Introduction

The topic of ingredients and the various roles an ingredient may play is a critical pattern in the IDMP ontology. The concept of something that is an ingredient is only meaningful in the context of the thing that it is an ingredient of (i.e., as a part of a product, product specification/recipe, story, etc.). The concept of ingredient is dependent on (1) a mapping to the thing that fills the role of being that ingredient (e.g., a pure substance), (2) the strength of that substance in the context of the "thing that it is an ingredient of", (3) an amount or percentage representing how much of that ingredient is required (which might be optional depending on whether the ingredient is referenced as part of a specific recipe or another context), and (4) a mapping to the thing that it is an ingredient of (the product, recipe, or something else). In other words, the concept, of ingredient, is not independent — it depends on other things, and would not exist outside of the context of a pharmaceutical product, manufactured item, recipe, or some other composite thing that has ingredients.

How much of a substance is consumed via its use in a product or item is a property of the relationship between the substance, its role as an ingredient, and the thing that consumes it per the IDMP 11238 and 11615 standards. The dependency is modeled in the ontology in two ways — one that relates the substance to the product of which it is a part (i.e., the product composition), and secondly, as a reified relationship, called ingredient (which is a role in description logic / OWL modeling terms), with an inheritance hierarchy refining the various roles in the product composition, that the ingredient has.

Related Competency Questions

UC-1, CQ 3-1: What is the basis of strength for <substance x> in <product y>?
UC-1, CQ 6: Which investigational/authorized medicinal products contain the substance <$Substance> or its active moiety?
UC-1, CQ 7: Which manufactured items contain substance <x> as an ingredient of type “active”?

Relation to ISO Standards

The figure included below is taken from the ISO 11615 standard:

In the diagram below, there appears to be no direct relationship between an ingredient and its strength in the context of some medicinal or pharmaceutical product (although the subject matter experts (SME) involved in the IDMP-O project believe this is incorrect). On the manufacturing floor, either the substance is used as an ingredient of a process with a specific strength (such as a solvent) or is combined with other things with a specific strength, regardless of how much is consumed via the process of manufacturing a specific product. Below the diagram the standard states, "There shall be one instance of the ingredient class for each actual ingredient of either the manufactured item or pharmaceutical product, as appropriate." With respect to ingredient role, it also says, "The role of the ingredient as part of the manufactured item/pharmaceutical product shall be specified using an appropriate controlled vocabulary. The controlled term and a term identifier shall be specified." For the substance class represented in the diagram, in section 9.7.2, where this material appears, it also says, "A substance can be specified for an ingredient in the role described. The substance shall be described in accordance with ISO 11238 and ISO/TS 19844 and its resulting terminology. A term and a term identifier shall be used.".

So this provides some hints: there is no direct relationship between ingredient and strength in the specification itself, only an indirect relationship via substance. However, none of the relationships between the boxes are named. The model appears to be a physical model for a relational implementation, where the lines are intended to represent foreign keys, not a graph model where relationships act as edges to be traversed to connect the dots. Further evidence of this includes the presence of (1) the notion of a measurement point, and (2) the concept of an association with one or more country codes, defined as "The country or countries for which the strength range (presentation) and (concentration) and associated measurement point are valid can be specified using values from the ISO 3166-1 alpha-2 codes. If a measurement point is specified, one or more countries shall be described as applicable." This is clearly shorthand notation. The relationship between the strength of some substance when it plays the role of an ingredient in a product and a country should be closer to "the strength (presentation and/or concentration) of a substance with respect to a specific manufactured item or pharmaceutical product, as approved through some marketing authorization, in a jurisdiction that has a geographic reach of some region(s) that is identified via some code." Many similar shortcuts occur throughout the specification, but for representing ingredients and related concepts, these are relevant.

The section that follows, 9.8, also says that a device can be an ingredient. Thus, making ingredient a direct subclass of substance, rather than as a role that a substance can fill, would disallow modeling a device as an ingredient. The same diagram, Figure 12, also appears in Figure D.1 in Annex D of ISO/TS 20443:2017. Further, in section D.2.4, the standard states that "A substance can be specified for each ingredient role described." This implies that from a modeling perspective, if one has a product composition with various ingredient roles, there should be a link from the role to the substance that fills that role in the product. In the ontology, the node in the graph representing that connection is named "ingredient", per the standard and diagram above.

Looking further into the context of these definitions, the TS 20443 implementation guide includes the following:

In this diagram (Figure 10 — Investigational Medicinal Products detailed diagram (full model)), there are connections between either a pharmaceutical product or manufactured item to an ingredient, and from an ingredient to a substance or specified substance, but again, no direct link to the strength details. The notion of an "ingredient" here, is the glue connecting a pharmaceutical product to the ingredients that are used in the manufacture of or are part of it, where the relationships are specified as ingredients (roles) that each of the substances plays in that product.

Note that the specification also implies that a device is an ingredient as mentioned, but also says: "The pharmaceutical product may be associated with a device class, which represents information about any integral device to support the administration of the product, and therefore is of type “integrated device”. In this case, the device is in effect an “ingredient” of the pharmaceutical product. The device can have a set of physical characteristics and other characteristics associated with it. ISO 11615:2017(E) Page 55."

Corner cases considered by the subject matter experts include:

Question: Can multiple substances be used to fill the same ingredient role in a given product, i.e., are they substitutable (the diagram says no — there can only be zero or one substance filling the ingredient role)? Can two distinct substances, foo and bar, interchangeably play the same role of active ingredient in a product that is made by a specific manufacturer under a specific marketing authorization (ignoring cases that have multiple active ingredients)? It is likely that two distinct substances could play a different role interchangeably, such as some excipient role, although perhaps not in the case of an active ingredient. The current model allows this, i.e., hasActiveIngredient is not functional at present. Answer: Currently no. If you change the substance it is a different product, even if it has the same pharmacological effect. This reinforces the notion that ingredient is a dependency.
Question: Can the same substance in the same or different amounts play two different roles in the same product, for example, the same chemical substance with the same molecular structure be an active ingredient and an excipient in the same pharmaceutical product? Answer: No

Modeling Pattern

The resulting partial, high-level model using a knowledge graph modeling approach corresponding to Figure 12, above, with some details elided, is as follows:

Figure 1. Ingredients, substances and products — high-level view

Note that in this view, and in general, the concept of ingredient is a dependent concept, meaning that it can only exist in the context of a particular product composition (recipe for a product, or in some other reified relation, such as in a formula used as a part of some manufacturing process). Table 1, below, itemizes the more granular ingredient roles specified in the ISO/TS 20443 implementation guide, clause D.2.1. Further, a substance might play a role other than that of an ingredient included in a manufactured item or pharmaceutical product, such as something used as an ancillary part of a manufacturing process. The model shown above accommodates both cases.

Role	Code	Description
Any	INGR	Ingredient not otherwise specified, used in cases of devices or foods where further classification is not common.
Active	ACTI	Active ingredient — ingredient that has pharmacological action. Use only if the basis of strength cannot be specified; otherwise, use ACTIB, ACTIM, or ACTIR.
Active	ACTIB	Active ingredient, where the entire substance is the basis of strength, e.g., propanolol hydrochloride quantified as the propranolol hydrochloride salt.
Active	ACTIM	Active ingredient, where the active moiety is the basis of strength, e.g., 287 mg amoxicillin trihydrate equivalent to 250 mg anhydrous amoxicillin. NOTE Require stoichiometric relationship between the active ingredient and BOSS.
Active	ACTIR	Active ingredient, where another reference substance is the basis of strength, e.g., metoprolol succinate quantified by the amount of metoprolol tartrate with the equal amount of metoprolol active moiety.
Adjuvant	ADJV	Adjuvant — ingredient that augments or promotes the pharmacological effect of the active ingredient(s) without itself being considered active (typically used with vaccines)
Inactive	IACT	Inactive ingredient, i.e., ingredients added for a purpose other than the intended pharmacological action.
Inactive	COLR	Colour ingredient — ingredient added to alter the colour appearance.
Inactive	FLVR	Flavour ingredient — ingredient added to alter the taste of the product.
Inactive	PRSV	Preservative ingredient — ingredient added to delay the risk of the product’s spoiling.
Inactive	STBL	Stabiliser ingredient — ingredient added to keep the mixture homogenic (e.g., prevent the phases of an emulsion to separate).
Inactive	MECH	Mechanical ingredient — ingredient which, as a whole, lends a spatial structure to the product, which structure is meaningful to the delivery of the pharmacologically active ingredients near the target site. For example, a collagen matrix used as a base for trans-planting skin cells. NOTE: Such ingredient has a function other than merely delivering the pharmacologically active substances into a systemic compartment (such as, for example, an ordinary capsule would have.)
Inactive	BASE	The base of a preparation, i.e., water, vaseline, ethanol.
Inactive	ADTV	Any additive added, use only when there is no described pharmacological action and classification as merely “inactive” ingredient is not appropriate.
Inactive	CNTM	Contaminant — ingredient whose presence is not intended but may not be reasonably avoided given the circumstances of the mixture's nature or origin.

Table 1: ingredient roles (classCodes). From ISO/TS 20443:2017, pages 112–113, in line with corresponding HL7 SPL specifications.

The roles identified above extend the ingredient class, with the codes expressed as a controlled vocabulary with code elements mapped to them. Figure 2, below, shows how the codes map to some of the roles, and how the model for ingredient corresponds to Figure 12 from the IDMP standard. Each of the roles specified in the IDMP standard will be subclasses of ingredient, signified by the proper code, and additional semantics for those roles, such as the connections to reference substances can be modeled directly for those roles that require that link in the graph. Elements in white are classes in the ontology. Elements in blue are instances, in this case, of codes.

Figure 2. Extended ingredients with ingredient role codes

As shown in Figure 12, strength is also inherent to the substance, but for the most part in the context of the IDMP ontology, the strength applies to the use of a substance as an ingredient. Many substances have multiple forms, each of which can have multiple strengths, and it is the form and strength of the substance that acts as an ingredient in some product. There are multiple ways to model a substance with respect to its form and strength, depending on whether there are processes applied to some raw form of a substance to achieve that strength or whether it is sourced that way. So the ontology allows this as well. The relationship between an ingredient of some specific strength in the context of a product composition, including the notion of whether or not it is considered an allergen at that strength, is shown in Figure 3. The model also allows for cases where a substance is an allergen no matter what the strength is, as needed, however.

Figure 3. The basic relationship between an ingredient and its defining strength

This becomes more complicated when defining the notion of a substance as an active ingredient in a given product, as in some cases the strength is required, and in others, a reference strength may be required. See Pattern: Representing Reference Substances, Reference Strength, and the Basis of Strength, including in Different Jurisdictions - APPROVED for further refinement with respect to modeling the basis of strength in the context of a given pharmaceutical product that is authorized for marketing or investigational use in a specific jurisdiction.

Example Instantiation of the Model Pattern

Figure 4, below, provides a partial example (with some details elided) of the representation of a chemical substance as an active ingredient with its strength. This example is also encoded in the set of examples provided with the ontology. Note that the elements in white are classes in the ontology. Elements in blue are instances of those classes, and in purple are literal values.

Figure 4. Example partial diagram for the substance amlodipine besylate as an active ingredient of the product Norvasc

Note that this pattern does not cover complexities such as the basis of strength, which are addressed in more detail on Pattern: Representing Reference Substances, Reference Strength, and the Basis of Strength, including in Different Jurisdictions - APPROVED. These complexities require more complete coverage of the relationships between a product and its constituents in the context of a specific marketing authorization in a given jurisdiction.

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