Parameter Ontology
This module contains terms and relations necessary for representing process intermediate and product quality attributes, process indicators and process parameters.
Cameron Gibbs, CrownPoint Technologies, LLC
Melissa Weller, CrownPoint Technologies, LLC
Stephen J. Granite, CrownPoint Technologies, LLC
Stephen Kahmann, CrownPoint Technologies, LLC
Copyright (c) 2022, 2023, 2024, 2025, 2026 Open Applications Group
critical process parameter
pH during the viral inactivation process; temperature during the fermentation process; agitation speed during the cell culture mixing step
See the expanded definition under the corresponding specification class. The term is formalized here as a defined class by referring to its corresponding specification class and exists primarily for ontological modeling and implementation convenience.
CriticalProcessParameter(x) ↔ ∃s(CriticalProcessParameterSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x))
process profile or temporal region or quality prescribed by a critical process parameter specification
every instance of 'critical process parameter' is defined as exactly an instance that is either a 'temporal region' or a 'process profile' or 'quality' and that is 'prescribed by' some 'critical process parameter specification'
critical process parameter specification
pH specification for the viral inactivation process, due to its impact on the viral clearance capability of the intermediate; temperature specification for the fermentation process, which affects product titer and impurity levels; agitation speed specification for the cell culture mixing step, where excessive shear stress can impact cell viability and product quality;
FROM ICH: process parameter specification whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process obtains the desired quality
CriticalProcessParameterSpecification(x) → ProcessParameterSpecification(x) ∧ ∃y (CriticalQualityAttributeSpecification(y) ∧ isAbout(x, y))
process parameter specification that prescribes a variable which has an impact on a critical quality attribute
There are insufficient constructs to have a set of necessary and sufficient conditions. In particular criticality determination is missing as well as a more semantically specific connection to a critical quality attribute specification
if x is a 'critical process parameter specification' then x is a 'process parameter specification' and x 'is about' some 'critical quality attribute specification'
critical quality attribute
host-cell protein impurity level in the clarified lysate; aggregate content in the purified monoclonal antibody; endotoxin level in the filled drug product; glycan composition of the monoclonal antibody drug substance
CriticalQualityAttribute(x) ↔ (Quality(x) ∨ Capability(x)) ∧ ∃s(CriticalQualityAttributeSpecification(s) ∧ prescribedBy(x, s))
quality or capability prescribed by a critical quality attribute specification
every instance of 'critical quality attribute' is defined as exactly an instance of 'quality' or 'capability' that is 'prescribed by' some 'critical quality attribute specification'
critical quality attribute specification
host-cell protein impurity specification in the clarified lysate;aggregate level specification for the purified monoclonal antibody; endotoxin level specification for the filled drug product; glycan profile specification for the monoclonal antibody drug substance
1) From ICH: critical quality attribute is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. The deviations of CQAs beyond defined limits have significant adverse impacts on product quality and, therefore, mandate stringent control, monitoring, and validation measures. 2) This specification serves as a formal constraint on a quality attribute that is critical to product performance, safety, or efficacy, and is used to assess the acceptability of materials or products in manufacturing and quality control processes. 3) Critical quality attributes are monitored throghout the manufacturing process and as such are measured on attributes of both final products and intermediate materials generated or used during the product production process .
CriticalQualityAttributeSpecification(x) → QualityAttributeSpecification(x)
quality attribute specifications that prescribes some quality, capability, constitution, or composition deemed critical to ensuring safety, efficacy, or performance of a material product
There are insufficient constructs to create necessary and sufficient conditions. In particular criticality determination is missing
if x is a 'critical quality attribute specification' then x is a 'quality attribute specification'
key performance indicator
average deviation rate per production step due to CPP excursions; yield consistency over successive purification runs; final harvest titer for a specific production batch; Viral clearance log reduction amount for the purification step; batch release time within the specified regulatory window
KeyPerformanceIndicator(x) ↔ ∃s(KeyPerfornanceIndicatorSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x) v ProcessCharacteristic(x))
process profile, temporal region, quality or process characteristic prescribed by a key performance indicator specification
every instance of 'key performance indicator' is defined as exactly an instance that is either a 'temporal region' or a 'process profile' or 'quality' or 'process characterstic' and that is 'prescribed by' some 'key performance indicator specification'
key performance indicator specification
Target final harvest titer for the production batch;Target viral clearance log reduction value for purification step; Target batch release time within specified regulatory window
ISO-22400 and https://www.gmp-compliance.org/gmp-news/fdas-current-thinking-on-kpis-and-quality-metrics
1) Per the ISO-22400 standard a good KPI has certain criteria which ensure its usefulness in achieving various goals in the manufacturing operation. For more details the user should take a look at the standard. Also the KPI specification should contain information about its context, including timing, audience, production methodology, effect model diagram, and notes. 2) In case of KPIs for (bio)pharmaceutical manufacturing processes KPIs are indirectly related to CQAs and therefore influenced, as well, by the CPPs. As the CPPs remain within the pre-defined limits, the KPIs should indicate that each production step proceeds accordingly resulting, in the end, in a product having its CQAs within the appropriate limits, too. Also, KPIs reflects the consistency or reproducibility of the associated manufacturing process.
KeyPerformanceIndicatorSpecification(x) → PerformanceIndicatorSpecification(x)
performance indicator specification that prescribes a measurable characteristic whose measurements reflect effectiveness with respect to some objective determined as important by a person or organization
This term is expected to remain primitive as different organizations have different criteria for establishing what is key.
if x is a 'key performance indicator specification' then x is a 'performance indicator specification'
key process parameter
temperature during media hold; buffer addition flow rate during diafiltration
KeyProcessParameter(x) ↔ ∃s(KeyProcessParameterSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x))
process profile or temporal region or quality prescribed by a key parameter specification
every instance of 'key process parameter' is defined as exactly an instance that is either a 'temporal region' or a 'process profile' or 'quality' and that is 'prescribed by' some 'key process parameter specification'
key process parameter specification
temperature specification for media hold, which is necessary to prevent microbial growth without affecting downstream CQAs; flow rate specification for diafiltration buffer addition, important for maintaining steady-state conditions but not directly impacting product purity;
KeyProcessParameterSpecification(x) → ProcessParameterSpecification(x)
process parameter specification that prescribes a variable which must be tightly controlled to ensure process consistency and that does not directly impact any critical quality attribute
There are insufficient constructs to create necessary and sufficient conditions.
if x is a 'key process parameter specification' then x is a 'process parameter specification'
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 process is designed to function under typical conditions. This range is distinct from the broader ranges, which may include values associated with abnormal operation or alarm conditions. When a process parameter remains within the normal operating range, no alarm is expected to trigger, as the process parameter is considered to be under control.
NormalOperatingRangeValueExpression(x) → ValueExpression(x) ∧ ∃y (ProcessParameterSpecification(y) ∧ continuantPartOfAtAllTimes(x, y)) ∧ ∃z (SetpointValueExpression(z) ∧ hasContinuantPartAtAllTimes(x, z))
value expression that is a range around a set point within which a particular process parameter is expected to vary during normal operation of a process 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 'value expression' and x is a 'continuant part of at all times' some 'process parameter specification' and x 'has continuant part at all times' some 'setpoint value expression'
performance indicator
Yearly sales, monthly throughput, quarterly overall equipment effectiveness, 12-month on-time delivery percentage.
PerformanceIndicator(x) ↔ ∃s(PerfornanceIndicatorSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x) v ProcessCharacteristic(x))
process profile, temporal region, quality or process characteristic prescribed by a performance indicator specification
every instance of 'performance indicator' is defined as exactly an instance that is either a 'temporal region' or a 'process profile' or 'quality' or 'process characterstic' and that is 'prescribed by' some 'performance indicator specification'
performance indicator specification
Target sales this year, target throughput this month, taraget overall equipment effectiveness this quarter, target 12-month on-time delivery percentage.
1) Performance indicators are: Measurable: It’s based on quantifiable data (e.g. percentages, counts, ratios). Goal-oriented: It reflects progress toward a defined objective. Actionable: It provides insight into what’s working and what might need improvement. 2) Also they are typically: S: Specific M: Measurable A: Achievable R: Relevant T: Time bound 3) A performance indicator differs from a process parameter in that it is typically not directly controllable. Instead, it often reflects the combined effect of multiple process parameters. For example, production yield is a performance indicator that may be influenced by parameters such as temperature, pH, and agitation speed.
PerformanceIndicatorSpecification(x) → InformationContentEntity(x) ∧ ∃y ( (TemporalRegion(y) ∨ Quality(y) ∨ ProcessProfile(y) ∨ProcessCharacteristic(y)) ∧ prescribes(x, y) ) ∧ ∃z ( ObjectiveSpecification(z) ∧ isAbout(x, z))
information content entity that prescribes some measurable characteristic whose measurements reflect the effectiveness of an agent, planned process, organization, or piece of equipment with respect to a particular objective
There are insufficient constructs to create necessary and sufficient conditions. As an example there is currently no construct to reflect if a characteristic is measurable
if x is a 'performance indicator specification' then x is an 'information content entity' and x 'prescribes' some 'temporal region' or 'quality' or 'process profile' or 'process characteristic' and x 'is about' some 'objective specification'
Measurable characteritics in this case can be some quality, temporal region, process profile or process characteristic which is reflected in the axiom.
process parameter
agitation speed during the mixing process in a cell culture step; incubation time of the cell expansion process; temperature during the fermentation process; flow rate during the loading phase of a chromatography process; pH of the solution in the neutralization process; residence time in the viral inactivation process
ProcessParameter(x) ↔ ∃s(ProcessParameterSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x))
process profile or temporal region or quality prescribed by a process parameter specification
every instance of 'process parameter' is defined as exactly an instance that is either a 'temporal region' or a 'process profile' or 'quality' and that is 'prescribed by' some 'process parameter specification'
process parameter specification
agitation speed specification for the mixing process in a cell culture step; incubation time specification for the cell expansion process; temperature specification for the fermentation process; flow rate specification for the loading phase of a chromatography process; pH specification for the neutralization process in buffer preparation; and residence time specification for the viral inactivation process
https://www.biophorum.com/wp-content/uploads/bp_downloads/CPV-Case-Study-Interactive-Version.pdf; https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-manufacture-finished-dosage-form-revision-1_en.pdf and ISA88
a material specification for a raw material, which defines material properties rather than process behavior; and a specification stating the amount of glucose to be added to a bioreactor, which is an input specification describing material inputs rather than a process parameter; model number of a chromatography column or chromatography type (affinity)
1) Process parameters must be defined with its target value or acceptable range. A process parameter may be critical or non-critical. 2) Ranges for process parameters are established during process development, and changes to operating ranges will be managed within the quality system. 3) Process parameters are used to describe and control the conditions under which a process operates, ensuring that the process achieves its intended results. 4) Process parameters are essential for defining how a process should be carried out and are typically specified in process documentation or recipes. They provide the necessary details for operators and control systems to maintain the process within desired conditions, supporting consistent product quality and process performance.
ProcessParameterSpecification(x) → InformationContentEntity(x) ∧ ∃y (PlanSpecification(y) ∧ continuantPartOfAtAllTimes(x, y)) ∧ ∃z ((TemporalRegion(z) ∨ ProcessProfile(z) ∨ Quality(z)) ∧ prescribes(x, z))
information content entity that prescribes a monitorable or controllable variable associated with some planned process
There are insufficient constructs to represent monitorable and controlable.
if x is a 'process parameter specification' then x is an 'information content entity' and x is a 'continuant part of at all times' some 'plan specification' and x 'prescribes' some 'temporal region' or 'process profile' or 'quality'
Process parameter specifications are used to prescribe process parameters, which may take the form of process profiles, qualities, or temporal regions. Process profiles may reflect the realization of capabilities inhering in equipment or consumables, such as the agitation speed of an impeller, or describe dynamic properties of participating entities, such as the flow rate of a fluid stream or the sampling frequency in a monitoring subprocess. Temporal parameters, such as incubation time or residence time, are modeled as temporal regions that represent the duration or timing of a process or subprocess. Qualities refer to intrinsic characteristics of process participants, such as temperature, pH, pressure, or concentration, which are constrained or controlled during the process. When prescribed by a specification, these qualities represent targeted or acceptable ranges of measurable features during the process. The axiom that a process parameter specification must prescribe some temporal region, process profile, or quality formally captures the scope of what qualifies as a process parameter.
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 it is typically narrower than the full instrument span. It defines the boundaries for making saleable product, and excursions outside this range are considered process deviations that may require investigation and corrective action.
ProvenAcceptableRangeValueExpression(x) → ValueExpression(x) ∧ ∃y (ProcessParameterSpecification(y) ∧ continuantPartOfAtAllTimes(x, y))
value expression range that has been validated through testing or documented experience and that is a prescribed range 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 'value expression' and x is a 'continuant part of at all times' some 'process parameter specification'
quality attribute
content uniformity of the dosage units in a batch; level of degradation products in the formulation; residual solvent level in the final product; rate or extent of drug release; dissolution capability dosage form; moisture content of the drug product; microbial load in the final product; color of the tablet or capsule; shape of the dosage form; size of the finished unit; odor of the drug product;
QualityAttribute(x) ↔ (Quality(x) ∨ Capability(x)) ∧ ∃s(QualityAttributeSpecification(s) ∧ prescribedBy(x, s))
quality or capability that is prescribed by a quality attribute specification
every instance of 'quality attribute' is defined as exactly an instance of 'quality' or 'capability' that is 'prescribed by' some 'quality attribute specification'
quality attribute specification
content uniformity specification; degradation product specification; residual solvent specification; drug release specification; dissolution specification; moisture content specification; microbial limit specification; color specification; shape specification; size specification; odor specification;
https://www.biophorum.com/wp-content/uploads/bp_downloads/CPV-Case-Study-Interactive-Version.pdf “https://pmc.ncbi.nlm.nih.gov/articles/PMC4070262/pdf/12248_2014_Article_9598.pdf
Specification stating that purification yield must be ≥ 70% - This is a process performance constraint, not a specification for a quality of the product or process intermediate material.
Attributes can be critical or not critical. In pharma criticality of an attribute is primarily based upon the severity of harm to the patient should the product fall outside the acceptable range for that attribute. Probability of occurrence, detectability, or controllability does not impact criticality of an attribute.
QualityAttributeSpecification(x) → OutputObjectiveSpecification(x) ∧ ∃q∃m((Quality(q) ∨ Capability(q)) ∧ (ProcessIntermediateMaterial(m) ∨ MaterialProduct(m)) ∧ ((∃z(MaterialEntity(z) ∧ continuantPartOfAtAllTimes(z, m) ∧ inheresIn(q, z))) ∨ inheresIn(q, m)) ∧ prescribes(x, q))
output objective specification that prescribes some quality, capability, constitution, or composition that a material product or process intermediate material must possess in order to satisfy predefined quality requirements
There are insufficient constructs to create necessary and sufficient conditions. Specifically the constructs for predefined quality requirements are missing.
if x is a 'quality attribute specification' then x is an 'output objective specification' and x 'prescribes' some 'quality' or 'capability' that 'inheres in' either: some 'material entity' that is 'continuant part of at all times' some 'process intermediate material' or 'material product', or that same 'process intermediate material' or 'material product
These specifications may refer to intrinsic physical or chemical properties (such as pH or viscosity), to capabilities (such as binding affinity), or to the identity and proportion of distinguishable components (such as glycoforms, excipients, or host cell proteins). In cases where constitution or composition is relevant, the specification typically should me modeled as a quality that inheres in a continuant part of the material, such as the concentration or proportion of a specific component which is the 'quality of' (inheres in) that specific component.
setpoint value expression
for a residential dwelling temperature control process, the set point might be 72 degrees Fahrenheit during the day and 68 degrees Fahrenheit during the day; 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
The setpoint represents the value of a physical condition that a control system aims to achieve and maintain. The set point is used by the control system as a reference for comparison against the actual measured value of the process parameter. Specifically, a control system performs regulation by actuating one or more final control devices to modify process parameters, thereby driving the process variable toward the set point. Representation of this control behavior will be included in a future version of the ontology
SetpointValueExpression(x) → ValueExpression(x) ∧ ∃y (ProcessParameterSpecification(y) ∧ continuantPartOfAtAllTimes(x, y))
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 'value expression' and x is a 'continuant part of at all times' some 'process parameter specification'