Targets Limits Ranges Ontology
The Targets Limits Ranges Ontology defines value-expression constructs for representing prescribed values, intervals, and thresholds used in process control, quality control, and material conformance contexts. It covers target values and target ranges, setpoints, normal operating ranges, proven acceptable ranges, specification limits, control limits, alert limits, action limits, and lifecycle-specific control limits. The module supports clear distinction between preferred values, acceptable operating ranges, process-control boundaries, early-warning thresholds, action-triggering thresholds, and specification-based conformance limits.
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acceptance limit value expression
An acceptance limit of 100 ng/mg for residual host cell protein indicates that values above 100 ng/mg do not satisfy the applicable acceptance criterion; An acceptance limit of 95 % purity indicates that values below 95 % do not satisfy the applicable acceptance criterion; An acceptance limit of 2.0 % relative standard deviation for analytical method suitability indicates that values above 2.0 % do not satisfy the applicable acceptance criterion
AcceptanceLimitValueExpression(x) ↔ LimitValueExpression(x) ∧ ∃a(AcceptanceCriteria(a) ∧ continuantPartOfAtAllTimes(x,a))
limit value expression beyond which an acceptance criterion is not satisfied
every instance of 'acceptance limit value expression' is defined as exactly an instance of 'limit value expression' that 'is continuant part of at all times' some 'acceptance criteria'
action limit value expression
Chromatography column pressure has a normal operating range with an upper boundary of 1.5 bar and an action limit of 2.0 bar. A pressure value beyond 2.0 bar requires action to address potential fouling or blockage and prevent column damage or product loss; dissolved oxygen in a bioreactor has a setpoint of 40 % air saturation, a normal operating range of 35–45 %, a lower action limit of 30 %, and an upper action limit of 50 %. Crossing either action limit requires action to restore dissolved oxygen to normal operating conditions and prevent impact on cell culture performance
https://www.biophorum.com/download/cvp-case-study-interactive-version/ and https://www.thermofisher.com/rs/en/home/industrial/microbiology/pharmaceutical-microbiology/environmental-monitoring/applications.html and https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
1) Exceeding an action limit requires the response prescribed for that limit. Depending on the application, this may include process adjustment, investigation, deviation or nonconformance handling, assessment of potential impact, and corrective or preventive action. 2) Action limits are part of the internal process control framework and are not regulatory reporting limits.
ActionLimitValueExpression(x) → LimitValueExpression(x)
limit value expression beyond which action is required to address a departure from normal operating conditions and prevent or mitigate potential impact on process performance or product quality
There are insufficient constructs to create necessary and sufficient conditions.
If x is an 'action limit value expression' then x is a 'limit value expression'
alert limit value expression
Chromatography column pressure has a normal operating range with an upper boundary of 1.5 bar, an alert limit of 1.8 bar, and an action limit of 2.0 bar. A pressure value beyond 1.8 bar provides an early warning of potential fouling or blockage before the action limit is reached
https://www.biophorum.com/download/cvp-case-study-interactive-version/ and https://www.gmp-publishing.com/content/en/gmp-questionoftheday/what-is-an-alert-limit#:~:text=Alert%20limit:%20A%20pre%2Ddetermined,to%20a%20predefined%20action%20plan. and https://www.thermofisher.com/rs/en/home/industrial/microbiology/pharmaceutical-microbiology/environmental-monitoring/applications.html and https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf
1) An alert limit serves as an early warning indicator of process drift. It is typically established from process data using statistical methods such as control charts or capability analysis and is periodically reassessed during continued process verification (CPV). 2) The alert limit does not represent a specification or regulatory boundary. Instead, it supports proactive control by identifying trends or variations that may lead toward an action limit or out-of-specification condition if the underlying condition persists or worsens. 3) Where corresponding alert and action limits are established, the alert limit ordinarily lies closer to the expected operating region than the action limit. 4) FDA Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice: Guidance for Industry states "Environmental monitoring data will provide information on the quality of the manufacturing environment. Each individual sample result should be evaluated for its significance by comparison to the alert or action levels. Averaging of results can mask unacceptable localized conditions. A result at the alert level urges attention to the approaching action conditions. A result at the action level should prompt a more thorough investigation."
AlertLimitValueExpression(x) → LimitValueExpression(x)
limit value expression beyond which an early warning of potential drift from normal operating conditions is triggered, prompting closer monitoring or investigation
If x is an 'alert limit value expression' then x is a 'limit value expression'
control limit value expression
For a temperature setpoint of 37 °C, the normal operating range is 36.5–37.5 °C and the operational control limits are 36.0 °C for the lower control limit and 38.0 °C for the upper control limit. Values outside the control limits indicate that the process is outside its expected controlled behavior and require investigation
https://www.biophorum.com/download/cvp-case-study-interactive-version/ and https://www.6sigma.us/cause-variation/what-are-control-limits/ and https://www.sigmaaldrich.com/RS/en/technical-documents/technical-article/pharmaceutical-and-biopharmaceutical-manufacturing/monoclonal-antibody-manufacturing/continued-process-verification
1) A statistical control limit is derived from process data (such as mean ± 3σ) and reflects the natural variability of a stable process. 2) An operational control limit is defined using process knowledge, equipment capability, or risk assessment when statistical data are limited or when physical or engineering constraints dictate the threshold. 3) In biopharmaceutical manufacturing, control limits are typically refined during continued process verification to support ongoing monitoring and evaluation of the validated state of control.
ControlLimitValueExpression(x) → LimitValueExpression(x)
limit value expression that is a statistical or operational threshold beyond which a process is considered to be out of control
If x is a 'control limit value expression' then x is a 'limit value expression'
initial control limit value expression
After installing a new sparger system, dissolved oxygen is monitored using initial control limits of 33 %–47 %, pending evaluation of additional process data to establish long-term control limits; during the first 10 batches after scale-up, temperature is monitored using initial control limits of 36–38 °C until sufficient data are available to establish statistically justified control limits
An initial (provisional) control limit is used at the start of continued process verification or after process changes when process history is still limited. It provides monitored boundaries for continued manufacturing while additional data are collected to confirm process stability and variability. Once adequate data are available, the initial control limits are replaced by control limits that represent the long-term state of control.
InitialControlLimitValueExpression(x) → ControlLimitValueExpression(x)
control limit established from limited process data or process knowledge and applicable only until sufficient information is available to establish statistically justified control limits
This term is expected to remain primitive as it is not expected that a formalization of sufficient information will be available that can fit all use cases.
If x is an 'initial control limit value expression' then x is a 'control limit value expression'
limit value expression
Chromatography column pressure has an alert limit of 1.8 bar and an action limit of 2.0 bar; temperature control limits are set at 36.5 °C for the lower control limit and 37.5 °C for the upper control limit
A limit value expression represents an expressed threshold used to interpret whether a value remains within, reaches, or crosses a relevant boundary. It is not the full range and not the entity or quantity to which the limit applies. More specific subclasses determine the meaning of the threshold, such as early warning, loss of control, required corrective action, or acceptance/non-acceptance. A limit value expression may represent an upper threshold, a lower threshold, or another boundary value, including in control, monitoring, specification, or acceptance contexts.
LimitValueExpression(x) → ValueExpression(x) ∧ ∃e((TemporalRegion(e) ∨ SpecificallyDependentContinuant(e) ∨ ProcessBoundary(e) ∨ ProcessCharacteristic(e)) ∧ isLimitValueExpressionOfAtSomeTime(x,e))
value expression that is the specified boundary value for a particular entity
Insufficient constructs are present to create necessary and sufficient conditions. In particular, constructs required to fully formalize boundaries are currently under development in IOF Core.
if x is a 'limit value expression' then x is a 'value expression' that 'is a limit value expression of at some time' some 'temporal region' or 'specifically dependent continuant' or 'process boundary' or 'process characteristic'
long-term control limit value expression
After one year of commercial production, temperature control limits of 36–38 °C are established as long-term control limits based on statistical analysis of 40 commercial manufacturing batches from a stable process
https://www.biophorum.com/download/cvp-case-study-interactive-version/ and https://www.kbibiopharma.com/our-resources/continued-process-verification#:~:text=Continued%20Process%20Verification%20 and https://www.biopharminternational.com/view/continued-process-verification-biopharma-manufacturing
A long-term control limit is established after sufficient manufacturing data have been collected to characterize normal process variability with statistical confidence. It serves as the boundary for routine monitoring, trend evaluation, and process capability assessment, replacing provisional control limits once stable operation is demonstrated. Long-term control limits are periodically reviewed and re-established as part of lifecycle maintenance.
LongTermControlLimitValueExpression(x) → ControlLimitValueExpression(x)
control limit established from statistically sufficient process data and used for routine monitoring and evaluation of stable long-term process performance
This term is expected to remain primitive as it is not expected that a formalization of sufficient process information will be available that can fit all use cases.
If x is a 'long-term control limit value expression' then x is a 'control limit value expression'
normal operating range value expression
36.5–37.5 °C as the normal operating range around the setpoint 37 °C for bioreactor temperature during mammalian cell culture; 15–25 minutes as the normal operating range for residence time in a chromatography column during protein purification
https://www.fda.gov/media/179081/download and https://www.ema.europa.eu/en/documents/scientific-guideline/questions-and-answers-improving-understanding-normal-operating-range-nor-proven-acceptable-range-par-design-space-dsp-and-normal-variability-process-parameters_en.pdf
NOR is the span within which a process parameter is expected to vary during normal operation. This range is distinct from broader ranges, which may include values associated with abnormal operation or alarm conditions. When a process parameter remains within its normal operating range, it is considered to be operating within its expected region of normal variability.
NormalOperatingRangeValueExpression(x) → RangeValueExpression(x) ∧ ∃z (SetpointValueExpression(z) ∧ hasContinuantPartAtAllTimes(x, z))
range value expression that is an interval around a setpoint within which a particular process parameter is expected to vary during normal operation of a process and that lies within the proven acceptable range for that parameter
if x is a 'normal operating range value expression' then x is a 'range value expression' and x 'has continuant part at all times' some 'setpoint value expression'
proven acceptable range value expression
35.0–38.0 °C as the proven acceptable range for bioreactor temperature during mammalian cell culture; pH 6.5–7.5 as the proven acceptable range for culture medium pH during fermentation
https://www.fda.gov/media/71535/download (Guidance for Industry Q8 R2 Development)
The PAR is established based on process development and validation activities and is typically narrower than the full instrument operating span. It defines the demonstrated boundaries for acceptable operation of the process parameter, and excursions outside this range may be treated as process deviations requiring assessment, investigation, or corrective action.
ProvenAcceptableRangeValueExpression(x) → RangeValueExpression(x)
range value expression that has been validated through testing or documented experience and that is a prescribed interval within which a single process parameter may vary without adversely affecting product quality, assuming all other process parameters are held constant at their target values
if x is a 'proven acceptable range value expression' then x is a 'range value expression'
range value expression
36.5–37.5 °C as the normal operating range around the setpoint 37 °C for bioreactor temperature during mammalian cell culture; pH 6.5–7.5 as the proven acceptable range for culture medium pH during fermentation
A range value expression represents the interval itself, not the individual values within the interval. The interval is used to interpret, prescribe, or evaluate values associated with a specified entity. The exact meaning of the interval depends on the more specific subclass or use context. For example, the interval may represent a target range, a normal operating range, or a proven acceptable range.
RangeValueExpression(x) → ValueExpression(x)
value expression that is an interval for values of a particular entity
Insufficient constructs are present to create necessary and sufficient conditions. In particular, constructs required to fully formalize intervals are currently under development in IOF Core.
if x is a 'range value expression' then x is a 'value expression'
setpoint value expression
for a residential dwelling temperature control process, the setpoint might be 72 degrees Fahrenheit during the day and 68 degrees Fahrenheit during the night; 250 rpm as the setpoint for agitation speed in a formulation tank; 20 minutes as the setpoint for residence time in the protein purification chromatography step
A setpoint is a prescribed target for a process parameter. It may be used by an automated control system, supervisory system, recipe, or operator as a reference for regulating or evaluating the realized process parameter. In a closed-loop control system, the measured process variable is compared with the setpoint and the resulting difference may be used to determine control action.
SetpointValueExpression(x) → TargetValueExpression(x)
target value expression which is a prescribed value that a process parameter should have at a particular time point or during a particular time interval of some planned process
if x is a 'setpoint value expression' then x is a 'target value expression'
specification limit value expression
upper specification limit for host cell protein concentration in a drug substance; lower specification limit for protein concentration in a formulated product; upper and lower specification limits for osmolality of a process intermediate; specification limit for aggregate percentage in a monoclonal antibody product; specification limit for bioburden in a material prior to further processing
SpecificationLimitValueExpression(x) → AcceptanceLimitValueExpression(x)
acceptance limit value expression that is part of a specification
There are insufficient constructs to create a set of necessary and sufficient conditions. In particular, formalization of a specification class in IOF Core is missing.
If x is a 'specification limit value expression' then x is an 'acceptance limit value expression'
target range value expression
target pH range of 7.0–7.4 for a prepared buffer before use; target osmolality range of 280–320 mOsm/kg for a prepared media lot at release; target viability range of 90–95 % for a cell culture before inoculation; target galactosylation range of 45–55 % for a product quality attribute at harvest
Target range is used to describe the preferred band for an attribute, indicator, or parameter and does not, by itself, state what variation is permissible. When a parameter range is intended to state permissibility or demonstrated acceptability, terms such as normal operating range (NOR) and proven acceptable range (PAR) should be used instead.
TargetRangeValueExpression(x) → RangeValueExpression(x)
range value expression that prescribes a preferred interval for a quality attribute, material attribute, performance indicator, or process parameter at a particular time point or during a particular time interval of some planned process
if x is a 'target range value expression' then x is a 'range value expression'
target value expression
37 °C as the target value for bioreactor temperature during cell culture; pH 7.2 as the target value for a prepared buffer before use; 300 mOsm/kg as the target osmolality for a prepared media lot at release; 95 % viability as the target value for a cell culture before inoculation; 5.0 g/L as the target product concentration at harvest
For material attributes, a target value may prescribe the required attribute value of an input material, such as a raw material, intermediate, or prepared solution, at a specified checkpoint in the planned process, for example at material receipt, at lot release, or at the time the material is introduced into the process
TargetValueExpression(x) → ValueExpression(x)
value expression which is a prescribed value that a quality attribute, material attribute, performance indicator, or process parameter should have at a particular time point or during a particular time interval of some planned process
If x is a 'target value expression' then x is a 'value expression'
is limit value expression of at some time
the lower pH limit of 6.8 for the pH of cell culture material during a production culture process; the upper harvest viability limit of 80 percent for the harvest viability ratio; the upper endotoxin level limit of 0.25 EU/mL for the endotoxin level of a prepared solution
1) The relevant value region may concern one characteristic, such as a permitted pH range, or several characteristics considered together, such as permitted combinations of pH and temperature. In a multidimensional value region, the value contained in the limit value expression may define a boundary for one characteristic or may be part of a rule that defines a boundary for the combined region. 2) The value contained in the limit value expression marks where the relevant value region is delimited. That value may be included in the region, or it may be an excluded limiting value that values within the region can approach but do not attain. For example, an upper boundary value may be the greatest value included in the region or an excluded upper limiting value, such as the supremum of the region. Correspondingly, a lower boundary value may be the least value included in the region or an excluded lower limiting value, such as the infimum of the region. 3) This relation on its own does not state whether a value equal to, below, or above the boundary represents conformance, an alert condition, an action condition, or a violation.
relation from a limit value expression to an entity indicating that the limit value expression contains a value that marks a boundary of a value region relevant to the entity
is lower side limit value expression of at some time
the lower pH limit of 6.8 for the pH of cell culture material during a production culture process; the lower dissolved oxygen limit of 30 percent air saturation for the dissolved oxygen saturation ratio of a cell culture; the lower acceptable harvest viability limit of 80 percent for the harvest viability ratio; the lower operating temperature limit of 35 °C for the temperature of process material in a production bioreactor
relation from a limit value expression to an entity indicating that the limit value expression contains a value that marks a lower-side boundary of a value region relevant to the entity with respect to an ordering in the relevant value space
is upper side limit value expression of at some time
the upper pH limit of 7.2 for the pH of cell culture material during a production culture process; the upper dissolved oxygen limit of 60 percent air saturation for the dissolved oxygen saturation ratio of a cell culture; the upper endotoxin level limit of 0.25 EU/mL for the endotoxin level of a prepared solution; the upper operating temperature limit of 37 °C for the temperature of process material in a production bioreactor
relation from a limit value expression to an entity indicating that the limit value expression contains a value that marks an upper-side boundary of a value region relevant to the entity with respect to an ordering in the relevant value space