Biopharma 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
agitation rate
an agitation rate of 500 revolutions per minute applied by an impeller in a stirred gas-fermentation vessel; an agitation rate of 120 revolutions per minute applied by a stir bar during buffer preparation; an agitation rate of 30 rocking cycles per minute applied by a rocking bioreactor platform; an agitation rate of 180 shaking cycles per minute applied by an orbital shaker during flask cultivation;
Agitation rate is the rate of imposed mechanical motion used to stir, mix, shake, rock, or otherwise agitate a material. It should be distinguished from the resulting degree of mixing, gas transfer, bubble size distribution, mass transfer performance, or product yield, which may be affected by agitation rate but are not themselves agitation rates. Depending on the agitation mechanism, agitation rate may be expressed in revolutions per minute, cycles per minute, hertz, strokes per minute, or another unit appropriate to the motion.
AgitationRate(x) → RateProcessProfile(x)
rate process profile at which imposed motion is applied to agitate a material
There are insufficient constructs to create necessary and sufficient conditions.
if x is an 'agitation rate' then x is a 'rate process profile'
biological activity
the target-binding biological activity of a monoclonal antibody drug product; the neutralizing biological activity of an antibody drug substance; the enzymatic biological activity of an enzyme therapeutic;
Biological activity is modeled as the capability of a drug substance, drug product, or relevant process intermediate material to produce the biological effect for which it is being evaluated. It should be distinguished from drug potency: biological activity is the capability, while drug potency is the quality that characterizes the degree to which that biological activity is exhibited
BiologicalActivity(x) → Capability(x) ∧ ∃m ((MaterialProduct(m) ∨ ProcessIntermediateMaterial(m)) ∧ capabilityOf(x, m))
capability of a drug substance, drug product, or relevant process intermediate material to achieve a defined biological effect
There are insufficient constructs to create a set of necessary and sufficient conditions.
if x is a 'biological activity' then x is a 'capability' that is the 'capability of' some 'material product' or some 'process intermediate material'
biomass specific productivity
recombinant protein mass produced per hour per gram dry cell weight during microbial fermentation; enzyme activity units produced per hour per gram biomass during an E. coli expression process;
1) In this context, biomass mass is commonly quantified as dry cell mass (e.g., dry cell weight), but may also be quantified using other biomass mass conventions (e.g., wet cell mass) when specified 2) Biomass mass may be the total biomass mass or, when specified, viable biomass mass.
BiomassSpecificProductivity(x) → ManufacturingProcessProductivity(x)
manufacturing process productivity whose magnitude is normalized by biomass mass
if x is a 'biomass specific productivity' then x is a 'manufacturing process productivity'
biomolecule primary structure
the primary structure of a monoclonal antibody heavy chain; the primary structure of a phosphorylated peptide; the primary structure of a methylated DNA molecule; the primary structure of an mRNA molecule; the primary structure of a protein variant with a single amino acid substitution
Biomolecule primary structure may be described together with covalent modifications of particular residues, such as methylation or phosphorylation; these modifications do not change the linear residue order.
BiomoleculePrimaryStructure(x) → Quality(x) ∧ ∃m∃s((DeoxyribonucleicAcid(m) ∨ RibonucleicAcid(m) ∨ Peptide(m) ∨ Protein(m)) ∧ qualityOf(x,m) ∧ BiologicalSequence(s) ∧ concretizesAtAllTimes(x,s) ∧ genericallyDependsOnAtSomeTime(s,m))
quality of a DNA, RNA, peptide, or protein molecule that is determined by the linear order of its nucleotide or amino acid residues
There are insufficient constructs for creating a set of necessary and sufficient conditions
if x is a 'biomolecule primary structure' then x is a 'quality' that is the 'quality of' some 'deoxyribonucleic acid', 'ribonucleic acid', 'peptide', or 'protein' m and x 'concretizes at all times' some 'biological sequence' that 'generically depends on at some time' that same m
carbon dioxide evolution rate
carbon dioxide evolution rate of a CHO fed-batch culture calculated from exhaust gas carbon dioxide concentration and gas flow rate;
CarbonDioxideEvolutionRate(x) → RateProcessProfile(x) ∧ ∃p(Process(p) ∧ processProfileOf(x,p) ∧ ∃c(CellCulture(c) ∧ hasParticipantAtSomeTime(p,c)))
rate process profile at which carbon dioxide is produced by cells within a cell culture
if x is a 'carbon dioxide evolution rate' then x is a 'rate process profile' that is the 'process profile of' some 'process' that 'has participant at some time' some 'cell culture'
cell culture doubling time
the cell culture doubling time of a CHO cell population during seed train expansion; the cell culture doubling time calculated from viable cell density measurements during exponential growth; the cell culture doubling time of an E. coli culture during fermentation;
CellCultureDoublingTime(x) → TemporalInterval(x)
temporal interval over which the size of a cell population doubles
if x is a 'cell culture doubling time' then x is a 'temporal interval'
cell population growth rate
cell population growth rate of a CHO cell population during fed-batch cultivation; viable cell population growth rate during seed train expansion;
CellPopulationGrowthRate(x) → PopulationGrowthRate(x) ∧ ∃c (CellPopulation(c) ∧ hasParticipantAtSomeTime(x, c))
population growth rate of a cell population with respect to change in its number of cells
if x is a 'cell population growth rate' then x is a 'population growth rate' that 'has participant at some time' some 'cell population'
cell specific productivity
monoclonal antibody mass produced per viable cell per day during a CHO fed-batch culture; recombinant protein amount produced per cell per hour during a mammalian cell culture process;
CellSpecificProductivity(x) → ManufacturingProcessProductivity(x)
manufacturing process productivity whose magnitude is normalized by cell amount, typically viable cell amount
if x is a 'cell specific productivity' then x is a 'manufacturing process productivity'
critical material attribute
manganese concentration in a chemically defined medium whose variation can affect glycosylation of the output material; glucose concentration in a feed medium whose variation can affect glycan profile of the output material;
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.
CriticalMaterialAttribute(x) ↔ (Quality(x) ∨ Capability(x)) ∧ ∃s(InputCriticalMaterialAttributeSpecification(s) ∧ prescribedBy(x, s))
quality or capability that is prescribed by an input critical material attribute specification
every instance of 'critical material attribute' is defined as exactly an instance of 'quality' or 'capability' that is 'prescribed by' some 'input critical material attribute specification'
critical process parameter
pH during the viral inactivation process; temperature during the fermentation process; agitation speed during the cell culture mixing step
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 throughout the manufacturing process and as such are measured on attributes of both final products and intermediate materials generated during the product production process.
CriticalQualityAttributeSpecification(x) → QualityAttributeSpecification(x)
quality attribute specification that prescribes some quality, capability, constitution, or composition deemed critical to ensuring the 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'
culture split ratio
1:3 culture split ratio in which one flask of cell culture is divided to establish three resulting flasks; 1:5 culture split ratio in which one part of source cell culture is transferred according to a passaging protocol and fresh medium is added to establish the resulting culture; 1:10 culture split ratio used during suspension-cell passaging to reduce culture density for continued growth; 1:2 culture split ratio in which a recovered culture is divided to establish two resulting cultures
ratio of a source cell culture to one or more resulting cell cultures established from that source culture during passaging
if x is a 'culture split ratio' then x is a 'ratio'
dissolution rate
dissolution rate of sodium chloride in water during buffer preparation; dissolution rate of powdered cell culture medium in water during media preparation; dissolution rate of sucrose in an aqueous reaction mixture; dissolution rate of an active pharmaceutical ingredient during formulation development;
https://www.fda.gov/media/148472/download and https://www.ncbi.nlm.nih.gov/books/NBK431100/#:~:text=%5B1%5D%5B2%5D%5B,/L%20or%20g/L
Dissolution rate describes how fast a solute enters solution under defined conditions and is typically expressed as an amount (or concentration) dissolved per unit time. It is a non-equilibrium, time-dependent behavior that precedes attainment of the solubility limit (equilibrium saturation). Dissolution occurs at the solid–liquid interface, where solvent contacts the solid surface and solute molecules detach and diffuse into the bulk liquid. The observed rate is governed by the solute’s surface area and physical form (e.g., particle size and wetting), solute–solvent interactions, temperature, mixing/agitation (hydrodynamics), and mass-transfer factors such as diffusion boundary layer thickness, as well as the driving force to saturation (difference between the saturation concentration and the current bulk concentration). Experimentally, dissolution rate is determined by monitoring how dissolved concentration (or dissolved mass) changes over time under a specified method, and it is used to evaluate and control how quickly solid components (e.g., salts, buffers, active ingredients) reach the required dissolved state in process preparation and formulation contexts.
DissolutionRate(x) → RateProcessProfile(x) ∧ ∃s (Solute(s) ∧ hasParticipantAtSomeTime(x, s)) ∧ ∃p (Process(p) ∧ processProfileOf(x, p) ∧ ∃v (Solvent(v) ∧ hasParticipantAtSomeTime(p, v)))
rate process profile at which a solute dissolves in a solvent
if x is a 'dissolution rate' then x is a 'rate process profile' that 'has participant at some time' some 'solute' and is the 'process profile of' some 'process' that 'has participant at some time' some 'solvent'
drug potency
the drug potency of a monoclonal antibody drug product determined by a cell-based neutralization assay; the drug potency of an enzyme therapeutic drug substance determined by an enzymatic activity assay; the drug potency of a cytokine drug product determined by a receptor-mediated bioassay; the drug potency of a vaccine antigen lot determined by an immunological potency assay
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-development-production-characterisation-and-specification-monoclonal-antibodies-and-related-products-revision-1_en.pdf and https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-6-b-test-procedures-and-acceptance-criteria-biotechnologicalbiological-products-step-5_en.pdf
According to ICH Q6B, a relevant validated potency assay should ordinarily be part of the specification for a biotechnological or biological drug substance or drug product. In justified cases, physicochemical methods may be used for quantitative assessment when sufficient physicochemical information is available, an appropriate correlation with biological activity has been demonstrated, and the manufacturing history or corresponding cross-stage assay strategy supports their use. Potency should be distinguished from a simple determination of product quantity because it characterizes the degree of the relevant biological activity.
DrugPotency(x) → Quality(x) ∧ ∃m∃a((MaterialProduct(m) ∨ ProcessIntermediateMaterial(m)) ∧ qualityOf(x,m) ∧ BiologicalActivity(a) ∧ capabilityOf(a,m) ∧ specificallyDependsOn(x,a))
quality of a drug substance, drug product, or relevant process intermediate material that is the quantitative degree of its biological activity
if x is a 'drug potency' then x is a 'quality' that is the 'quality of' some 'material product' or 'process intermediate material' m and 'specifically depends on' some 'biological activity' that is the 'capability of' that same m
flow rate
mass flow rate of air supplied to a bioreactor sparger; mass flow rate of carbon dioxide in an exhaust gas stream; volumetric flow rate of buffer through a chromatography column; volumetric flow rate of permeate through an ultrafiltration membrane
FlowRate(x) → RateProcessProfile(x) ∧ ∃m(MaterialEntity(m) ∧ hasParticipantAtSomeTime(x,m))
rate process profile at which material is transported across a specified surface or boundary
if x is a 'flow rate' then x is a 'rate process profile' that 'has participant at some time' some 'material entity'
input critical material attribute specification
the CMA specification for manganese concentration in a chemically defined medium when variation in manganese concentration can affect glycosylation of the output material; the CMA specification for glucose concentration in a feed medium when variation in glucose concentration can affect glycan profile of the output material; the CMA specification for culture medium osmolality when variation in osmolality can affect charge variant profile or aggregation level of the output material;
InputCriticalMaterialAttributeSpecification(x) → InputMaterialAttributeSpecification(x)
input material attribute specification that prescribes some quality, capability, constitution, or composition whose variation can have a significant impact on the quality of the output material
if x is an 'input critical material attribute specification' then x is an 'input material attribute specification'
input material attribute
pH of a buffer used for elution; vitamin concentration of a cell culture medium used in a production culture process;
InputMaterialAttribute(x) ↔ (Quality(x) ∨ Capability(x)) ∧ ∃s(InputMaterialAttributeSpecification(s) ∧ prescribedBy(x, s))
quality or capability that is prescribed by an input material attribute specification
every instance of 'input material attribute' is defined as exactly an instance of 'quality' or 'capability' that is 'prescribed by' some 'input material attribute specification'
input material attribute specification
the input material attribute specification for pH of a buffer used as an input material; the input material attribute specification for osmolality of a culture medium used as an input material; the input material attribute specification for glucose concentration in a feed medium;
https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf and https://pmc.ncbi.nlm.nih.gov/articles/PMC4070262/
Input materials can be raw materials, process intermediate materials, or production consumables, which is reflected in the prescription axiom
InputMaterialAttributeSpecification(x) → InputSpecification(x) ∧ ∃a (prescribes(x, a) ∧ (Quality(a) ∨ Capability(a)) ∧ ∃m (inheresIn(a, m) ∧ ((RawMaterial(m) ∨ ProcessIntermediateMaterial(m) ∨ ProductionConsumable(m)) ∨ (MaterialEntity(m) ∧ ∃w (continuantPartOfAtAllTimes(m, w) ∧ (RawMaterial(w) ∨ ProcessIntermediateMaterial(w) ∨ ProductionConsumable(w)))))))
input specification that prescribes some quality, capability, constitution, or composition of an input material that can have an impact on process performance or on the quality of the output material
if x is an 'input material attribute specification' then x is an 'input specification' that 'prescribes' some 'quality' or 'capability' that 'inheres in' either some 'raw material', 'process intermediate material', or 'production consumable', or in some 'material entity' that is a 'continuant part of at all times' some 'raw material', 'process intermediate material', or 'production consumable'
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 (KeyPerformanceIndicatorSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x) ∨ 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', 'process profile', 'quality', or 'process characteristic' and that is 'prescribed by' some 'key performance indicator specification'
key performance indicator specification
final harvest titer specification for the production batch, measured in pooled harvested cell culture fluid at completion of harvest, with a target range of 3.5 to 5.0 grams per liter; viral clearance log reduction value specification for the purification step, calculated from the viral loads measured before and after the step, with a target of at least 4.0; batch release cycle time specification for the production batch, measured from completion of manufacturing to authorization of the batch for release, with a target of no more than 10 calendar days
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 (bio)pharmaceutical manufacturing, some process-focused KPIs may be related to CQAs and influenced by CPPs. Such KPIs can provide evidence of process consistency, reproducibility, or performance and can support assessment of whether manufacturing steps are proceeding as expected. Other KPIs may address operational performance, such as throughput, cycle time, equipment utilization, or schedule adherence, without being directly related to CQAs or CPPs.
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, temporal region, or quality prescribed by a key process 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
if x is a 'key process parameter specification' then x is a 'process parameter specification'
manufacturing process productivity
monoclonal antibody mass produced per day during a fed-batch manufacturing process; recombinant enzyme activity units produced per hour during a microbial fermentation process;
Manufacturing process productivity concerns production of process intermediate material or material product per unit time. It should be distinguished from labor productivity, equipment effectiveness, process yield, resource efficiency, and economic productivity.
ManufacturingProcessProductivity(x) → RateProcessProfile(x) ∧ ∃m∃p((ProcessIntermediateMaterial(m) ∨ MaterialProduct(m)) ∧ ManufacturingProcess(p) ∧ hasParticipantAtSomeTime(x,m) ∧ processProfileOf(x,p) ∧ hasSpecifiedOutput(p,m))
rate process profile at which process intermediate material or material product is produced in a manufacturing process under specified conditions
if x is a 'manufacturing process productivity' then x is a 'rate process profile' that 'has participant at some time' some 'process intermediate material' or 'material product' m and is the 'process profile of' some 'manufacturing process' that 'has specified output' that same m
mass flow rate
mass flow rate of air supplied to a bioreactor sparger; mass flow rate of carbon dioxide in an exhaust gas stream; mass flow rate of buffer through a chromatography column; mass flow rate of liquid feed through a process line
flow rate whose magnitude is determined by the mass of material transported across the specified surface or boundary per unit of elapsed time
if x is a 'mass flow rate' then x is a 'flow rate'
metabolite uptake rate
glucose uptake rate by a CHO cell population during fed-batch cultivation; glutamine uptake rate by a mammalian cell culture during early growth phase; amino acid uptake rate by a cell population during a nutrient-limited culture process;
MetaboliteUptakeRate(x) → RateProcessProfile(x) ∧ ∃p(Process(p) ∧ processProfileOf(x,p) ∧ ∃c(CellCulture(c) ∧ hasParticipantAtSomeTime(p,c))) ∧ ∃me(MolecularEntity(me) ∧ hasParticipantAtSomeTime(x,me))
rate process profile at which a metabolite is taken up by cells within a cell culture
if x is a 'metabolite uptake rate' then x is a 'rate process profile' that is the 'process profile of' some 'process' that 'has participant at some time' some 'cell culture' and x 'has participant at some time' some 'molecular entity'
normalized flow rate
permeate flow rate normalized to membrane area during ultrafiltration, expressed as L m⁻² h⁻¹; a perfusion culture operated at 1 VVD, meaning one working volume of medium is exchanged over one day;
The reference quantity used for normalization may be, for example, membrane area, working volume, or cell amount. The resulting normalized flow rate may therefore have different units depending on the reference quantity. Normalization in this sense does not refer to conversion of a gas flow rate to standard or normal temperature and pressure conditions.
flow rate whose magnitude is expressed relative to a specified reference quantity
if x is a 'normalized flow rate' then x is a 'flow rate'
oxygen uptake rate
oxygen uptake rate of a CHO cell culture during fed-batch cultivation; oxygen uptake rate of an E. coli fermentation during exponential growth;
OxygenUptakeRate(x) → RateProcessProfile(x) ∧ ∃o (DioxygenMolecule(o) ∧ hasParticipantAtSomeTime(x, o)) ∧ ∃p (Process(p) ∧ processProfileOf(x, p) ∧ ∃c (CellCulture(c) ∧ hasParticipantAtSomeTime(p, c)))
rate process profile at which oxygen is consumed by cells within a cell culture
if x is an 'oxygen uptake rate' then x is a 'rate process profile' that 'has participant at some time' some 'dioxygen molecule' and is the 'process profile of' some 'process' that 'has participant at some time' some 'cell culture'
performance indicator
Yearly sales, monthly throughput, quarterly overall equipment effectiveness, 12-month on-time delivery percentage.
PerformanceIndicator(x) ↔ ∃s (PerformanceIndicatorSpecification(s) ∧ prescribedBy(x, s)) ∧ (TemporalRegion(x) ∨ ProcessProfile(x) ∨ Quality(x) ∨ 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', 'process profile', 'quality', or 'process characteristic' and that is 'prescribed by' some 'performance indicator specification'
performance indicator specification
annual sales revenue specification for the organization for the applicable fiscal year, with a target of at least USD 10 million; monthly production throughput specification for the manufacturing line, expressed as conforming units completed per operating hour, with a target range of 120 to 150 units per hour; quarterly overall equipment effectiveness specification for the production line, calculated as availability multiplied by performance multiplied by quality, with a target of at least 85 percent; rolling 12-month on-time delivery percentage specification for customer orders, calculated from orders delivered on or before the committed delivery date relative to the applicable orders in the reporting period, with a target of at least 95 percent
https://database.ich.org/sites/default/files/Q10%20Guideline.pdf and ISO 22400
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 characteristics in this case can be some quality, temporal region, process profile or process characteristic which is reflected in the axiom.
planned process yield
the yield of a purification step calculated as purified protein mass relative to protein mass loaded onto the column; the yield of a synthesis process calculated as actual product amount relative to theoretical product amount; the yield of a harvest process calculated as recovered product amount relative to product amount present before harvest;
The specified reference quantity is a quantity associated with a participant in the planned process, such as an input quantity, starting-material quantity, limiting-component quantity, theoretical output quantity, expected output quantity, or intermediate-material quantity. Planned process yield should be distinguished from the output quantity itself: 8 g of purified protein is an output quantity, whereas 80% yield is a process characteristic relating the output quantity to a specified reference quantity.
PlannedProcessYield(x) → ProcessCharacteristic(x) ∧ ∃p (PlannedProcess(p) ∧ processCharacteristicOf(x, p) ∧ ∃o (MaterialEntity(o) ∧ hasSpecifiedOutput(p, o)))
process characteristic that is the ratio of a specified output quantity produced in a planned process to a specified reference quantity associated with that planned process
if x is a 'planned process yield' then x is a 'process characteristic' that is the 'process characteristic of' some 'planned process' that 'has specified output' some 'material entity'
population growth rate
population growth rate of a CHO cell population during fed-batch cultivation; population growth rate of an E. coli population during exponential growth; viable cell population growth rate during seed train expansion; microbial population growth rate during fermentation
PopulationGrowthRate(x) → RateProcessProfile(x)
rate process profile that captures change in the size of a population per unit of elapsed time
if x is a 'population growth rate' then x is a 'rate process profile'
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; 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 specified with their 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 controllable.
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.
product titer
titer of 3.2 g/L monoclonal antibody in a cell culture harvest on day 14; titer of 2.8 g/L monoclonal antibody in a clarified harvest after depth filtration; titer of 12 g/L monoclonal antibody in a protein A eluate after elution;
1) In this context, ‘target product’ denotes the specified substance of interest for the manufacturing objective and may be a drug substance, process intermediate, or other designated active or functional component. Product titer is evaluated at a specified time point and may vary over time due to dilution, degradation, or changes in process volume. 2) Here, process material means a material that is being transformed or modified in a manufacturing process, including process intermediate material and the material product. It does not include raw materials or consumables.
ProductTiter(x) → Concentration(x) ∧ ∃m ((ProcessIntermediateMaterial(m) ∨ MaterialProduct(m)) ∧ qualityOf(x, m))
concentration of a process intermediate material or material product that is determined by the amount of a target product in that process intermediate material or material product per unit volume
if x is a 'product titer' then x is a 'concentration' that is the 'quality of' some 'process intermediate material' or some 'material product'
protein secondary structure
the alpha-helical secondary structure of a protein; the beta-sheet secondary structure of an antibody domain; the turn structure connecting two beta strands in a protein; the loop structure in an enzyme active-site region; the altered secondary structure of a protein after thermal stress
ProteinSecondaryStructure(x) → PhysicalStructure(x) ∧ ∃p (Protein(p) ∧ qualityOf(x, p))
physical structure of a protein that is the local three-dimensional arrangement of segments of its polypeptide backbone, commonly characterized by recurring backbone hydrogen-bonding patterns
if x is a 'protein secondary structure' then x is a 'physical structure' that is the 'quality of' some 'protein'
protein tertiary structure
the folded three-dimensional structure of a single-domain antibody molecule; the folded structure of an antibody-derived single-chain variable fragment; the folded structure of a recombinant human growth hormone molecule; the folded three-dimensional structure of an erythropoietin molecule stabilized by disulfide bonds and glycosylation; the compact globular structure of a myoglobin molecule; the beta-barrel structure of a green fluorescent protein molecule
ProteinTertiaryStructure(x) → PhysicalStructure(x) ∧ ∃p (Protein(p) ∧ qualityOf(x, p))
physical structure of a protein that is the overall three-dimensional arrangement arising from the conformation of its polypeptide chain, including the spatial organization of its secondary structure elements relative to one another
if x is a 'protein tertiary structure' then x is a 'physical structure' that is the 'quality of' some 'protein'
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; dissolution capability of a 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 and 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' that 'prescribes' some 'quality' or 'capability' q that either 'inheres in' some 'process intermediate material' or 'material product' m, or 'inheres in' some 'material entity' z that is a 'continuant part of at all times' m
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 be 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.
rate process profile
glucose consumption rate during a fed-batch cell culture process; product formation rate during a fermentation process; biomass formation rate during microbial cultivation; feed addition rate during a material feeding process; number of Tetra Pak cartons filled per hour by a packaging line; rate of potable water output from a water treatment plant
http://purl.allotrope.org/ontologies/process#AFP_0003454 and http://purl.allotrope.org/ontologies/result#AFR_0000954 and https://philpapers.org/archive/SMICPA-5.pdf
An attribute captured by a rate process profile may itself be represented by another process profile, as when an acceleration profile captures variation in a speed profile per unit of elapsed time.
RateProcessProfile(x) → ProcessProfile(x)
process profile that captures variation in an attribute of a process or one of its participants per unit of elapsed time
This term is expected to be further formalized in the IOF Core.
if x is a 'rate process profile' then x is a 'process profile'
specific cell population growth rate
specific growth rate of an E. coli population during exponential growth; specific cell population growth rate of a CHO cell population during seed train expansion; specific growth rate calculated from viable cell density measurements over a defined interval;
SpecificCellPopulationGrowthRate(x) → CellPopulationGrowthRate(x)
cell population growth rate whose magnitude is normalized by the size of that cell population
if x is a 'specific cell population growth rate' then x is a 'cell population growth rate'
total material added
a viral inactivation process has total material added of 0.5 L acid solution from a single bolus addition for pH adjustment; a production culture process has total material added of 73 g galactose from multiple bolus additions during the production phase; a chromatography column equilibration process has total material added of 6 column volumes of equilibration buffer
Total material added is evaluated over one or more material addition events in a planned process. The added material may be supplied in a single addition, multiple bolus additions, or continuous feeding. The quantity may be expressed as mass, volume, amount of substance, or another specified material quantity. This characteristic should be distinguished from addition rate or feed rate, which describe the rate of material addition.
TotalMaterialAdded(x) → ProcessCharacteristic(x) ∧ ∃p(PlannedProcess(p) ∧ processCharacteristicOf(x,p))
process characteristic that is the total quantity of a particular material that is added during a particular process
if x is a 'total material added' then x is a 'process characteristic' that is the 'process characteristic of' some 'planned process'
vessel volumes per day
a perfusion culture operated at 1 VVD, meaning one working volume of medium is exchanged over one day; a 2 L working-volume bioreactor with 2 L of medium exchanged per day, corresponding to 1 VVD; a perfusion process reported as 0.5 VVD when the daily exchanged medium volume is half of the working volume;
VVD is typically intended to represent the total medium exchange normalized by working volume. In some uses, VVD is computed only from the spent-medium outlet flow, while other withdrawals such as sampling, bleed, or additional removal streams are not included. When this narrower accounting is used, the reported VVD can underestimate the true total exchange and can lead to misleading comparisons unless the boundary is made explicit.
VesselVolumesPerDay(x) → NormalizedFlowRate(x)
normalized flow rate whose magnitude is the volume of medium exchanged per day relative to the working volume
if x is a 'vessel volumes per day' then x is a 'normalized flow rate'
volumetric flow rate
volumetric flow rate of buffer through a chromatography column; volumetric flow rate of permeate through an ultrafiltration membrane; volumetric flow rate of liquid feed through a process line;
flow rate whose magnitude is determined by the volume of material transported across the specified surface or boundary per unit of elapsed time
if x is a 'volumetric flow rate' then x is a 'flow rate'
volumetric productivity
monoclonal antibody mass produced per liter of culture working volume per day during a CHO fed-batch process; recombinant protein mass produced per liter of microbial fermentation volume per hour; viral vector genome copies produced per liter of culture volume per day; enzyme activity units produced per liter of culture working volume per hour;
In upstream biopharma manufacturing process volume is typically the culture working volume
VolumetricProductivity(x) → ManufacturingProcessProductivity(x)
manufacturing process productivity whose magnitude is normalized by a specified reference volume of process material
if x is a 'volumetric productivity' then x is a 'manufacturing process productivity'
working volume
the 120 L working volume of a CHO cell culture in a 250 L bioreactor during a fed-batch cultivation process; the 3 L working volume of buffer in a mixing vessel during buffer preparation;
Working volume is the actual volume of process material present in a vessel during a planned process. It should be distinguished from working volume capacity, which is a capacity of the vessel, and from total vessel volume, which is a geometric volume of the vessel. For example, a bioreactor may have a total vessel volume of 250 L, a working volume capacity of 50–200 L, and a working volume of 120 L during a particular cell cultivation process
WorkingVolume(x) → Volume(x) ∧ ∃m (MaterialEntity(m) ∧ qualityOf(x, m) ∧ ∃p (PlannedProcess(p) ∧ participatesInAtSomeTime(m, p)))
volume that is a quality of process material and that is the volume occupied by that process material in a vessel during a planned process
if x is a 'working volume' then x is a 'volume' that is the 'quality of' some 'material entity' that 'participates in at some time' some 'planned process'
yield per biomass
the yield per biomass of a microbial fermentation calculated as recombinant protein mass produced per gram of biomass formed; the yield per biomass of an E. coli enzyme expression process calculated as enzyme activity units recovered per gram dry cell weight; the yield per biomass of a yeast production process calculated as product mass produced per biomass amount accumulated during cultivation;
YieldPerBiomass(x) → PlannedProcessYield(x)
planned process yield that characterizes the quantity of a specified material output produced in a planned process relative to the quantity of biomass formed in that planned process
if x is a 'yield per biomass' then x is a 'planned process yield'
yield per substrate
the yield per substrate of a microbial fermentation calculated as recombinant protein mass produced per gram of glucose consumed; the yield per substrate of a levansucrase reaction calculated as levan mass produced per gram of sucrose consumed; the yield per substrate of an E. coli enzyme expression process calculated as enzyme activity units recovered per gram of glycerol consumed;
YieldPerSubstrate(x) → PlannedProcessYield(x) ∧ ∃p∃m(PlannedProcess(p) ∧ MaterialEntity(m) ∧ processCharacteristicOf(x,p) ∧ hasInput(p,m))
planned process yield that characterizes the quantity of a specified material output produced in a planned process relative to the quantity of a specified substrate consumed in that planned process
if x is a 'yield per substrate' then x is a 'planned process yield' that is the 'process characteristic of' some 'planned process' that 'has input' some 'material entity'
has performance indicator
manufacturing organization has performance indicator 12-month on-time delivery percentage; sales organization has performance indicator yearly sales; production culture process has performance indicator product titer; chromatography purification process has performance indicator product recovery
relation between an agent, planned process, organization, or piece of equipment and a performance indicator indicating that measurements of the indicator are used to evaluate the effectiveness of that entity with respect to a particular objective
has process parameter
cell culture expansion process has process parameter pH; production culture process has process parameter temperature; production phase has process parameter agitation speed
relation between a planned process and a process parameter indicating that the parameter is monitored or controlled during the execution of that planned process
When this relation is used, it implies that the plan specification (e.g., a rec:RecipeProcessElement or other process plan) that prescribes the planned process must include as a continuant part the corresponding process parameter specification that prescribes the monitored or controlled parameter. In other words, the monitoring or control of a process parameter at execution level must be traceable to a parameter specification at the plan level via bfo:continuantPartOf
is performance indicator of
12-month on-time delivery percentage is performance indicator of a manufacturing organization; yearly sales is performance indicator of a sales organization; product titer is performance indicator of a production culture process; product recovery is performance indicator of a chromatography purification process
relation between a performance indicator and an agent, planned process, organization, or piece of equipment indicating that measurements of the indicator are used to evaluate the effectiveness of that entity with respect to a particular objective
is process parameter of
pH is process parameter of a cell culture expansion process; temperature is process parameter of a production culture process; agitation speed is process parameter of a production phase
relation between a process parameter and a planned process indicating that the parameter is monitored or controlled during the execution of that planned process