Note: Descriptions are shown in the official language in which they were submitted.
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PHAGE DISPENSING SYSTEM
TECHNICAL FIELD
[001] The present disclosure relates to dispensing systems for pharmaceutical
compositions. In a particular form the present disclosure relates to
dispensing system
for pharmaceutical compositions including Bacteriophages ("phages").
BACKGROUND
[002] In the following discussion, certain articles and methods will be
described for
background and introductory purposes. Nothing contained herein is to be
construed as
an "admission" of prior art. Applicant expressly reserves the right to
demonstrate, where
appropriate, that the articles and methods referenced herein do not constitute
prior art
under the applicable statutory provisions.
[003] Multiple drug resistant (MDR) bacteria are emerging at an alarming rate.
Currently, it is estimated that at least 2 million infections are caused by
MDR organisms
every year in the United States leading to approximately 23,000 deaths.
Further, the
overuse of antibiotics as well as bacteria's natural evolution will likely
lead to the
generation of more virulent microorganisms. Genetic engineering and synthetic
biology
may also lead to the generation of additional highly virulent microorganisms.
[004] For example, Staphylococcus aureus are gram positive bacteria that can
cause
skin and soft tissue infections (SSTI), pneumonia, necrotizing fasciitis, and
blood stream
infections. Methicillin resistant S. aureus ("MRSA") is an MDR organism of
great
concern in the clinical setting as MRSA is responsible for over 80,000
invasive
infections, close to 12,000 related deaths, and is the primary cause of
hospital acquired
infections. Additionally, the World Health Organization (WHO) has identified
MRSA as
organisms of international concern.
[005] In view of the potential threat of rapidly occurring and spreading
virulent
microorganisms and antimicrobial resistance, alternative clinical treatments
against
bacterial infection are being developed. One such potential treatment for MDR
infections involves the use of phage. Bacteriophages ("phages") are a diverse
set of
viruses that replicate within and can kill specific bacterial hosts. The
possibility of
harnessing phages as an antibacterial was investigated following their initial
isolation
early in the 20th century, and they have been used clinically as antibacterial
agents in
some countries with some success. Notwithstanding, phage therapy was largely
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abandoned in the U.S. after the discovery of penicillin, and only recently has
interest in
phage therapeutics been renewed, particularly in light of the development
Multiple Drug
Resistant Infections (MDRI) such as due to antibiotic resistant bacteria.
[006] Therapeutic use of phage typically comprises first identifying a phage
strain
likely to be efficacious against a bacteria associated with an infection
(including a MDRI)
of a specific patient. Phage are grown in batches at a manufacturing facility,
and the
purified phage is placed in a glass dispensing vial along with associated
pharmaceutical
ingredients such as excipients, carriers, buffers, and/or diluents. These may
be stored in
a low temperature (e.g. -80 C) store at the dispensary. When provided with a
phage
prescription, a pharmacist removes a vial containing the desired phage from
the low
temperature store and must then extract an appropriate dose from the vial and
combine
with other pharmaceutical ingredients to manufacture a (patient ready) phage
based
treatment. The phage based treatment is then dispensed to the patient to treat
the
infection.
[007] However, phage are quite different than most pharmaceutical compositions
and
creates a number of challenges in developing an efficient dispensing system.
Most
notably, there is significant batch to batch variability during manufacture of
phage
including concentration and contaminants, all of which the pharmacist must
take into
account when dispensing. Additionally the potency may change over time, and
this will
also vary based on batch and/or date of production, even for phage grown from
the
same batch, but subject to different processing and storage. Thus, unlike most
pharmaceutical compositions stored at a dispensary that have uniform
ingredients and
potency (such that individual packages are readily interchangeable), the
individual
phage vials available in a cold store containing the same phage but
manufactured in
different batches and/or at different times may have intrinsic variability
which the
pharmacist must take into account when dispensing. Phage are also expensive to
manufacture, and thus storage and inventory at clinical sites must be
efficiently
managed to ensure sufficient supply. Phage Dispensing must thus take into
account a
range of patient, clinical, logistical and manufacturing factors. Additionally
existing
dispensing systems are often paper based or email based, and are typically
cumbersome to use.
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[008] There is thus a need to develop a dispensing system which can manage
these
factors to ensure accurate and/or efficient dispensing at the point of care,
or to at least
to provide a useful alternative to existing dispensing systems.
SUMMARY
[009] According to a first aspect, there is provided a computer implemented
method
for dispensing a phage prescription, the method comprising:
receiving a phage prescription for a patient, the phage prescription
comprising
one or more phage to be dispensed, and determining a target phage dose range
for
each of the one or more phages to be dispensed;
receiving a patient weight and determining a maximum contaminant level for one
or more contaminants based on the patient weight;
generating a dispensing set comprised of one or more phage vials stored in a
phage storage apparatus by performing a dose calculation, comprising:
identifying, for each phage in the phage prescription, at least one
candidate phage vials in the phage storage apparatus that contain the
respective phage
and determining a dispensing volume for one or more candidate phage vials
based on a
titer of the respective candidate phage vial such that the total dispensing
volume from
combining the dispensing volume for the one or more candidate phage vials will
contain
an amount of phage within the target phage dose range for the respective phage
and an
amount of contaminant, for each contaminant in the one or more contaminants,
that is
below the maximum contaminant level for the respective contaminant;
providing a storage location and dose preparation instructions for each of the
one
or more candidate phage vials in the dispensing set to a user, wherein the
dose
preparation instructions comprises the associated dispensing volume for each
of the
phage vials in the dispensing set; and
receiving a phage vial identifier (ID) obtained from a phage vial and checking
the
phage vial ID matches a stored phage vial ID of one of the phage vials in the
dispensing
set, and if the phage vial ID matches then updating an electronic phage
inventory to
record the dispensing of the phage vial otherwise issuing a warning to the
user.
[0010] In one form, the phage prescription comprises a target phage dose for
each of
the one or more phages to be dispensed and the target phage dose range for
each of
the one or more phages to be dispensed is determined from the respective
target phage
dose.
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[0011] In a further form, a set of predefined non-overlapping target phage
dose ranges
are stored, and determining the target phage dose comprises determining which
target
phage dose range in the set contains the target phage dose.
[0012] In one form, a plurality of dose range labels and associated dose
ranges are
stored, and the phage prescription includes the dose range label and
determining the
target phage dose range comprises looking up the dose range associated with
the dose
range label.
[0013] In one form, the target phage dose is an upper limit of target phage
dose range.
[0014] In one form, determining a dispensing volume for one or more candidate
phage
vials comprises determining a dispensing volume for a first candidate phage
vial using
the titer of the first candidate phage vial, and if the dispensing volume is
less than the
volume required to dispense the phage prescription for the respective phage,
then
searching for one or more additional candidate phage vials which are identical
phage
vials to the first candidate phage vial and if one or more identical phage
vials to the first
phage candidate phage vial are located, then adding one or more of the one or
more
identical phage vials to the candidate set and storing an associated
dispensing volume
for each of the one or more identical phage vials if the amount of
contaminant, for each
contaminant in the one or more contaminants, is below the maximum contaminant
level
for the respective contaminant, and if the dispensing set does not comprise
sufficient
candidate phage vials and associated dispensing volumes to enable dispensing
of the
phage prescription for the respective phage, then repeating until the
dispensing set
comprises sufficient candidate phage vials to dispense the phage prescription
for the
respective phage such that the amount of each contaminant is below the maximum
contaminant level for the respective contaminant.
[0015] In a further form, two vials are identical if their titer and
contaminant levels are
within a predefined range of each other, and/or two vials are identical if
they have the
same lot number.
[0016] In a further form, the method further comprises determining a target
phage dose
for each of the one or more phages to be dispensed and using an optimization
method
to search for a combination of candidate phage vials and associated dispensing
volumes which when combined generate a total dose closest to the target dose
subject
to the constraint that the amount of contaminant, for each contaminant in the
one or
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more contaminants, is below the maximum contaminant level for the respective
contaminant.
[0017] In a further form, the one or more contaminants comprising an endotoxin
level,
and the associated maximum contaminant level is weight (in kg) x 5 EU/kg.
[0018] In one form, a computing apparatus is operatively connected to the
phage
storage apparatus, the phage vial identifier (ID) is a barcode or a radio
frequency
identification (RFID) tag, and the computing apparatus comprises;
at least one processor,
at least one memory;
at least one display device;
one or more user interface devices; and
a reader apparatus configured to read a barcode and/or a RFID tag,
wherein the one or more user interface devices is configured to request a user
input the patient weight, and on receiving the patient weight the computing
apparatus
generates the dispensing set and displays the storage location and dose
preparation
instructions for each of the candidate phage vials in the dispensing set on
the display
device and obtaining the phage vial identifier comprises reading the barcode
or the
RFID tag of a vial using the reader apparatus.
[0019] In one form, providing a storage location and dose preparation
instructions
further comprises printing and/or emailing the storage location and dose
preparation
instructions to the user.
[0020] In one form, the computing apparatus is a portable computing apparatus
and the
display device is a touch screen device which also acts as a user interface
device.
[0021] In one form, the computing apparatus displays an electronic certificate
of
analysis for each of the phage vials in the dispensing set.
[0022] In one form, the electronic phage inventory comprises a phage record
for each
of the plurality of vials stored in the phage storage apparatus, and each
phage record
stores a phage location, a phage titer, at least one contaminant level, a
phage vial ID
and an electronic certificate of analysis for the respective phage vial.
[0023] In one form, after updating the electronic phage inventory, a request
is sent to a
remote store to ship additional phage vials to the phage storage apparatus.
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[0024] According to a second aspect, there is provided a phage dispensing
apparatus
cornprising:
at least one memory, and
at least one processor wherein the memory comprises instructions to configure
the processor to:
receive a phage prescription for a patient, the phage prescription comprising
one
or more phage to be dispensed, and determine a target phage dose range for
each of
the one or more phages to be dispensed;
receive a patient weight and determining a maximum contaminant level for one
or more contaminants based on the patient weight;
generate a dispensing set comprised of one or more phage vials stored in a
phage storage apparatus by performing a dose calculation, comprising:
identifying, for each phage in the phage prescription, at least one
candidate phage vials in the phage storage apparatus that contain the
respective phage
and determining a dispensing volume for one or more candidate phage vials
based on a
titer of the respective candidate phage vial such that the total dispensing
volume from
combining the dispensing volume for the one or more candidate phage vials will
contain
an amount of phage within the target phage dose range for the respective phage
and an
amount of contaminant, for each contaminant in the one or more contaminants,
that is
below the maximum contaminant level for the respective contaminant;
provide a storage location and dose preparation instructions for each of the
one
or more candidate phage vials in the dispensing set to a user, wherein the
dose
preparation instructions comprises the dispensing volume for each of the phage
vials in
the dispensing set; and
receive a phage vial identifier (ID) obtained from a phage vial and checking
the
phage vial ID matches a stored phage vial ID of one of the phage vials in the
dispensing
set, and if the phage vial ID matches then updating an electronic phage
inventory to
record the dispensing of the phage vial otherwise issuing a warning to the
user.
[0025] In one form, the phage prescription comprises a target phage dose for
each of
the one or more phages to be dispensed and the target phage dose range for
each of
the one or more phages to be dispensed is determined from the respective
target phage
dose.
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[0026] In a further form, a set of predefined non-overlapping target phage
dose ranges
are stored, and determining the target phage dose comprises determining which
target
phage dose range in the set contains the target phage dose.
[0027] In one form, a plurality of dose range labels and associated dose
ranges are
stored, and the phage prescription includes the dose range label and
determining the
target phage dose range comprises looking up the dose range associated with
the dose
range label.
[0028] In one form, the target phage dose is an upper limit of target phage
dose range.
[0029] In one form, determining a dispensing volume for one or more candidate
phage
vials comprises determining a dispensing volume for a first candidate phage
vial using
the titer of the first candidate phage vial, and if the dispensing volume is
less than the
volume required to dispense the phage prescription for the respective phage,
then
searching for one or more additional candidate phage vials which are identical
phage
vials to the first candidate phage vial and if one or more identical phage
vials to the first
phage candidate phage vial are located, then adding one or more of the one or
more
identical phage vials to the candidate set and storing an associated
dispensing volume
for each of the one or more identical phage vials if the amount of
contaminant, for each
contaminant in the one or more contaminants, is below the maximum contaminant
level
for the respective contaminant, and if the dispensing set does not comprise
sufficient
candidate phage vials and associated dispensing volumes to enable dispensing
of the
phage prescription for the respective phage, then repeating until the
dispensing set
comprises sufficient candidate phage vials to dispense the phage prescription
for the
respective phage such that the amount of each contaminant is below the maximum
contaminant level for the respective contaminant.
[0030] In a further form, two vials are identical if their titer and
contaminant levels are
within a predefined range of each other, and/or two vials are identical if
they have the
same lot number.
[0031] In a further form, the method further comprises determining a target
phage dose
for each of the one or more phages to be dispensed and using an optimization
method
to search for a combination of candidate phage vials and associated dispensing
volumes which when combined generate a total dose closest to the target dose
subject
to the constraint that the amount of contaminant, for each contaminant in the
one or
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more contaminants, is below the maximum contaminant level for the respective
contaminant.
[0032] In a further form, the one or more contaminants comprising an endotoxin
level,
and the associated maximum contaminant level is weight (in kg) x 5 EU/kg.
[0033] In one form, the phage dispensing apparatus is operatively connected to
the
phage storage apparatus, the phage vial identifier (ID) is a barcode or a
radio frequency
identification (RFID) tag, and the phage dispensing apparatus further
comprises;
at least one display device;
one or more user interface devices; and
a reader apparatus configured to read a barcode and/or a RFID tag,
wherein the one or more user interface devices is configured to request a user
input the patient weight, and on receiving the patient weight the computing
apparatus
generates the dispensing set and displays the storage location and dose
preparation
instructions for each of the candidate phage vials in the dispensing set on
the display
device, and obtaining the phage vial identifier comprises reading the barcode
or RFID
tag of a vial using the reader apparatus.
[0034] In one form, providing a storage location and dose preparation
instructions
further comprises printing and/or emailing the storage location and dose
preparation
instructions to the user.
[0035] In one form, the phage dispensing apparatus is a portable computing
apparatus
and the display device is a touch screen device which also acts as a user
interface
device.
[0036] In one form, the phage dispensing apparatus displays an electronic
certificate of
analysis for each of the phage vials in the dispensing set.
[0037] In one form, the electronic phage inventory comprises a phage record
for each
of the plurality of vials stored in the phage storage apparatus, and each
phage record
stores a phage location, a phage titer, at least one contaminant level, a
phage vial ID
and an electronic certificate of analysis for the respective phage vial.
[0038] In one form, after updating the electronic phage inventory, a request
is sent to a
remote store to ship additional phage vials to the phage storage apparatus.
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[0039] According to a third aspect, there is provided a non-transitory,
computer
program product comprising computer executable instructions for dispensing a
phage
prescription, the instructions executable by a computer to:
receive a phage prescription for a patient, the phage prescription comprising
one
or more phage to be dispensed, and determine a target phage dose range for
each of
the one or more phages to be dispensed;
receive a patient weight and determining a maximum contaminant level for one
or more contaminants based on the patient weight;
generate a dispensing set comprised of one or more phage vials stored in a
phage storage apparatus by performing a dose calculation, comprising:
identifying, for each phage in the phage prescription, at least one
candidate phage vial in the phage storage apparatus that contain the
respective phage
and determining a dispensing volume for one or more candidate phage vials
based on a
titer of the respective candidate phage vial such that the total dispensing
volume from
combining the dispensing volume for the one or more candidate phage vials will
contain
an amount of phage within the target phage dose range for the respective phage
and an
amount of contaminant, for each contaminant in the one or more contaminants,
that is
below the maximum contaminant level for the respective contaminant;
providing a storage location and dose preparation instructions for each of the
one
or more candidate phage vials in the dispensing set to a user, wherein the
dose
preparation instructions comprises the dispensing volume for each of the phage
vials in
the dispensing set; and
receiving a phage vial identifier (ID) obtained from a phage vial and checking
the
phage vial ID matches a stored phage vial ID of one of the phage vials in the
dispensing
set, and if the phage vial ID matches then updating an electronic phage
inventory to
record the dispensing of the phage vial otherwise issuing a warning to the
user.
[0040] According to a fourth aspect, there is provided a phage dispensing
system
comprising:
a phage management apparatus comprising:
at least one memory, and
at least one processor wherein the memory comprises instructions to configure
the processor to implement an electronic phage inventory, wherein the
electronic phage
inventory comprise a phage record for each of a plurality of vials, and each
phage
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record stores a phage location, a phage titer, at least one contaminant level,
a phage
vial ID and an electronic certificate of analysis for the respective phage
vial; and
a plurality of phage dispensing apparatus which in use are located at a
plurality
of clinical sites, each phage dispensing apparatus comprising:
a phage storage apparatus that stores a plurality of phage vials; and
a phage dispensing apparatus comprising at least one memory, and at least one
processor wherein each phage dispensing apparatus is configured to:
receive a phage prescription for a patient, the phage prescription comprising
one
or more phage to be dispensed, and determine a target phage dose range for
each of
the one or more phages to be dispensed;
receive a patient weight and determine a maximum contaminant level for one or
more contaminants based on the patient weight;
generate a dispensing set comprised of one or more phage vials stored in a
phage storage apparatus by performing a dose calculation, comprising:
identifying, for each phage in the phage prescription, at least one
candidate phage vials in the phage storage apparatus that contain a phage and
determining a dispensing volume for one or more candidate phage vials based on
a titer
of the respective candidate phage vial such that the total dispensing volume
from
combining the dispensing volume for the one or more candidate phage vials will
contain
an amount of phage within the target phage dose range for the respective phage
and an
amount of contaminant, for each contaminant in the one or more contaminants,
that is
below the maximum contaminant level for the respective contaminant;
provide a storage location and dose preparation instructions for each of the
one
or more candidate phage vials in the dispensing set to a user, wherein the
dose
preparation instructions comprise the dispensing volume for each of the
respective
phage vials in the dispensing set; and
receive a phage vial identifier (ID) obtained from a phage vial and checking
the
phage vial ID matches a stored phage vial ID of one of the phage vials in the
dispensing
set, and if the phage vial ID matches then sending an update to the electronic
phage
inventory to record the dispensing of the phage vial otherwise issuing a
warning to the
user.
[0041] In one form, the phage management apparatus is further configured to
communicate with each of the plurality of phage dispensing apparatus to store
a record
of each dispensed phage prescription.
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[0042] In one form, the phage management apparatus is further configured to
monitoring the dispensed phage and generate manufacturing orders to a phage
manufacturer and/or movement requests between phage storage sites.
[0043] In one form, the phage management apparatus is further configured to
communicate with a phage testing laboratory to receive phage susceptibility
test results
for a patient sample, and sends a treatment recommendation to a treating
clinician
including a proposed phage prescription.
BRIEF DESCRIPTION OF DRAWINGS
[0044] Embodiments of the present disclosure will be discussed with reference
to the
accompanying drawings wherein:
[0045] Figure 1A is a schematic diagram of an embodiment of a phage dispensing
system;
[0046] Figure 1B is a flow chart of a method for dispensing a phage
prescription
according to an embodiment;
[0047] Figure 2A is a flowchart of a dispensing method 200 according to an
embodiment;
[0048] Figure 2B is a flowchart of a dose calculation according to another
embodiment;
[0049] Figure 3 is a schematic diagram of a computing apparatus according to
an
embodiment; and
[0050] Figure 4 is a representation of a certificate of analysis of a phage
vial according
to an embodiment.
[0051] In the following description, like reference characters designate like
or
corresponding parts throughout the figures.
DESCRIPTION OF EMBODIMENTS
[0052] As used in the specification and claims, the singular form "a", "an"
and "the"
include plural references unless the context clearly dictates otherwise. For
example, the
term "a cell" includes a plurality of cells, including mixtures thereof. The
term "a nucleic
acid molecule" includes a plurality of nucleic acid molecules. "A phage
formulation" can
mean at least one phage formulation, as well as a plurality of phage
formulations, i.e.,
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more than one phage formulation. As understood by one of skill in the art, the
term
"phage" can be used to refer to a single phage or more than one phage.
[0053] The present invention can "comprise" (open ended) or "consist
essentially of"
the components of the present invention as well as other ingredients or
elements
described herein. As used herein, "comprising" means the elements recited, or
their
equivalent in structure or function, plus any other element or elements which
are not
recited. The terms "having" and "including" are also to be construed as open
ended
unless the context suggests otherwise. As used herein, "consisting essentially
of"
means that the invention may include ingredients in addition to those recited
in the
claim, but only if the additional ingredients do not materially alter the
basic and novel
characteristics of the claimed invention.
[0054] As used herein, a "subject" is a vertebrate, preferably a mammal, more
preferably a human. Mammals include, but are not limited to, murines, simians,
humans, farm animals, sport animals, and pets. In other preferred embodiments,
the
"subject" is a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine
(e.g., a
mouse), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), a
primate,
simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), or an ape
(e.g.,
gorilla, chimpanzee, orangutan, gibbon). In other embodiments, non-human
mammals,
especially mammals that are conventionally used as models for demonstrating
therapeutic efficacy in humans (e.g., murine, primate, porcine, canine, or
rabbit animals)
may be employed. Preferably, a "subject" encompasses any organisms, e.g., any
animal or human, that may be suffering from a bacterial infection,
particularly an
infection caused by a multiple drug resistant bacterium.
[0055] As understood herein, a "subject in need thereof" includes any human or
animal
suffering from a bacterial infection, including but not limited to a multiple
drug resistant
bacterial infection, a microbial infection or a polymicrobial infection.
Indeed, while it is
contemplated herein that the methods may be used to target a specific
pathogenic
species, the method can also be used against essentially all human and/or
animal
bacterial pathogens, including but not limited to multiple drug resistant
bacterial
pathogens. Thus, in a particular embodiment, by employing the methods of the
present
invention, one of skill in the art can design and create personalized phage
formulations
against many different clinically relevant bacterial pathogens, including
multiple drug
resistant (MDR) bacterial pathogens.
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[0056] As understood herein, an "effective amount" of a pharmaceutical
composition
refers to an amount of the composition suitable to elicit a therapeutically
beneficial
response in the subject, e.g., eradicating a bacterial pathogen in the
subject. Such
response may include e.g., preventing, ameliorating, treating, inhibiting,
and/or reducing
one of more pathological conditions associated with a bacterial infection.
[0057] The term "dose" or "dosage" as used herein refers to physically
discrete units
suitable for administration to a subject, each dosage containing a
predetermined
quantity of the active pharmaceutical ingredient calculated to produce a
desired
response.
[0058] The term "about" or "approximately" means within an acceptable range
for the
particular value as determined by one of ordinary skill in the art, which will
depend in
part on how the value is measured or determined, e.g., the limitations of the
measurement system. For example, "about" can mean a range of up to 20%,
preferably
up to 10%, more preferably up to 5%, and more preferably still up to 1% of a
given
value. Alternatively, particularly with respect to biological systems or
processes, the
term can mean within an order of magnitude, preferably within 5 fold, and more
preferably within 2 fold, of a value. Unless otherwise stated, the term
"about" means
within an acceptable error range for the particular value, such as 1-20%,
preferably
1-10% and more preferably 1-5%. In even further embodiments, "about" should
be
understood to mean+/-5%.
[0059] Where a range of values is provided, it is understood that each
intervening
value, between the upper and lower limit of that range and any other stated or
intervening value in that stated range is encompassed within the invention.
The upper
and lower limits of these smaller ranges may independently be included in the
smaller
ranges, and are also encompassed within the invention, subject to any
specifically
excluded limit in the stated range. Where the stated range includes one or
both of the
limits, ranges excluding either or both of those included limits are also
included in the
invention.
[0060] All ranges recited herein include the endpoints, including those that
recite a
range "between" two values. Terms such as "about," "generally,"
"substantially,"
"approximately" and the like are to be construed as modifying a term or value
such that
it is not an absolute, but does not read on the prior art. Such terms will be
defined by the
circumstances and the terms that they modify as those terms are understood by
those
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of skill in the art. This includes, at very least, the degree of expected
experimental error,
technique error and instrument error for a given technique used to measure a
value.
[0061] Where used herein, the term "and/or" when used in a list of two or more
items
means that any one of the listed characteristics can be present, or any
combination of
two or more of the listed characteristics can be present. For example, if a
composition is
described as containing characteristics A, B, and/or C, the composition can
contain A
feature alone; B alone; C alone; A and B in combination; A and C in
combination; B and
C in combination; or A, B, and C in combination.
[0062] The term "phage sensitive" or "sensitivity profile" means a bacterial
strain that is
sensitive to infection and/or killing by phage and/or in growth inhibition.
That is phage is
efficacious or effective in inhibiting growth of the bacterial strain.
[0063] The term "phage insensitive" or "phage resistant" or "phage resistance"
or
"resistant profile" is understood to mean a bacterial strain that is
insensitive, and
preferably highly insensitive to infection and/or killing by phage and/or
growth inhibition.
That is phage is not efficacious or is ineffective in inhibiting growth of the
bacterial
strain.
[0064] The term "intermediate phage sensitive" is understood to mean a
bacterial strain
that exhibits a sensitivity to infection by phage that is in between the
sensitivity of phage
sensitive and phage insensitive strains.
[0065] As used herein, "predictive patterns" are genomic patterns identified
in the
plurality of bacterial strains and/or in the plurality of phage strains that
are associated
correlate with a "sensitivity profile", "resistant profile", or "intermediate
sensitivity profile"
of a bacterium.
[0066] As used herein, a "phage-host specificity profile" is used
interchangeably with a
"phage-host sensitivity profile" and a "phage susceptibility test" for a
bacterial isolate,
and comprises data relating to a bacterium's sensitivity or resistance to a
plurality of
different phage. The phage-host specificity profile or phage susceptibility of
a bacterial
isolate can be experimentally derived, computationally predicted, or some
combination.
[0067] A "phage treatment", "therapeutic phage formulation", "therapeutically
effective
phage formulation", "phage formulation" or like terms as used herein are
understood to
refer to a composition comprising one or more phage which can provide a
clinically
beneficial treatment for a bacterial infection when administered to a subject
in need
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thereof. A "therapeutic phage cocktail", "therapeutically effective phage
cocktail",
"phage cocktail" or like terms as used herein are understood to refer to a
composition
comprising a plurality of phage which can provide a clinically beneficial
treatment for a
bacterial infection when administered to a subject in need thereof Preferably,
therapeutically effective phage cocktails are capable of infecting the
infective parent
bacterial strain as well as the emerging resistant bacterial strains that may
grow out
after elimination of the parent bacterial strain.
[0068] As used herein, the term "composition" encompasses "phage based
treatments", "phage formulations" and the like which include, but are not
limited to,
pharmaceutical compositions comprising one or more purified phage.
"Pharmaceutical
compositions" are familiar to one of skill in the art and typically comprise
active
pharmaceutical ingredients formulated in combination with inactive ingredients
selected
from a variety of conventional pharmaceutically acceptable excipients,
carriers, buffers,
and/or diluents. The term "pharmaceutically acceptable" is used to refer to a
non-toxic
material that is compatible with a biological system such as a cell, cell
culture, tissue, or
organism (or at least non-toxic in amounts typically used). Examples of
pharmaceutically acceptable excipients, carriers, buffers, and/or diluents are
familiar to
one of skill in the art and can be found, e.g., in Remington's Pharmaceutical
Sciences
(latest edition), Mack Publishing Company, Easton, Pa. For example,
pharmaceutically
acceptable excipients include, but are not limited to, wetting or emulsifying
agents, pH
buffering substances, binders, stabilizers, preservatives, bulking agents,
adsorbents,
disinfectants, detergents, sugar alcohols, gelling or viscosity enhancing
additives,
flavoring agents, and colors. Pharmaceutically acceptable carriers include
macromolecules such as proteins, polysaccharides, polylactic acids,
polyglycolic acids,
polymeric amino acids, amino acid copolymers, trehalose, lipid aggregates
(such as oil
droplets or liposomes), and inactive virus particles. Pharmaceutically
acceptable
diluents include, but are not limited to, water, saline, and glycerol.
[0069] As used herein, the term "purified" refers to a preparation that is
substantially
free of unwanted substances in the composition, including, but not limited to
biological
materials e.g., toxins, such as for example, endotoxins, nucleic acids,
proteins,
carbohydrates, lipids, or subcellular organelles, and/or other impurities,
e.g., metals or
other trace elements, that might interfere with the effectiveness of the
cocktail. As used
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herein, terms like "high titer and high purity", and "very high titer and very
high purity"
refers to degrees of purity and titer that are familiar to one of skill in the
art.
[0070] As used herein, the term "vial" encompasses a range of containers which
can
be used to contain or store an individual phage in solution or a phage
cocktail and
include lids. Vials may be single dose or multi dose containers. Single dose
containers
may be sealed including ampules and other hermetically sealed vials. Multi
dose
containers may store phage at a specific concentration or comprise a
partitioned
interior. Vials may be made of suitable glasses, plastics, composites or
metal, that can
store the phage in a viable state for an extended period of time, including at
low
temperatures such as -80 C.
[0071] Bacteria to be treated using the phage based treatment and compositions
described herein include any bacterial pathogen that poses a health threat to
a subject.
These bacterial include, but are not limited to the "ESKAPE" pathogens
(Enterococcus
faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii,
Pseudomonas aeruginosa, and Enterobacter sp), which are often nosocomial in
nature
and can cause severe local and systemic infections. Among the ESKAPE
pathogens, A.
baumannii is a Gram-negative, capsulated, opportunistic pathogen that is
easily spread
in hospital intensive care units. Many A. baumannii clinical isolates are also
MDR, which
severely restricts the available treatment options, with untreatable
infections in traumatic
wounds often resulting in prolonged healing times, the need for extensive
surgical
debridement, and in some cases the further or complete amputation of limbs.
Further
preferred bacteria strains include G. me/lone/Ia.
[0072] One of skill in the art will appreciate that bacteria subject to the
method
described herein include, but are not limited to, multidrug resistant
bacterial strains. As
understood herein, the terms, "multidrug resistant", "multiple drug
resistant', "multiple
drug resistance" (MDR) and like terms may be used interchangeably herein, and
are
familiar to one of skill in the art, i.e., a multiple drug resistant bacterium
is an organism
that demonstrates resistance to multiple antibacterial drugs, e.g.,
antibiotics.
[0073] In preferred embodiments, examples of MDR bacteria are methicillin
resistant S.
aureus (MRSA) and vancomycin-resistant Enterococci (VRE).
[0074] As understood herein, the term "diverse sources" includes a wide
variety of
different places where phage may be found in the environment including, but
not limited
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to, any place where bacteria are likely to thrive. In fact, phage are
universally abundant
in the environment, making the isolation of new phage very straightforward.
The primary
factors affecting the successful isolation of such phage are the availability
of a robust
collection of clinically relevant bacterial pathogens to serve as hosts, and
access to
diverse environmental sampling sites.
[0075] As used herein, the term "determining" encompasses a wide variety of
actions.
For example, "determining" may include calculating, computing, processing,
estimating,
deriving, investigating, looking up (e.g., looking up in a table, a database
or another
data structure), ascertaining and the like. Also, "determining" may include
receiving
(e.g., receiving information), accessing (e.g., accessing data in a memory)
and the like.
Also, "determining" may include resolving, selecting, choosing, establishing
and the like.
[0076] Embodiments of computer implemented methods for dispensing a phage
prescription and associated phage dispensing systems will now be described
with
reference to Figures 1A and 1B. Figure 1A is a schematic diagram of an
embodiment of
a phage dispensing system 1 and Figure 1B is a flow chart of a method 100 for
dispensing a phage prescription according to an embodiment.
[0077] As shown in Figure 1A a phage dispensing apparatus 20 is located at a
clinical
site 10. There may be multiple clinical sites (10') and each clinical site may
have one or
more phage dispensing apparatus 20. The system further includes one or more
testing
laboratories 40 that perform phage susceptibility tests, one or more a
manufacturing
sites 50, a phage management apparatus 60, and one or more phage storage sites
70.
A testing laboratory 40, the phage management system 60, and a storage site
may all
be hosted at a phage manufacturing site 50.
[0078] The phage dispensing apparatus 20 comprises a computing apparatus 21,
such
as a desktop computer or mobile computing device (e.g., tablet, laptop) and a
phage
storage apparatus 27 such as a low temperature (-80C) refrigerator used to
store phage
vials to be used in preparing phage prescriptions to produce phage based
treatments
for dispensing to patients 12. The computing apparatus 21 comprises at least
one
memory, at least one processor 24 and one or more user interface devices, and
is
configured to execute a phage dispensing application (i.e., software) 22 which
provides
a user interface to guide dispensing of a phage prescription by a pharmacist.
The one or
more user interface devices may include one or more display devices, such as a
LCD
screen or a touchscreen, and a reader apparatus 26 configured to read a phage
vial
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identifier (ID) in the form of a barcode and/or an RFID tag located on or
adhered to the
vial (e.g. in the form of a label with an adhesive backing). The reader
apparatus 26 may
be a barcode scanner with an optical source and optical receiver, or camera
used to
capture an image containing the barcode which is then processed (scanned) to
extract
or recognize the barcode in the image. Alternatively or additionally the
reader apparatus
may be configured to read a RFID tag on the vial. The reader apparatus may
comprise
an antenna which transmits an interrogator signal and a receiver which
receives a reply
signal (a message) encoding the phage vial identifier from an RFID tag. The
reader
apparatus is configured to process the received signal to extract (e.g.
decode) the
phage vial identifier from the reply signal. The RFID tag may store additional
information, such as lot number, date of manufacture, etc., which may also be
encoded
in the reply signal, and which is also extracted from the replay signal. The
one or more
user interface devices may be integral or incorporated in the computer
apparatus 21
such as a touchscreen, camera and microphone, or they may be peripheral
input/output
devices such as a printer 25 and reader apparatus (e.g. barcode scanner or
RFID
reader) 26 which are operatively connected to the computing apparatus 21 over
a wired
or wireless connection. The phage dispensing software 22 may also communicate
with
a dispensing application 32 executing on a computing device 30 such as a
smartphone,
tablet computer or desktop computer of a clinician or pharmacist. For example,
a
clinician may prepare a phage prescription using the dispensing application 32
which is
sent to the phage dispensing software 22 for dispensing by a pharmacist. The
phage
dispensing software 22 may also communicate with a phage management
application
62 as part of a remotely located phage management system 60. In one embodiment
the
phage management system 62 is further configured to interface or communicate
with a
Laboratory Information Management System (LIMS) associated with the treatment
site
(e.g. the hospital) and/or an electronic health record (EHR) system to record
the
dispensing of the prescription to the patient (in their EHR record).
Communication with
LIMS or EHR systems may be used to lookup data stored in such systems or to
record
dispensing actions such as to update a patient record.
[0079] The phage storage apparatus 27 is divided into a plurality of storage
locations
28. These may be arranged as a regular array of boxes to allow each box to be
assigned a two dimensional coordinate such as (row, column), e.g. Figure 1A
shows 32
bays arranged as Rows A to H and columns 1 to 4. Each box may be further
divided
into a series of bays within the box to give a third dimension to the location
(coordinate).
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In one embodiment each bay stores an individual phage vial thus allowing each
phage
vial to be assigned a unique location within the phage storage apparatus
according to a
three dimensional coordinate e.g. (Row, Column, Bay). In other embodiments
multiple
phage vials may be placed within the same box or bay, in which case the
location may
be shared with other phage vials.
[0080] The phage manufacturing site 50 performs manufacture (production) of
phage
using manufacturing equipment 53 such as bioreactors used to grow phage in
batches.
Purified phage is extracted and combined with associated pharmaceutical
ingredients
such as excipients, carriers, buffers, and/or diluents and sealed into phage
vials. Phage
vials may contain a single phage, or multiple phage. Each phage vial is thus a
phage
formulation or composition comprising one or more purified phage. The phage
manufacturing site may additionally include quality control (or quality
assurance)
laboratories 54, phage hunting/identification facilities 54 and genomics
laboratories, for
example which identify genomic patterns in bacteria or phage which may be used
to
determine sensitivity or resistance profiles, or these functions may be
outsourced to
other sites. The site may also include a process control and management system
52
with an associated memory 51 such as a database, which is used to control,
monitor,
and log the production and quality control activities performed at the phage
manufacturing site.
[0081] The phage management system 60 comprises one or more computing
apparatus including one or more memories 61 and one or more processors 64 and
is
configured to execute the phage management application 62. The phage
management
system may be located at a manufacturing site 50, at a clinical site 10,
including as part
of phage dispensing apparatus, or at a separate location such as a data center
or
hosted in a cloud computing environment. The phage management application may
include one or more databases and is used to store and maintain a record of
the phage
manufactured, stored and dispensed in the system 1. The phage management
application 62 may include an electronic phage inventory which stores a phage
record
for each vial that including tracking data, manufacturing data, pharmaceutical
data and
QC/QA data. This may include the current storage location of the phage vial,
manufacturing lot number, date of manufacture, and test results such as phage
titer, pH,
and levels of contaminants such as an endotoxin level. The metadata for a
phage vial
may include an electronic certificate of analysis generated by the quality
control
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laboratory 54 or a link to a remotely stored electronic certificate of
analysis. The phage
management application 62 may communicate with the process control and
management system 52 at each manufacturing site for example to obtain
manufacturing
data and quality control data on phage manufactured by the site. The phage
management application 62 may maintain a count of the number of vials
available for
each phage strain, their locations, the age of vials (and expiry dates), and
relevant
pharmaceutical properties, such as contained in a certificate of analysis.
[0082] After manufacture, phage is distributed (shipped) to phage storage
apparatus 27
at clinical sites 10 and or other storage sites 70 such as pharmacies,
regional hospitals
and/or warehouses. Each storage site 70 may execute a local phage management
application 72 which maintains a record of locally stored phage and which may
communicate with the phage management application 62 (and the electronic phage
inventory). The phage management application 62 may be used to monitor phage
stocks at each storage site (including expiry date of stored phage), and send
manufacturing orders for specific phage batches to a manufacturing site and/or
movement requests (shipping orders) to resupply a phage storage site, and/or
move
(redistribute) phage stocks between different storage locations. The phage
management application 72 may also perform data analytics and provide input
for
phage hunting, including orders to send samples from the phage testing
laboratory to
the manufacturing site to assist in phage hunting.
[0083] The testing laboratory 40 is used to perform phage susceptibility tests
44 on
samples obtained from patients to identify one or more phage likely to be
efficacious
against the patient's infection (or more specifically bacteria associated with
the patient's
infection). The testing laboratory may be located at a clinic 10, an
independent site, or
as part of the manufacturing facility 50. A range of phage susceptibility
tests may be
performed which measure bactericidal activity of phage against the bacteria in
the
patient sample, or a bacterial isolate obtained from the patient sample. These
include
phage that can generate clear point plaques on the bacterial sample, phage
that
demonstrate lytic characteristics using a rapid streak method on a plate,
bacterial lysis
of through assessment of absorbance difference in turbidity with small or
large batch
assays, or delay in bacterial growth. Typically, the testing will be performed
in parallel,
testing many (e.g., hundreds or thousands) of phage against the bacterial
isolate to
identify which phage strains are likely to be efficacious against the
patient's infection. In
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one embodiment the phage susceptibility test is a plaque assay and/or a host-
phage
response assay (using the bacterial isolate as the host) including a
colorimetric assay
that measures bacterial respiration as a proxy for bacterial growth performed
using an
automated OmniLog TM system. A laboratory management application 42 records
details
of the patient sample and the phage susceptibility tests and generates
associated
reports containing the test results and recommendations. These reports may
also take
into account geographic information such as the presence of similar infections
at the
patient site, which may indicate a common bacterial strain infecting patient's
at the site,
as well as genomic and bioinformatics analysis of the bacterial isolate to
identify
possible efficacious phage.
[0084] Turning now to Figure 1B, there is shown a flow chart of a method 100
for
dispensing a phage prescription according to an embodiment.
[0085] As a precursor to the dispensing a phage prescription is first
generated by a
treating clinician. For example, a treating clinician may identify that a
patient 12 may
benefit from a phage based treatment and proceed to collect a patient sample
which is
sent to a phage susceptibility laboratory for testing 102. In one embodiment
the clinician
may access a user interface of the dispensing application 32 to request a
phage
susceptibility test 44 of a patient sample by the phage laboratory 40. The
user interface
is configured to collect a patient identifier as well as any other relevant
information
regarding the patient and their condition, as well as logistical details such
as patient
sample location or where they are to be treated. The user interface may also
be
configured to interact with other computing systems such as patient records
systems or
other clinical system to assist in collection of any required information. The
information
may also be sent to the phage management application 62 to log patient sample
details
104. The patient sample details logged by the phage management application may
include date of the date of the sample collection, bacterial identifier (ID),
a geographic
location of the patient (or clinic), clinical indications, Antimicrobial or
Antibiotic
Susceptibility Testing (AST) data, patient data and historical outcomes of
other patients.
[0086] In one embodiment the phage management application determines the most
suitable phage susceptibility laboratory 40 to send the sample to, and
coordinates
transportation of the patient sample to the phage susceptibility laboratory 40
and
subsequent phage susceptibility testing. Once the patient sample arrives at
the phage
susceptibility laboratory 40, a phage susceptibility test is performed on the
patient
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sample 106. The results are provided to the phage management application 62
and
used to identify a potential phage treatment such as one or more phage types
(or
strains) and respective doses 108. The patient record may be updated with the
phage
susceptibility test results. Once a potential phage treatment is identified a
report is sent
to the clinician including a treatment recommendation that includes a proposed
phage
prescription (or treatment) 110. This may include the suggested phage type (or
strain)
and target dose level (for each phage type. The target dose level (PFU) may be
used to
determine a dispensing volume (mL) from a vial using the titer (PFU/mL) of the
vial such
as by dividing the titer by the target dose level. The target dose level may
be a specific
value, a target dose range, or both a target dose level and an allowable
target dose
range, i.e. the dose should be as close as possible to the target dose level,
but any
dose within the target dose range is regarded as acceptable. The clinician may
then
approve the phage prescription and provide to the pharmacist or dispensing
apparatus
for subsequent dispensing.
[0087] Phage susceptibility tests typically take many hours (10-24 or more).
Thus, in
one embodiment the phage management application 62 may make an initial therapy
available to enable treatment to begin immediately upon receipt of patient
sample
details 104. This may be based on details such as patient location, symptoms
and
historical data such as similar infections at the same site which were
successfully
treated using a phage composition. For example, a cluster of similar cases at
the patient
site may suggest the patient has contracted the same infection as previous
patients,
and thus a previously successful phage treatment may be recommended to the
clinician
as an early intervention (from which the clinician can prepare a phage
prescription).
[0088] The phage dispensing application 22 (executing on a computing apparatus
operatively connected to a phage dispensing apparatus 20) then receives a
phage
prescription for the patient 12. The phage prescription may comprise one or
more phage
to be dispensed, and one or both of a target phage dose or target phage dose
range, for
each of the one or more phages to be dispensed (i.e., the regiment
description), along
with other metadata such as patient name or identifier, treating clinician,
time and date,
location, etc. This may be electronically sent to the phage dispensing
application 22 by
the dispensing application 32 used by the clinician, or, upon electronic
approval of the
proposed phage prescription by the clinician 110 (for example via a dispensing
application 32), the system may send the approved phage prescription to the
phage
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23
dispensing application 22. Alternatively, a physical or electronic
prescription may be
provided to a pharmacist who manually enters details of the phage prescription
into the
phage dispensing application 22.
[0089] The target phage dose range comprises a lower range limit and an upper
range
limit. The lower range limit and upper range limits will typically be
inclusive or one will be
inclusive and the other exclusive. For example the lower limit may be
inclusive and the
upper limit may be exclusive so that the range extends up to, but not
including the upper
range limit (e.g. lower limit range < upper limit) or vice versa. In one
embodiment both
lower range limit and upper range limits are exclusive limits.
[0090] In one embodiment the phage prescription defines a target dose range
(e.g. 1e9
- 3e9 PFU) or a label for a predefined target dose range (e.g. low = 1e9-3e9
PFU; high
=1 e10 - 3e10 PFU). The label and the associated target dose range may be
stored by
the phage dispensing apparatus or another storage device accessible by the
phage
dispensing application. In this case determining the target phage dose range
comprises
mapping the label to the predefined range (e.g. looking up the target dose
range using
the label as the search key). If a target phage dose is not specified, a
target phage dose
(within the range) may be defined according to a predefined rule, such as the
upper limit
of the provided dose range, the midpoint of the provided dose range or the
lower limit of
the provided dose range.
[0091] In one embodiment the phage prescription includes a target phage dose
for a
phage, which is then used to determine the target phage dose range. For
example the
target phage dose may be a specific number (e.g. 2e9 PFU) and the dose range
may
be determined based on a predetermined amount (e.g. 1e9 PFU) or percentage
(e.g.
5%). The amounts or percentages may be based on a log scale. Additionally the
target
dose value need not be the mid-point of the range. That is a lower interval,
defined as
the (absolute) difference between a lower range limit to the target dose
value, may be
different from an upper interval defined as the (absolute) difference between
the target
dose value and upper range limit (i.e. uneven intervals). In some embodiments
the
phage dispensing apparatus may store a predefined set of non-overlapping
target
phage dose ranges (i.e. multiple ranges), and determining the target dose
range may
include determining which one of the multiple dose ranges the target dose
range falls
within. The set of non-overlapping target phage dose ranges may be contiguous
ranges
where an upper limit of a first range is exclusionary (i.e. the range is up to
the upper
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range limit) and the lower range limit of the next range is the same value as
the upper
range limit of the previous range, but is inclusive of the lower range limit
(or vice versa
where a lower range limit is exclusionary and the previous upper range limit
is
inclusive). In one embodiment if the target dose range does not fall within
any of the
multiple dose ranges a warning may be issued requesting a manual dose range to
be
entered. Alternatively a nearest dose range may be determined, such as a
closest dose
range with an upper range limit below the target dose range, or the closest
dose range
within a predefined percentage (e.g. 5%). In one embodiment the user interface
may
present the target phage dose range to the clinician (or pharmacist) or
request the
clinician (or pharmacist) to confirm the target phage dose range. In one
embodiment the
user interface may allow the clinician to enter the target dose range (and log
the entry).
[0092] The phage dispensing application 22 is also configured to receive the
patient's
weight 114. In one embodiment the user interface of the phage dispensing
application
22 prompts the pharmacist for the patient's weight. In one embodiment further
processing of the dispensing is paused until the patient's weight is received.
Sanity
checks may also be performed to ensure the weight is within a typical range to
prevent
data errors (and the pharmacist may be prompted to recheck the weight in cases
of
large variation from a previous weight or typical range). In another
embodiment, a
patient weight may be provided by the clinician as part of metadata associated
with the
prescription, or obtained from a recent measurement such as a measurement
stored in
an electronic health record for the patient, and the clinician is asked to
verify (or
confirm) the use of the weight measurement. Metadata regarding the
measurement,
such as the person who made the measurement, the location where the
measurement
was made, and the time of the measurement may also be provided. The valid
period for
the recent measurement may be within the previous 12, 24, 36, 48, 72 hours or
even
168 hours. If the pharmacist does not consider the measurement is sufficiently
recent,
they can re-measure and reenter a new measurement. The phage dispensing
application 22 uses the patient's weight to determine a maximum contaminant
level for
one or more contaminants that may be present in the vials. In one embodiment
the one
or more contaminants includes an endotoxin (EU) level and the maximum
endotoxin
level (Max EU) is calculated as weight (kg) *5 EU/kg.
[0093] The phage dispensing application 22 then proceeds to generate a
dispensing
set comprised of one or more phage vials stored in the phage storage apparatus
27 by
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performing a dose calculation 116. The dose calculation determines an
associated
dispensing volume for each phage vial in the dispensing set such that the
total
dispensing volume contains an amount of phage within the target phage dose
range for
the respective phage. This comprises identifying, for each phage in the phage
prescription, at least one (and typically a plurality of) candidate phage
vials in the phage
storage apparatus that contain the respective phage.
[0094] We then determine a dispensing volume for one or more candidate phage
vials
based on a titer of the respective candidate phage vial such that the total
dispensing
volume from combining the one or more candidate phage vials will contain an
amount of
phage within the target phage dose range for the respective phage and an
amount of
contaminant, for each contaminant in the one or more contaminants, that is
below the
maximum contaminant level for the respective contaminant. The dispensing
volume is
based on the titer of the vial, which is expressed in PFU/mL. The target phage
dose (or
dose range) is given in units of PFU and thus a dispensing volume (e.g. the
amount to
draw into a syringe from the vial) is calculated from the titer by dividing
the target dose
by the titer (noting the titer is expressed in units of PFU/mL).
[0095] This may involve determining whether a single candidate phage vial has
a titer
such that a dispensing volume can be dispensed which will contains an amount
of
phage within the target dose range. In some embodiments if the titer is much
larger than
is required (e.g. such that the dispensing volume would be very small), then
this may
require diluting the phage. However if a single phage vial contains
insufficient phage
(titer too low) then a combination of candidate phage vials can be selected
and
combined such that the amount of phage in the total dispensing volume is
within the
target dose range. This determination is performed subject to the constraint
that the
amount of each of the one or more contaminants in the total dispensed volume
is below
the maximum contaminant level for the respective contaminant. In some
embodiments
this may be performed by performing a search to identify the set of one or
more
candidate phage vials which contain an amount of phage closest to the target
phage
dose.
[0096] After generation of the dispensing set and the associated dose
calculation to
determine the dispensing volumes, the user interface provides the storage
location
(e.g., box C2, bay 10) and dose preparation instructions 118 for each of the
candidate
phage vials in the dispensing set to the user. The dose preparation
instructions
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comprise the dispensing volume (based on the titer) for each phage vial in the
dispensing set along with any relevant instructions or direction on how to
generate a
dispensing dose for delivery to the patient. For example it may specify the
dose is to be
delivered by intravenous IV and provide instructions such as obtaining a 25mL
0.9%
saline minibag and then using a syringe, extract the dispensing dose from each
vial and
inject into a port in the saline bag or IV line to deliver to the dose to the
patient. The
prescription may also specify if any other pharmaceutical preparations are to
be added.
[0097] The pharmacist may then remove a vial from the phage storage apparatus
(e.g.
a freezer, a refrigerator, or a cooler) 27. To ensure accurate dispensing the
system then
requires the pharmacist to input the phage vial identifier (ID), such as by
reading (e.g.
scanning) a barcode (1D or 2D) or reading a RFID tag located on the vial, or
entering a
serial number located on the phage vial 120 in order to ensure the correct
vial is
removed. The phage vial ID may be a serial number printed in a machine
readable
format, such as a barcode, on the vial or directly onto the vial which encodes
the serial
number. The phage vial ID may be stored in a machine readable format by an
RFID tag
which is attached or adhered to the vial, such as in the form of a label with
an adhesive
backing. The serial number may also be printed on the label or directly on the
vial along
with the barcode representing the phage vial identifier (e.g., serial number)
in machine
readable form, or just the barcode may be printed onto the label or vial. The
barcode
may be a 1D or linear barcode, of a 2D barcode such as a Quick Response (QR)
code,
PDF417 a Data Matrix, Aztec, Codablock-F, MaxiCode, MicroPDF417, Han Xin, Dot
Codes, and variants such as SnapCodes, and High Capacity Color Barcodes. The
barcode may encode a phage vial identifier such as a serial number, along with
additional information such as a Uniform Resource Locator (URL) or Uniform
Resource
Identifier (URI) link to a webpage or document with details of the vial
contents such as
batch, titer, contaminants, or a certificate of analysis. In one embodiment
the RFID tag
is a passive tag comprising a microchip or integrated circuit, an antenna and
a substrate
with an adhesive backing allowing it to be used as a label which is stuck on
the vial. The
RFID tag may operate in the UHF range (e.g. 865MHz to 928MHz) and operate
according to the ISO/IEC 18000 standard. The microchip or integrated circuit
may store
the phage vial ID and transmit the phage vial ID as part of a reply message
when the
RFID tag is read (i.e. receives an interrogator signal). In some embodiments
the phage
vial identifier is a factory assigned tag ID (e.g. assigned by the RFID tag
manufacturer),
and when the label is attached to the vial the tag ID is associated (e.g. is
used as a
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lookup key) with a phage record of a database. In this embodiment the reader
apparatus reads the tag ID and then uses the tag ID to lookup the phage
record. In one
embodiment, the phage vial ID is a separate serial number to the tag ID which
is stored
in the phage record, and the factory assigned tag ID is used to obtain the
phage vial ID
(e.g. by looking up the phage vial ID in the phage record. In some embodiments
the
RFID tag stores additional information regarding the vial such as lot number,
date of
manufacture, etc. which is included in the reply message. In some embodiments
active
RFID tags may be used. In some embodiments the RFID tag and adhesive are
formed
of materials suitable for low temperature storage. The phage dispensing
application 22
thus receives a phage vial identifier (ID) obtained (e.g. read, scanned,
manually input,
or otherwise input or obtained) from the removed phage vial, for example via
reader
apparatus 26 .In one embodiment the reader apparatus is a barcode scanner
comprising a light source and light sensor, or a camera of the computing
apparatus 21
and associated software configured to extract (read, scan or recognize) the
barcode
from a captured image. In another embodiment the reader apparatus 26 is an
RFID
reader, which transmits interrogatory signals and receives a reply signal (or
message)
from an RFID tag on the vial (or adhered to the vial) which includes the phage
vial ID or
includes data from which the phage vial ID may be obtained, such as by looking
up in a
database record. In the case the barcode is damaged, or the reader apparatus
26 fails
to read the barcode, the user interface may be configured to receive the phage
vial
identifier by another user interface device, such as by the user manually
typing the
serial number using a keyboard or touchscreen, or speaking the serial number
into a
microphone which captures the audio and converts the audio to a serial number.
The
read/scanned phage vial ID is then checked (compared) to ensure that it
matches a
stored phage vial ID of one of the phage vials in the dispensing set. If the
phage vial ID
matches (i.e., the correct vial has been removed) then the electronic phage
inventory is
updated 122 to record the dispensing of the phage vial. Confirmation of
removal of a
phage vial may further trigger a request for new stock (resupply) 124 by the
electronic
phage inventory. However, if there is no match then a warning is used to the
user, for
example to double check the correct vial has been removed. Once all phage
vials have
been read/scanned and approved, the pharmacist can use the phage vials and
instructions to prepare the phage treatment, which is then dispensed to the
clinician 126
for treating the patient. The electronic phage inventory may be locally
maintained by the
phage dispensing application 22, or the phage dispensing application 22 may
send the
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confirmation of phage dispensing to the phage management application 62
executing
on a remote server (including a cloud server) or to a database associated with
the
phage management application 62, which maintains the local inventory.
[0098] Figure 2A is a flowchart of a dispensing method 200 according to an
embodiment. As noted above the patient weight 202 is used to determine the
maximum
contaminant level 204 and the phage prescription 219 is used to determine a
target
dose range 220 for a phage. Generation of the dispensing set comprises
identifying
vials containing the target phage 203, selecting a first candidate phage vial
205 and
determining a dispensing volume 207 based on the titer 208 of the first
candidate phage
vial. A test 214 may also be performed to check that the contaminant level 206
of the
vial is less than the maximum contaminant level 204. If not then we calculate
if the vial
can be diluted to reduce the contaminant level below the maximum 215, and if
so add
the vial to the dispensing set and recalculate the dispensing volume 207,
otherwise we
can discard and select another candidate phage vial 205. If the dispensing
volume is
less than the volume required to dispense the phage prescription for the
respective
phage 221, then we perform a search for one or more additional candidate phage
vials
which are identical phage vials to the first candidate phage vial 223. An
identical phage
vial is a vial with the same titer and contaminant levels, or their values are
within a
predefined range of each other (e.g. 0.1%, 0.5%, 1%, 2%, 5% or 100,
/0) Alternatively (or
additionally), an identical phage vial may be a phage vial grown in the same
batch, or
grown in the same batch and undergone the same post batch processing (e.g.
purification and dispensing into a vial) such that the vial was filled and
sealed on the
same day or within a predefined time limit (e.g. within 12, 24 or 48 hours).
Such vials
may be assigned the same lot number and thus vials with the same lot number
are
considered identical phage vials and determining if two phage vials are
identical
comprises checking if they have the same lot number.
[0099] As the phage are identical the known titer 202 and contaminant levels
206 can
be used to determine how many additional candidate phage vials are required to
generate the required total dispensing volume whilst ensuring that the
contaminant
levels remain below the maximum value. If the search identified sufficient
identical
candidate phage vials, then these are progressively added to the dispensing
set, along
with the associated dispensing volume 223. For example if the vials are lml
vials, and
the total dispensing dose was 3.6m1, then taking into account 1mL from the
first
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candidate vial, we would select 3 additional identical candidate vials, with
associated
dispensing volumes of 1mL, 1mL and 0.6m L from the second, third and fourth
candidate
vials.
[00100] If an insufficient number of identical candidate phage
vials are located to
enable dispensing of the total dispensing dose, then we may select all of the
identical
candidate phage vials located and add them to the dispensing set along with an
associated dispensing volume set to their maximum dispensing volume. For
example in
the previous case, if only two identical vials were located, we would add them
both with
dispensing volumes of 1mL and 1mL. If there are none found, we move to the
next
candidate phage vial 205.
[00101] We then repeat the above process (e.g. Loop 205 to 221)
as many times
as needed for each additional phage 225 until the dispensing set contains
sufficient
candidate phage vials to enable dispensing of the total dispensing volume 221
whilst
ensuring that the contaminant levels remain below the maximum contaminant
level (for
each contaminant) 214. That is we identify another candidate phage vial 205
containing
the target phage and determine the dispensing volume from the titer 207 and
check the
contaminant level(s) 214 are still below the maximum, and if so add this to
the
dispensing set. If there is still insufficient vials to enable dispensing of
the total
dispensing volume then we perform another search for identical candidate phage
vials
(to this additional candidate phage vial), and determine if these additional
identical
candidate phage vials can be added. Candidate vials with contaminant levels,
which
when added to the dispensing set, would result in the maximum contaminant
level being
exceeded may be discarded from the search, and alternative candidate phage
vials
identified.
[00102] In one embodiment we may first identify sets of identical
phage vials, and
identifying at least one candidate phage vials for a phage may involve
sequentially
selecting a candidate phage vial from each identical set, and then using the
rest of the
phage vials in the identical set as required.
[00103] In one embodiment the search may involve searching for a
combination of
candidate phage vials which when combined generate a total dose closest to a
target
dose within the target dose range. This may be subject to a constraint on the
combination with the minimum contaminant levels. In one embodiment an
optimization
method may be used to search for an optimal combination that is closest to the
target
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phage dose whilst minimizing contaminants. For example if the optimizer
minimizes a
cost function (such that low costs are better) the cost function could include
a dose term
which uses a parabolic or V shaped weight function centered on the target dose
range
and which becomes infinite or very large outside of the target phage dose
range limits
and a term for each contaminant which increases linearly or exponentially up
to the
maximum contaminant level after which it becomes infinite or very large. In
the case of
multiple contaminants, different contaminants could use different weights to
priorities
the importance of different contaminants.
[00104] The above methodology can be extended to phage
prescription
comprising multiple phage. The search for candidate phage vials may be
performed
sequentially for each phage in the prescription. Alternatively the search may
be
performed in parallel to identify combination of vials which contain
dispensing volumes
for each of the respective phage, and for which the total contaminant levels
are below
the maximums. Optimization methods discussed above can be used for parallel
searching.
[00105] Figure 2B is a flowchart of a dose calculation method 201
for a candidate
phage vial used to generate the dispensing set according to another
embodiment. The
dose calculation method 201 calculates a dispensing volume, based on the
titer, for a
candidate phage vial, or combination of candidate phage vials, or determines
that a
candidate phage vial is unsuitable for dispensing to the patient due to
excessive
contaminants (alone or when combined with other candidate phage vials). The
dose
calculation begins with the patient weight 202, the target phage dose range
220, a titer
of the candidate phage vial 208 and one or more contaminant levels which in
this
embodiment is a single contaminant in the form of an endotoxin (EU) level of
the
candidate phage vial 206. In this embodiment the target phage dose range 220
is either
a low dose range 222 or a high dose range 230. The low dose range 222 has a
range
from a LowDose-low limit 224 to a LowDose-high limit 226 as shown at the
bottom of
Figure 2B. In this embodiment the LowDose-low limit is 1e9 PFU/ml and the
LowDose-
high limit is 3e9 PFU/ml (a PFU is a plaque forming unit). The high dose 230
has a high
dose range from a HighDose-low limit 232 to a HighDose-high limit 234. In this
embodiment the HighDose-low limit 232 is 1e10 PFU/ml and the HighDose-high
limit
234 is 3e19 PFU/ml. The full dosage range 228 is thus from the LowDose-low
limit 224
to HighDose-high limit 234.
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[00106] An acceptable endotoxin (EU) level is calculated at 204
by multiplying the
patient weight by 5 EU/kg to obtain a Max EU level ¨ the maximum acceptable
endotoxin level. We then compare 214 the endotoxin level 206 of the candidate
phage
vial (obtained from the certificate of analysis) to the maximum acceptable
endotoxin
level (max EU) 214. If the endotoxin level of the candidate phage vial exceeds
the
calculated maximum acceptable endotoxin level (EU > Max EU) then at 216 we
determine a reduced titer level 218 by multiplying the titer 208 of the
candidate phage
vial by the ratio of the maximum acceptable endotoxin level 204 to the
endotoxin level
206 of the candidate phage vial. We then check if the reduced titer level
exceeds the
minimum dose titer 210. If the reduced titer level is less than the minimum
dose (the
LowDose-low dose 1e9) 210 then we can either determine if the diluted phage
vial can
be combined with another candidate phage vial to deliver a total dose in the
target
range, or we can reject and discard the candidate phage vial 212. If the
reduced titer
level exceeds the minimum dose we use the reduced titer level calculated at
218 in
place of the actual titer level 208 of the candidate phage vial for the rest
of the dose
calculation. Similarly, if the titer 208 of the candidate phage vial is less
than the
minimum dose then we can either determine if the diluted phage vial can be
combined
with another candidate phage vial to deliver a total dose in the target range,
or we can
reject and discard the candidate phage vial 212.
[00107] If the titer exceeds the minimum dose and the endotoxin
level is less than
the maximum acceptable endotoxin level we then check 236 if the titer of the
candidate
phage vial is between the LowDose-low limit and the LowDose-high limit. If the
target
dose is the low dose 238 then we use the titer 208 of the candidate phage vial
as the
dose titer 240 and add the candidate phage vial to the dispensing set. If the
target dose
is the high dose then we reject the candidate phage vial 242 as not suitable
for the
patient.
[00108] We then check 244 if the titer of the candidate phage
vial is between the
LowDose-high limit and the HighDose-low limit. If yes and the target dose is
the low
dose 246 then we set the dose titer to the LowDose-high titer and add the
candidate
phage vial to the dispensing set 248. If the target dose is the high dose 264
we then
check 250 if the candidate phage vial can be combined with a second candidate
phage
vial to obtain a titer in the high dose range 252 (i.e., between HighDose-low
and
HighDose-high). If the dose is outside this range, we reject the candidate
phage vial 254
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as not suitable for the patient. We also check that one or more excipients are
in an
acceptable range 256. If not 258 (fail) we reject the candidate phage vial 254
as not
suitable for the patient and if yes (pass) we add the candidate phage vial and
the
second candidate phage vial to the dispensing set for use as the high dose
260.
[00109] If check 244 returned no (the titer of the candidate
phage vial is now
between the LowDose-high limit and the HighDose-low limit), we next check 262
if the
titer of the candidate phage vial is between the HighDose-low limit and the
HighDose-
high limit and if yes and the target dose is the low dose 264 then we set the
dose titer to
the LowDose-high titer 266 and add the candidate phage vial to the dispensing
set. If
the target dose is the high dose 268 then we use the titer of the candidate
phage vial as
the dose titer and add the candidate phage vial to the dispensing set.
[00110] If check 262 returned no then the titer of the candidate
phage vial exceeds
the HighDose-high limit (this can be explicitly checked) 270 and if the target
dose is the
low dose 272 then we set the dose titer to the LowDose-high titer 274 and add
the
candidate phage vial to the dispensing set and if the target dose is the high
dose 276
then we set the dose titer to the HighDose-high titer and add the candidate
phage vial to
the dispensing set.
[00111] Figure 3 depicts an exemplary computing system configured
to perform
any one of the computer implemented methods described herein. The computing
system may comprise one or more processors including multi-core CPUs and
Graphical
Processing Units (GPUs) operatively connected to one or more memories which
store
instructions to configure the processor to perform embodiments of the method.
In this
context, the computing system may include, for example, one or more processors
(CPUs, GPUs), memories, storage, networking interfaces and input/output
devices
(e.g., monitor, keyboard, disk drive, network interface, Internet connection,
etc.).
However, the computing system may include circuitry or other specialized
hardware for
carrying out some or all aspects of the processes. The computing system may be
a
computing apparatus such as an all-in-one computer, desktop computer, laptop,
tablet
or mobile computing apparatus, server, and any associated peripheral devices.
The
computer system may be a distributed system including server-based systems and
cloud-based computing systems. In some operational settings, the computing
system
may be configured as a system that includes one or more units, each of which
is
configured to carry out some aspects of the processes either in software,
hardware, or
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some combination thereof. For example, the user interface may be provided on a
desktop computer or tablet computer, whilst the dose calculations may be
performed on
a server-based system including cloud-based server systems, and the user
interface is
configured to communicate with such servers. The user interface may be
provided as a
web portal, allowing a user on one computer to upload data (e.g. user ID, site
ID, patient
ID) which may be processed on a remote computing apparatus or system (e.g.,
server
or cloud system) and which provides the results (i.e., the dispensing
instructions) back
to the user, or to other users on other computing apparatus.
[00112] Figure 3 depicts an exemplary computing system (300) with
a number of
components that may be used to perform the processes described herein. For
example,
an input/output ('I/O) interface 330, one or more central processing units
("CPU")
(340), and a memory section (350). The I/O interface (330) is connected to
input and
output devices such as a display (320), a keyboard (310), a disk storage unit
(390) such
as a SSD, and a media drive unit (360) configured to read/write a removable
computer-
readable medium (370), which can contain programs (380) and/or data. The disk
storage unit (390) may also be used to store programs (380) and/or data,
including
programs or data downloaded from a website or read from media inserted in the
media
drive unit. The I/O interface may comprise a network interface and/or
communications
module for communicating with an equivalent communications module in another
device
using a predefined communications protocol (e.g., Bluetooth, Zigbee, IEEE
802.15,
IEEE 802.11, TCP/IP, UDP, etc.). A computer program or application may be
written, for
example, in a general-purpose programming language (e.g., Swift, Python, Java,
C,
C++, C#, Pascal, JSON, etc.) or some specialized application-specific language
to
implement the system or components and may call software libraries/packages.
[00113] The dose preparation instructions are displayed on the
screen and may
also be printed by printer 25 and/or emailed to the pharmacist. For example,
the dosing
instructions may include patient ID, phage vial location (C2, bay 10), target
dose (e.g.,
low dose), the dispensing volume and preparation instructions such as
= "Remove vial from the freezer location";
= "Touch camera icon to scan the vial's barcode";
= "withdraw 1.00mL from the vial"; and
= "then inject volume into a 25m L minibag (NS).
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[00114] The electronic certificate of analysis for each of the
phage vials in the
dispensing set may also be displayed to the pharmacist. Figure 4 is a
representation of
a certificate of analysis 400 of a phage vial according to an embodiment. This
may be
generated by quality control laboratory 54 of the manufacturer 50 and an
electronic
copy stored by the phage management system 60. The certificate of analysis
comprises
manufacturing data 410 such as the product description, manufacturing lot
number and
date of manufacturer. Details of the storage vial (Schott glass vial) and
storage
conditions (-80 C) may also be provided. A test description table 420 includes
details on
tests such as appearance, potency (to obtain the titer 422), identity,
transduction, pH,
sterility and contaminant tests/levels such as host cell protein levels,
residual detergent,
and endotoxin level 424. The data from the certificate of analysis may be
stored in a
phage record by phage management system 60.
[00115] The phage management system 60 may also perform
administrative tasks
and may include a traceability database that logs activities such as user
logins (time
and IP address) and actions, such as patients selected, which boxes were
accessed by
a pharmacist, and barcode scans, RFID reads, weight data and weight changes,
app
alerts, and whether the user has pressed buttons to print or send dose
instructions or
view the certificate of analysis. The phage management system may also
coordinate
exchange of data between the various applications at different sites. In one
embodiment
the phage management system is further configured to interface or communicate
with
LIMS and/or EHR systems to look up data or record the dispensing of the
prescription to
the patient.
[00116] Embodiments of the system and method provide a more
accurate and
efficient dispensing system for phage based treatments, thus assisting
pharmacists to
accurately dispense phage based treatments. The system also monitors
dispensing and
coordinates data exchanges between various distributed components to ensure
supplies of phage are maintained at dispensing sites.
[00117] The system and method allows personalized and dynamic
dosing
instructions to be delivered to the pharmacist based on the specific phage
treatment in
order to effectively treat the patient. Pharmacists are not accustomed to the
drug
product being different from type to type (e.g., due to batch to batch
variability) and thus
the system and method is configured to both guide the pharmacist and checks
their
activities to ensure accurate and efficient dispensing. The system also
provides a
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detailed audit trail to assist in meeting any traceability and auditability
requirements
(e.g., FDA 21 part 11) which is more reliable than current paper and email-
based
methods.
[00118] The steps of a method or algorithm described in
connection with the
embodiments disclosed herein may be embodied directly in hardware, in a
software
module executed by a processor, or in a combination of the two. For a hardware
implementation, processing may be implemented within one or more application
specific
integrated circuits (ASICs), digital signal processors (DSPs), digital signal
processing
devices (DSPDs), programmable logic devices (PLDs), field programmable gate
arrays
(FPGAs), processors including CPU and CPUs, controllers, micro-controllers,
microprocessors, other electronic units designed to perform the functions
described
herein, or a combination thereof. Software modules, also known as computer
programs,
computer codes, or instructions, may contain a number of source code or object
code
segments or instructions, and may reside in any computer readable medium such
as a
memory (including RAM, flash, ROM, EPROM, registers, etc.), hard disks
(including
SSDs), networked storage, a removable disk, a CD-ROM, a DVD-ROM, a Blu-ray
disc,
or any other form of computer readable medium. In some aspects the computer-
readable media may comprise non-transitory computer-readable media (e.g.,
tangible
media). In another aspect, the computer readable medium may be integral to the
processor. The processor and the computer readable medium may reside in an
ASIC or
related device. The software codes may be stored in a memory unit and the
processor
may be configured to execute them. The memory unit may be implemented within
the
processor or external to the processor, in which case it can be
communicatively coupled
to the processor via various means as is known in the art.
[00119] A non-transitory computer-program product or storage
medium comprising
computer-executable instructions for carrying out any of the methods described
herein
can also be generated. A non-transitory computer-readable medium can be used
to
store (e.g., tangibly embody) one or more computer programs for performing any
one of
the above-described processes by means of a computer. Further provided is a
computer system comprising one or more processors, memory, and one or more
programs, wherein the one or more programs are stored in the memory and
configured
to be executed by the one or more processors, the one or more programs
including
instructions for carrying out any of the methods described herein.
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[00120] Those of skill in the art would understand that
information and signals may
be represented using any of a variety of technologies and techniques. For
example,
data, instructions, commands, information, signals, bits, symbols, and chips
may be
referenced throughout the above description may be represented by voltages,
currents,
electromagnetic waves, magnetic fields or particles, optical fields or
particles, or any
combination thereof.
[00121] Those of skill in the art would further appreciate that
the various illustrative
logical blocks, modules, circuits, and algorithm steps described in connection
with the
embodiments disclosed herein may be implemented as electronic hardware,
computer
software or instructions, or combinations of both. To clearly illustrate this
interchangeability of hardware and software, various illustrative components,
blocks,
modules, circuits, and steps have been described above generally in terms of
their
functionality. Whether such functionality is implemented as hardware or
software
depends upon the particular application and design constraints imposed on the
overall
system. Skilled artisans may implement the described functionality in varying
ways for
each particular application, but such implementation decisions should not be
interpreted
as causing a departure from the scope of the present invention.
[00122] Throughout the specification and the claims that follow,
unless the context
requires otherwise, the words "comprise" and "include" and variations such as
"comprising" and "including" will be understood to imply the inclusion of a
stated integer
or group of integers, but not the exclusion of any other integer or group of
integers.
[00123] The reference to any prior art in this specification is
not, and should not be
taken as, an acknowledgement of any form of suggestion that such prior art
forms part
of the common general knowledge.
[00124] It will be appreciated by those skilled in the art that
the disclosure is not
restricted in its use to the particular application or applications described.
Neither is the
present disclosure restricted in its preferred embodiment with regard to the
particular
elements and/or features described or depicted herein. It will be appreciated
that the
disclosure is not limited to the embodiment or embodiments disclosed, but is
capable of
numerous rearrangements, modifications and substitutions without departing
from the
scope as set forth and defined by the following claims.
CA 03231482 2024- 3- 11
