Note: Descriptions are shown in the official language in which they were submitted.
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System and Method for Simulation, Modeling
and Scheduling of Process Support Operations in
Biopharmaceutical Batch Process Manufacturing Facilities
Background of the Invention
S 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 batch process
facilities.
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 biopharmaceuticals are
synthesised from chemicals
or extracted from natural plant or animal tissues, respectively.
The process for producing biopharmaceuticals 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 biopharmaceuticals 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
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introduced in the initial design ofthe 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
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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
eiflciency 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
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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&ms 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 (and
the facility itself) drives inaccurate initial design. Often, these
inaccuracies result in changes to the
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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.
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 production
process, solution preparation and equipment preparation activities. The
quantity and sensitivity of
these sampling and testing procedures requires considerable preparation and
planning. However,
planning tools that assist with the integration between manufacturing
operations and quality control
activities are virtually non existent.
Solution preparation is one of the primary consumers of capital and utility
resources in the
construction and operation of a biopharmaceutical facility. Often, the
facility and process designers
specify equipment that is many times what is required to support their
solution preparation needs in
order to ensure that all of the processes in the facility can be supported.
Equipment, utility and
cleaning equipment costs are a function by the preparation and use of
solutions. The excess capacity,
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therefore, results in wasted construction capital and continuous losses during
the operation of the
plant.
After the biopharmaceutical production process and solution preparation
process have been
designed, the equipment preparation procedures for the cleaning of equipment
soiled by the
biopharmaceutical production process and solution preparation procedure must
be determined. The
protocols for cleaning soiled equipment are determined through experimentation
and testing. Once
the protocols and procedures for cleaning the soiled equipment have been
determined, however, it
is difficult to determine the needed cleaning equipment capacity and the
equipment cleaning
procedure schedules necessary to clean the soiled process equipment. Often,
designers of
biopharmaceutical facilities design extra equipment preparation capacity into
the biopharmaceutical
facility in order to ensure a steady supply of clean, sterile equipment.
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. Cleaning and sterilizing (preparation) equipment associated with
equipment preparation
activities are capital and utility intensive, and inefficient designs result
in increased costs of
construction and operation of the biopharmaceutical facility.
What is needed, therefore, is a system and method for simulation, modeling and
scheduling
of process support operations in a biopharmaceutical manufacturing facility.
The process support
operations include those associated with the biopharmaceutical production
facility: (1) equipment
maintenance and calibration; and {2) quality control sampling and testing; and
those associated with
the batch production process within the facility: (3) solution preparation;
and (4) equipment
preparation.
Summary of the Invention
The present invention is directed to a system and method for simulation,
modeling and
scheduling of process support operations in a biopharmaceutical manufacturing
facility which satisfies
the above-stated needs.
For equipment maintenance, the system and method includes the steps of
identifying
maintenance and calibration data associated with biopharmaceutical production
process equipment.
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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.
For quality control and sampling, the system and method includes the steps of
identifying
quality control sampling and testing data associated with biopharmaceutical
production process tasks.
After the quality control sampling and testing data is identified,
biopharmaceutical production process
equipment data is used to generate a table of equipment and quality control
sampling and testing data.
After the table of equipment and data is generated, the table is compared with
a procedure time line
to determine the schedule of quality control sampling and testing for the
process tasks in the
biopharmaceutical production process
For solution preparation, the system and method includes the steps of
identifying a solution
for preparation and its associated volume. After the solution for preparation
is identified, a
predetermined start date and one successive start date for solution
preparation for the solution are
identified. After the solution, start and successive start dates are
identified, the solution is assigned
to a preparation vessel. After the solution has been assigned to a preparation
vessel, the duration of
the solution preparation procedure is determined and assigned to the solution
preparation vessel.
For equipment preparation, the system and method includes the steps of
identifying soiled
process components and their associated equipment preparation procedures.
After the soiled process
components are identified, a master list of soiled process components and
their associated equipment
preparation procedure is generated. After the soiled process components and
the equipment
preparation procedures are identified, the equipment preparation procedures
are scheduled out based
on preparation equipment protocols to generate a equipment preparation load
summary table. Next,
the size and capacity of the preparation equipment is determined based on the
information in the load
summary table. After the size and capacity of the preparation equipment is
determined, an equipment
preparation time line is generated.
One advantage of the present invention is that it directly and more accurately
links
maintenance and calibration scheduling to cumulative equipment service hours
than previously
possible. The result is more efficient planning and scheduling of equipment
maintenance and
calibration activities and enhanced integrity of manufacturing operations.
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Another advantage of the present invention is that it allows designers to
reduce the number
of errors introduced into plant design at the earliest stages, validates the
production process design
and maximizes the efficiency of the plant by finding optimum equipment
configurations. The present
invention generates detailed specifications for the scheduling of equipment
and solution preparation
that smooths the transition throughout all of the design phases and fixes the
cost of design and
construction of a biopharmaceutical facility. The present invention can also
be used for determining
the cost of goods for a product.
Yet another advantage of the present invention is that it allows process
modeling capability
which accurately plans resource demands on quality control and other
resources. The present
invention increases the efficiency of work flow of day-to-day quality control
operations, thereby
insuring the adequate control of manufacturing systems.
Brief Description of the Figures
The features and advantages of the present invention will become more apparent
from the
detailed description set forth below when taken in conjunction with the
drawings in which like
reference numbers indicate identical or functionally similar elements.
Additionally, the left-most digit
of a reference number identifies the drawing in which the reference number
first appears.
FIG. 1 illustrates a flow diagram of the process to generate a block flow
diagram and a
process time line according to the present invention.
FIG. 2 illustrates a flow diagram of the process for determining the necessary
reactor volume
according to the present invention.
FIG. 3 illustrates a unit operation list for a microbial fermentation process.
FIG. 4 illustrates a unit operation list for a mammalian cell culture process.
FIG. 5 illustrates a flow diagram for cross-referencing a unit operation list
with a process
parameters table according to the present invention.
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FIG. 6 illustrates an exemplary process parameters table.
FIG. 7 illustrates the process for generating a block flow diagram according
to the present
invention.
FIG. 8 illustrates an exemplary block flow diagram according to the present
invention.
FIG. 9 illustrates a block flow diagram for the process of generating a
process time line
according to the present invention.
FIGS. 10-11 illustrate a high-level process time line according to the present
invention.
FIGS. 12A-12H illustrate a detailed process time line according to the present
invention.
FIG. 13 is a block flow diagram illustrating an overview of the process for
scheduling and
simulating solution preparation in a biopharmaceutical production process.
FIG. 14 is a block flow diagram illustrating the step of determining the
solution preparation
time associated with each solution preparation vessel.
FIG. 15 illustrates an exemplary list of solution preparation parameters.
FIG. 16 is a block flow diagram illustrating the step of assigning the
solutions required by the
biopharmaceutical production process to particular solution preparation
vessels.
FIG. 17 illustrates an exemplary list of solution preparation procedure
parameters.
FIG. 18 illustrates an exemplary preparation vessel to solution assignment
list.
FIG. 19 illustrates an exemplary computer according to an embodiment of the
present
invention.
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FIG. 20 is a block flow diagram illustrating the step of determining the
calculated preparation
start date and next solution preparation date for each solution.
FIG. 21 illustrates an exemplary master quality control protocol table.
FIG. 22 is a block flow diagram illustrating the step of generating a solution
preparation
equipment quality control time line.
FIG. 23 is a block flow diagram illustrating the step of generating a
preparation equipment
quality control time line.
FIG. 24 is a block flow diagram illustrating the step of determining the
earliest solution
preparation start date for each solution preparation vessel.
FIG. 25 is a block flow diagram illustrating the step of determining the
latest solution
preparation start date for each solution preparation vessel.
FIG. 26 is a block flow diagram illustrating the step of calculating solution
preparation vessel
utilization time.
FIG. 27 is a block flow diagram illustrating the step of calculating the
cumulative solution
preparation time for each solution preparation vessel.
FIG. 28 is a block flow diagram illustrating the step of determining the
percentage utilization
of each solution preparation vessel.
FIG. 29 is a block flow diagram illustrating the step of generating an initial
solution prep shift
schedule.
FIG. 30 is a block flow diagram illustrating the step of back scheduling
solution preparation
in the initial solution prep shift schedule.
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FIG. 31 illustrates an exemplary initial solution preparation shift schedule.
FIG. 32 is a block flow diagram illustrating the process for generating a
solution preparation
schedule.
FIG. 33 is a block flow diagram illustrating an overview of the process for
scheduling and
simulating solution preparation in a biopharmaceutical production process.
FIG. 34 is a block flow diagram illustrating the step of generating the
preparation equipment
protocol table.
FIG. 35 is a block flow diagram illustrating the step of generating the
equipment preparation
procedure table.
FIGS. 36A-36H illustrate exemplary preparation equipment protocol tables.
FIGS. 37A-37B illustrate an exemplary equipment preparation procedure table.
FIG. 38 is a block flow diagram illustrating the step of generating the
equipment dimension
table.
FIG. 39 illustrates an exemplary equipment dimension table.
FIG. 40 is a block flow diagram illustrating the step of generating the master
list of equipment
requiring preparation.
FIG. 4 i is a block flow diagram illustrating the step of generating the
equipment preparation
load table.
FIGS. 42A-42D illustrate an exemplary equipment preparation load table.
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FIG. 43 is a block flow diagram illustrating the step of generating the
equipment preparation
load summary table.
FIG. 44 is a block flow diagram illustrating the step of determining the
capacities of the
preparation equipment.
FIGS. 45A-45I illustrate an exemplary process equipment quality control assay
sample time
line.
FIG. 46 is a block flow diagram illustrating the step of generating the
equipment preparation
time line.
FIG. 47 is a block flow diagram illustrating the step of generating the
preparation equipment
list with functional specification and costs.
FIG. 48 is a block flow diagram illustrating the step of generating the
preparation equipment
utility time line.
FIG. 49 is a block flow diagram illustrating the step of generating a process
equipment
maintenance table.
FIG. 50 is a block flow diagram illustrating the step of generating a process
equipment
maintenance time line.
FIG. 51 is a block flow diagram illustrating the step of generating a solution
preparation
equipment maintenance table.
FIG. 52 is a block flow diagram illustrating the step of generating a solution
preparation
equipment maintenance time line.
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FIG. 53 is a block flow diagram illustrating the step of generating a
preparation equipment
maintenance table.
FIG. 54 is a block flow diagram illustrating the step of generating a
preparation equipment
maintenance time line.
FIG. 55 is a block flow diagram illustrating the step of generating a process
equipment
calibration table.
FIG. 56 is a block flow diagram illustrating the step of generating a process
equipment
calibration time line.
FIG. 57 is a block flow diagram illustrating the step of generating a solution
preparation
equipment calibration table.
FIG. 58 is a block flow diagram illustrating the step of generating a solution
preparation
equipment calibration time line.
FIG. 59 is a block flow diagram illustrating the step of generating a
preparation equipment
calibration table.
FIG. 60 is a block flow diagram illustrating the step of generating a
preparation equipment
calibration time line.
FIG. 61 is a block flow diagram illustrating the step of generating a master
quality control
protocol table.
FIG. 62 is a block flow diagram illustrating the step of generating a master
quality control
sample table.
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FIG. 63 is a block flow diagram illustrating the step of generating a process
equipment quality
control time line.
FIGS. 64A-64AB illustrate an exemplary process equipment maintenance time
line.
FIGS. 65A-65G illustrate a detailed example of a process parameters table
showing a list of
unit operations and their associated parameters.
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
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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 ofunit 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
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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 appear in 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
1 S 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
1 i 0. 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
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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. l, 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
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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. The latter two
levels of scheduling cycles have an associated unit operation starting point
and unit operation end
point. That is, Columns 312 and 314 specify the start and end unit operations,
respectively, for cycles
per batch, and Columns 320 and 322 specify the start and end unit operations,
respectively, for cycles
per process.
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, S, 6, 1, 2, 3, 4 ,5,
6, i, 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
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fermentation production process continues at resuspension/surfactant, unit
operation sequence
number I I.
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,
r 30 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
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time period between the cycles per unit operation. In the example ofFIG. 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
shown 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.
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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.
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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 ofthe 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
Retentate/Filtrate Rate 20 to 1
Flush Volume 21.5 Liters/square meter
Prime Volume 21.5 Liters/square meter
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Wash Volume 0.5 % of Process Volume
Regenerate Volume 10.8 Liters/square meter
Storage Volume 21.5 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 1.5 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.
1,000 Liters / 125 L/SM/Hr / 2 Hours = 4.0 SM of 0.2 nvcron 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 x 4.0 SM = 86 Liters
Prime volume 21. S Liters/SM x 4.0 SM = 86 Liters
Wash Volume S % of 1,000 Liters = 50 Liters
Regenerate 21.5 Liters/SM x 4.0 SM = 86 Liters
Storage 10.8 Liters /SM x 4.0 SM = 42 Liters
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The flow rate of the filtrate is calculated from the volume to be filtered and
the required
process time.
1,000 Liters / 2 Hours = 8.3 Liters/minute
The flow rate of the retentate is calculated based on the above
retentate/filtrate ratio.
8.3 Liters per minute x 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-1 O 1 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
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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
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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 I 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 . S 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 ofthe 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. I2A-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
lA, 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 ai~ect the
start and end times of following unit operations. The start and finish date
and times for the set up and
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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 Iiters/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. S hours. Each task in
a unit operation that is
volume dependent has its duration calculated in order to generate the process
time line ofFIGS 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
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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
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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 deternunes 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.
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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 131 I 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).
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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 I 312
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
S) 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 13 I4 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
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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
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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
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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.
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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 I 412 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 1 O 1 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 1 O 1 may be prepared
in three preparation cycles per batch of fifty liters each, yielding a 150
liter batch of solution 101.
Alternatively, solution I O 1 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
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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 Iiter 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
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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
S 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
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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-Ol 12,
S-Ol 15, S-0117, and
S-0120. Similarly, column 1724 illustrates solution preparation vessel #109 is
associated with
solutions S-0116, S-Ol 18, 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
I 610. 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.
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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
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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 131 l, calculating solution preparation
vessel utilization time
for each solution preparation vessel 2604. Solution preparation vessel
utilization time 2604 for each
S preparation vessel is that time during which the vessel is occupied with the
preparation of solutions)
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
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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
ofthe 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
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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
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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
ofthree 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.
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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.
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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, iftwo 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. 1 S 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.
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3.0 Equipment Preparation Scheduling Module
The object ofthe 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
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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. Dii~erent 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
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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.
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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 fizrther 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
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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 for the
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 ofFIG. 36G illustrates exemplary
values for the total
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time in minutes required for each ofthe different steam sterilizer protocols
(protocol identifiers SS-l,
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.
S Equipment preparation procedure table 3512 includes data associated with
each equipment
preparation procedure, including the sequence ofpreparation 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
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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-S.
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 3 804 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
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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 (FB) in inches. Row 3 of rows 3904 illustrates exemplary values for
top-to-bottom
dimensions (TB) 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 fi~rther 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
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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
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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
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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 in step 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
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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 3 512. 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 3 512 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 3 S 12 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
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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.
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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 fi~nction
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 system and method 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
fi~nctional 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
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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 form unit operation list 508.
Process equipment list
4908 also includes fiznctional 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 filnctional
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 replaceable, resales, labor, cycle life and the cost of the
associated maintenance item. Some
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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 fi~nctional specifications 4908 is matched with process
equipment maintenance
data 4902 based on a comparison of fianctional 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
b408 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 b4D illustrates exemplary maintenance data
for lubricant
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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. S 1 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 S 108 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 fiznctional specifications associated with
each piece of solution
preparation equipment in solution preparation equipment list 4809. The
functional specifications for
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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 fiznctional specifications 5108 and solution
preparation equipment
maintenance data 5102. Solution preparation equipment maintenance data 5102
includes fiznctional
specifications for each piece of solution preparation equipment and their
associated maintenance
information. Solution preparation equipment maintenance data 5102 includes
replaceable, resales,
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 S 102 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
1 S with solution preparation equipment maintenance data S 102, 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 S 106.
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 S 106. 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
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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 fixnctional specifications 4706 and preparation equipment
maintenance data 5302.
Preparation equipment list 4706 also includes fiznctional 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
replaceable,
resales, 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 fi~nctional 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
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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.
S.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 system and method 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
fiznctional 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
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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 oftime required to perform the calibration), the calibration period
(i.e., the amount ofuse
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 fi~nctional specifications in the process
equipment list 4908 and the
process equipment calibration data 5502. Step 5504 copies the process
equipment calibration data
5 502 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
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usage time for each piece of equipment and schedules calibration on the
equipment at the times
specified by the process equipment calibration table 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 oftime 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
fixnctional 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 fi~nctional
specifications for each piece of solution preparation equipment and their
associated calibration data.
Step 5704 matches solution preparation equipment list and fixnctional
specifications 5108 with
solution preparation equipment calibration data 5702 to generate solution
preparation equipment
calibration table 5706. Solution preparation equipment list with fi~nctional
specifications 5108 is
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matched with solution preparation equipment calibration data 5702 based on a
comparison of
fi~nctional 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 includes 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 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 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 includes functional specifications associated with
each piece of preparation
equipment as determined in step 3314. Preparation equipment calibration data
5902 includes
fiznctional 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.
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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 fiznctional 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 includes 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. D 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.
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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 samples) 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 zn 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 X 10 samples)
and 0.5 man-hours
to clean up.
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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 all exemplary process equipment quality control time
line 6304. Fig.
45A illustrates unit operations lA-6A in column 4502. Scheduling for each of
the tasks in unit
operations lA-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 lA-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.
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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
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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 i 912. 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.
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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
S 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
(ASICs).
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. D 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.
