure indicators and transmitters, temperature indicators and
 transmitters, level sensors, flow meters, etc. All of these calibration
 points are required for the reliable operation of these process systems.
 Given equipment functional specifications, equipment calibration
 requirements and production schedules for biopharmaceutical production
 process equipment, equipment calibration can be modeled and scheduled.
 FIG. 55 illustrates the process of generating process equipment calibration
 table 5506. Process equipment calibration table 5506 includes calibration
 procedures, calibration duration (i.e., the amount of time required to
 perform the calibration), the calibration period (i.e., the amount of use
 before the equipment must be serviced), and the number of hours required
 to complete the calibration tasks for the equipment.
 Step 5504 generates process equipment calibration table 5506 from process
 equipment list with functional specifications 4908 and process equipment
 calibration data 5502. Process equipment calibration data 5502 includes
 functional specifications for each piece of process equipment and their
 associated calibration information. Process equipment calibration data
 5502 includes replaceables, reusables, labor, cycle life and the cost of
 the associated calibration item. As mentioned above, some examples of
 replaceables and reusables are: filters, gaskets, bearings, seals, belts,
 crank-shafts, lubricants and thermal media. Associated with each
 calibration item is the number and identifier for the item, the quantity,
 the cycle life (i.e., the amount of time or use before replacement), and
 the cost per cycle. Also included in process equipment calibration data
 5502 are the amount of labor associated with each calibration item and the
 number of dollars per cycle for the labor.
 Step 5504 matches process equipment list with functional specifications
 4908 with process equipment calibration data 5502, to generate process
 equipment calibration table 5506. Process equipment list with functional
 specifications 4908 is matched with process equipment calibration data
 5502 based on a comparison of functional specifications in the process
 equipment list 4908 and the process equipment calibration data 5502. Step
 5504 copies the process equipment calibration data 5502 for each piece of
 process equipment in the process equipment list 4908, thereby creating
 process equipment calibration table 5506.
 FIG. 56 illustrates the process of generating the process equipment
 calibration time line 5604. Process equipment calibration time line 5604
 is a schedule calibration items or procedures for process equipment in the
 biopharmaceutical production process. Step 5602 generates process
 equipment calibration time line 5604 by applying the equipment scheduling
 data from the process equipment time line 906 data to the process
 equipment calibration table 5566. Step 5602 calculates the accumulated
 usage time for each piece of equipment and schedules calibration on the
 equipment at the times specified by the process equipment calibrationtable
 5566. Process equipment calibration time line 5604 includes process
 equipment calibration data from process calibration data 5566 and the
 specific time and date when each piece of process equipment should be
 serviced. Step 5602, therefore, determines the number of unit operations
 or process cycles required to attain the cycle life rating on the
 calibration item in order to trigger the calibration processes.
 FIG. 57 illustrates the process of generating solution preparation
 equipment calibration table 5706. Solution preparation equipment
 calibration table 5706 includes calibration procedures, calibration
 duration (i.e., the amount of time required to perform the calibration),
 reusables (i.e., those calibration items that must be replaced
 periodically), disposables (i.e., those calibration items that must be
 replaced after every use), the calibration period (i.e., the amount of use
 before the equipment must be serviced), and the number of hours required
 to complete the calibration tasks for the equipment.
 Step 5704 generates solution preparation equipment calibration table 5706
 from the solution preparation equipment list and functional specifications
 5108 and solution preparation equipment calibration data 5702. Solution
 preparation equipment list 5108 is generated from preparation vessel
 identifier and associated volume list 1402. Preparation vessel identifier
 and associated volume list 1402 includes the solution preparation
 equipment associated with each solution preparation vessel. The solution
 preparation equipment list 5108, therefore, includes a list of solution
 preparation equipment from preparation vessel identifier and associated
 volume list 1402. Solution preparation equipment list 5108 also includes
 functional specifications associated with each piece of solution
 preparation equipment in solution preparation equipment list 4809. The
 functional specifications for each solution preparation vessel and its
 associated solution preparation equipment are included in preparation
 vessel identifier and associated volume list 1402 when it is defined.
 Step 5704 generates solution preparation equipment calibration table 5706
 from solution preparation equipment list with functional specifications
 5108 and solution preparation equipment calibration data 5702. Solution
 preparation equipment calibration data 5702 includes functional
 specifications for each piece of solution preparation equipment and their
 associated calibration data.
 Step 5704 matches solution preparation equipment list and functional
 specifications 5108 with solution preparation equipment calibration data
 5702 to generate solution preparation equipment calibration table 5706.
 Solution preparation equipment list with functional specifications 5108 is
 matched with solution preparation equipment calibration data 5702 based on
 a comparison of functional specifications in the solution preparation
 equipment list 5108 and the solution preparation equipment calibration
 data 5702. Step 5704 copies the solution preparation equipment calibration
 data 5702 for each piece of solution preparation equipment in the solution
 preparation equipment list 5108, thereby creating solution preparation
 equipment calibration table 5706.
 FIG. 58 illustrates the process of generating the solution preparation
 equipment calibration time line 5804. Solution preparation equipment
 calibration time line 5804 is a schedule of calibration items and
 procedures for solution preparation equipment in the biopharmaceutical
 production process. Step 5802 generates process equipment calibration time
 line 5804 by applying the equipment scheduling data from the solution
 preparation equipment time line 3210 data to the solution preparation
 equipment calibration table 5706. Step 5802 calculates the accumulated
 usage time for each piece of equipment and schedules re-calibration on the
 equipment at the times specified by the solution preparation equipment
 calibration table 5706. Solution preparation equipment calibration time
 line 5804 includew solution preparation equipment calibration data from
 process calibration data 5706 and the specific time and date when each
 piece of solution preparation equipment should be calibrated. Step 5802,
 therefore, determines the number of unit operations or process cycles
 required to attain the cycle life rating on the calibration of the
 equipment in order to trigger re-calibration of the equipment.
 FIG. 59 illustrates the process of generating preparation equipment
 calibration table 5906. Preparation equipment calibration table 5906
 includew calibration procedures, calibration duration (i.e., the amount of
 time required to perform the calibration), the calibration period (i.e.,
 the amount of use before the equipment must be serviced), and the number
 of hours required to complete the calibration tasks for the equipment.
 Step 5904 generates preparation equipment calibration table 5906 from
 preparation equipment list with functional specifications 4706 and
 preparation equipment calibration data 5902. Preparation equipment list
 4706 also includew functional specifications associated with each piece of
 preparation equipment as determined in step 3314. Preparation equipment
 calibration data 5902 includew functional specifications for each piece of
 preparation equipment and their associated calibration data. Preparation
 equipment calibration data 5902 includes labor, and cycle life of the
 associated with calibration.
 Step 5904 matches preparation equipment list and functional specifications
 4706 with preparation equipment calibration data 5902, to generate
 preparation equipment calibration table 5906. Preparation equipment list
 with functional specifications 4706 is matched with preparation equipment
 calibration data 5902 based on a comparison of functional specifications
 in the preparation equipment list 4706 and the preparation equipment
 calibration data 5902. Step 5904 copies the preparation equipment
 calibration data 5902 for each piece of preparation equipment in the
 preparation equipment list 4706, thereby creating preparation equipment
 calibration table 5906.
 FIG. 60 illustrates the process of generating the preparation equipment
 calibration time line 6004. Preparation equipment calibration time line
 6004 is a calibration schedule calibration for preparation equipment in
 the biopharmaceutical production process. Step 6002 generates process
 equipment calibration time line 6004 by applying the equipment scheduling
 data from the preparation equipment time line 4610 data to the preparation
 equipment calibration table 5906. Step 6002 calculates the accumulated
 usage time for each piece of equipment and schedules calibration on the
 equipment at the times specified by the preparation equipment calibration
 table 5906. Preparation equipment calibration time line 6004 includew
 preparation equipment calibration data from process calibration data 5906
 and the specific time and date when each piece of preparation equipment
 should be calibrated. Step 6002, therefore, determines the number of unit
 operations or process cycles required to attain the cycle life rating on
 the calibration item in order to trigger the calibration processes.
 6.0 Quality Control Module
 Quality control in a biopharmaceutical production facility is necessary to
 ensure the safety and quality of the biopharmaceutical product. Quality
 control sampling and testing, at various points in the biopharmaceutical
 production process ensures contamination-free product during the process,
 solution preparation and equipment preparation. The type and frequency of
 quality control sampling and testing required in a biopharmaceutical
 production process is a function of the particular equipment used in the
 process, the frequency and nature of the equipment use and the particular
 step or task in which the equipment is engaged. Often, quality control
 testing, frequency and cost are not planned prior to the design of a
 biopharmaceutical production facility. Quality control, sampling and
 testing, however, play a significant role in scheduling the operation of a
 biopharmaceutical facility. Modeling and scheduling quality control
 sampling and testing in a biopharmaceutical production facility is based
 on the definitions of the basic steps in the biopharmaceutical production
 process. Quality control testing and sampling steps are specified for the
 production process, the solution preparation process and equipment
 preparation protocols.
 FIG. 61 illustrates the process for generating a master quality control
 protocol table 6110. Quality control protocols are assays and testing
 procedures associated with quality control sampling and testing. Quality
 control protocols 6102 are defined by the biopharmaceutical facility
 designer, determined through testing and experimentation or specified by
 the vendor of the equipment in the biopharmaceutical facility. Quality
 control protocols 6102 include quality control protocol parameters.
 Quality control parameters are values that define the quality control
 assays. Examples of quality control parameters are the category and title
 of the assay, the setup time for the assay, the time required to draw each
 sample, the time required to clean up after taking the sample(s) and the
 disposal material necessary to dispose of the samples after testing.
 Step 6104 generates quality control protocol identifiers 6108 for each of
 quality control protocols 6102. Quality control protocol identifiers 6108
 are tags or codes that identify individual quality control protocols 6102.
 Step 6106 assigns quality control protocol identifiers 6108 to the quality
 control protocols 6102 resulting in master quality control protocol table
 6110. Master quality control protocol table 6110 includes quality control
 protocols 6102 and a unique quality control identifier 6108 associated
 with each of quality control protocols 6102.
 FIG. 21 illustrates an exemplary master quality control protocol table
 6110. Column 2102 illustrates three exemplary categories of quality
 control protocols including environmental, analytical, and in vitro
 biological quality control protocols. Column 2104 illustrates exemplary
 quality control protocol identifiers 6108. Column 2106 illustrates
 exemplary values for quality control protocol parameters. More
 specifically, column 2106 illustrates quality control protocol parameters
 for the number of man-hours required to setup, draw each sample and
 cleanup the sampling operations associated with each quality control
 protocol. Setup and cleanup parameters define the amount of time necessary
 to setup prior to and cleanup after quality control protocol sampling. The
 per sample quality control protocol parameter defines the amount of time
 required to draw each sample. For example, 10 samples of temperature
 (quality control protocol identifier E-1) would require 0.5 man-hours to
 set up, 1.0 man-hours to sample (0.1 hours/sample.times.10 samples) and
 0.5 man-hours to clean up.
 FIG. 62 illustrates the process of generating master quality control sample
 table 6208. Master quality control sample table 6208 includes all of the
 tasks and quality control sampling protocols associated with the
 production of a biopharmaceutical product. Each task or step in the
 process time line, the solution preparation schedule or the preparation
 equipment time line that has an associated quality control protocol 6102
 is included in master unit operation list 6206. Each task or step in
 master unit operation list 6206 also includes a quality control protocol.
 The quality control protocol parameters of master quality control protocol
 table 6110 is used to generate master quality control sample list in step
 6202. The master quality control sample list 6202 lists all the codes of
 the quality control protocols from the master QC protocol table 6110. Step
 6204 uses the master quality control sample list to assign sampling assays
 to each step in master unit operation list 6206 according to which quality
 control protocol is assigned to each step in master unit operation list
 6206. The result of step 6204 is a master QC sample table 6208 which
 includes all of the steps in the biopharmaceutical production process,
 solution preparation and equipment preparation as well as their associated
 quality control protocol and sample list.
 FIG. 63 illustrates the process for generating the process equipment
 quality control time line 6304. Quality control process equipment time
 line 6304 is a table of all the unit operations associated with process
 equipment time line 906 as well as the schedule of quality control assays
 and samples associated with each. Step 6302 generates the process
 equipment quality control time line 6304. Step 6302 matches the process
 steps of process equipment 906 with master unit operation list 6206 to
 determine which assays need to be assigned to the tasks in process
 equipment time line 906. Step 6302 assigns the quality control samples to
 be taken in each of the associated tasks from master quality control
 sample table 6208 to each of the tasks in process equipment time line 906,
 resulting in process equipment quality control time line 6304.
 FIGS. 45A-45I illustrate an exemplary process equipment quality control
 time line 6304. FIG. 45A illustrates unit operations 1A-6A in column 4502.
 Scheduling for each of the tasks in unit operations 1A-6A is illustrated
 in columns 4504. Columns 4506 of FIGS. 45A-45B illustrate the quality
 control assays from master quality control protocol table 6110. Although
 columns 4506 are empty, if quality control samples where scheduled for
 unit operations 1A-6A in column 4502, columns 4506 would contain the
 number of samples to be taken at the scheduled time, as defined in master
 quality control sample table 6208. FIGS. 45C-45I illustrate the balance of
 the tasks and unit operations for the process equipment quality control
 time line 6304.
 FIG. 22 illustrates the process for generating the solution preparation
 equipment quality control time line 2204. Quality control solution
 preparation equipment time line 2204 is a table of all the tasks
 associated with solution preparation schedule 3210, as well as the
 schedule of quality control assays and samples associated with each task.
 Step 2202 generates the solution preparation equipment quality control
 time line 2204. Step 2202 matches the solution preparation tasks of
 solution preparation schedule 3210 with master unit operation list 6206 to
 determine which assays need to be assigned to the tasks in solution
 preparation schedule 3210. Step 2202 assigns the quality control samples
 to be taken in each of the associated tasks with from master quality
 control sample table 6208 to each of the tasks in process equipment time
 line 906, resulting in process equipment quality control time line 2204.
 FIG. 23 illustrates the process for generating preparation equipment
 quality control time line 2304. Quality control preparation equipment time
 line 2304 is a table of all the tasks associated with preparation
 equipment time line 4610, as well as the schedule of quality control
 assays and samples associated with each task in the preparation equipment
 protocols. Step 2302 generates the preparation equipment quality control
 time line 2304. Step 2302 matches the equipment preparation tasks of
 preparation equipment time line 4610 with master unit operation list 6206
 to determine which assays need to be assigned to the tasks in preparation
 equipment time line 4610. Step 2302 assigns the quality control samples to
 be taken in each of the associated tasks from master quality control
 sample table 6208 to each of the tasks in process equipment time line 906,
 resulting in process equipment quality control time line 2304.
 7.0 Environment
 The present invention may be implemented using hardware, software or a
 combination thereof and may be implemented in a computer system or other
 processing system. In fact, in one embodiment, the invention is directed
 toward a computer system capable of carrying out the functionality
 described herein. An example computer system 1901 is shown in FIG. 19. The
 computer system 1901 includes one or more processors, such as processor
 1904. The processor 1904 is connected to a communication bus 1902. Various
 software embodiments are described in terms of this example computer
 system. After reading this description, it will become apparent to a
 person skilled in the relevant art how to implement the invention using
 other computer systems and/or computer architectures.
 Computer system 1902 also includes a main memory 1906, preferably random
 access memory (RAM), and can also include a secondary memory 1908. The
 secondary memory 1908 can include, for example, a hard disk drive 1910
 and/or a removable storage drive 1912, representing a floppy disk drive, a
 magnetic tape drive, an optical disk drive, etc. The removable storage
 drive 1912 reads from and/or writes to a removable storage unit 1914 in a
 well known manner. Removable storage unit 1914, represents a floppy disk,
 magnetic tape, optical disk, etc. which is read by and written to by
 removable storage drive 1912. As will be appreciated, the removable
 storage unit 1914 includes a computer usable storage medium having stored
 therein computer software and/or data.
 In alternative embodiments, secondary memory 1908 may include other similar
 means for allowing computer programs or other instructions to be loaded
 into computer system 1901. Such means can include, for example, a
 removable storage unit 1922 and an interface 1920. Examples of such can
 include a program cartridge and cartridge interface (such as that found in
 video game devices), a removable memory chip (such as an EPROM, or PROM)
 and associated socket, and other removable storage units 1922 and
 interfaces 1920 which allow software and data to be transferred from the
 removable storage unit 1922 to computer system 1901.
 Computer system 1901 can also include a communications interface 1924.
 Communications interface 1924 allows software and data to be transferred
 between computer system 1901 and external devices. Examples of
 communications interface 1924 can include a modem, a network interface
 (such as an Ethernet card), a communications port, a PCMCIA slot and card,
 etc. Software and data transferred via communications interface 1924 are
 in the form of signals which can be electronic, electromagnetic, optical
 or other signals capable of being received by communications interface
 1924. These signals 1926 are provided to communications interface via a
 channel 1928. This channel 1928 carries signals 1926 and can be
 implemented using wire or cable, fiber optics, a phone line, a cellular
 phone link, an RF link and other communications channels.
 In this document, the terms "computer program medium" and "computer usable
 medium" are used to generally refer to media such as removable storage
 device 1912, a hard disk installed in hard disk drive 1910, and signals
 1926. These computer program products are means for providing software to
 computer system 1901.
 Computer programs (also called computer control logic) are stored in main
 memory and/or secondary memory 1908. Computer programs can also be
 received via communications interface 1924. Such computer programs, when
 executed, enable the computer system 1901 to perform the features of the
 present invention as discussed herein. In particular, the computer
 programs, when executed, enable the processor 1904 to perform the features
 of the present invention. Accordingly, such computer programs represent
 controllers of the computer system 1901.
 In an embodiment where the invention is implemented using software, the
 software may be stored in a computer program product and loaded into
 computer system 1901 using removable storage drive 1912, hard drive 1910
 or communications interface 1924. The control logic (software), when
 executed by the processor 1904, causes the processor 1904 to perform the
 functions of the invention as described herein.
 In another embodiment, the invention is implemented primarily in hardware
 using, for example, hardware components such as application specific
 integrated circuits (ASDICS). Implementation of the hardware state machine
 so as to perform the functions described herein will be apparent to
 persons skilled in the relevant art(s).
 In yet another embodiment, the invention is implemented using a combination
 of both hardware and software.
 8.0 Conclusion
 While the invention has been particularly shown and described with
 reference to preferred embodiments thereof, it will be understood by those
 skilled in the relevant art that various changes in form and details may
 be made therein without departing from the spirit and scope of the
 invention.