Medicinal Product model diagrams

The diagrams below show the overall basic medicinal product model. Note that in each diagram, no role, structure, or disposition grouper concepts are shown. Definitions and detailed descriptions are given in the sections following this overall model introduction.

MP classes = shades of blue

MPF classes = shades of yellow

CD class = green

This first diagram is a class model illustrating the five classes of concepts in the model and the relationships between them, in their three groups (MP, MPF and CD) plus an additional optional sixth sub-class to be populated in limited cases and likely in national extensions only (MP Precise Only). Two classes use the existential restriction (MP and MPF) and four use the (proxy for the) universal restriction (MP only, MPF only, CD and MP Precise Only). MP Precise Only is the optional sub-class that represents a product described explicitly and only by its precise active ingredient substances, i.e. including clinically significant modification such as "dexamethasone sodium phosphate ".

Figure: Medicinal Product concept model - International edition

The next diagram below is in SNOMED notation (inferred view), and shows only the five classes that will be populated in the international release, at least for the foreseeable future. The Medicinal Product model is parented by the proximal primitive 763158003 |Medicinal product (product)| concept, an abstract concept representing an item that "has been formulated and manufactured for administration to humans (or animals) for treatment or prevention of disease, for diagnosis of illness or to restore, correct or modify physiological function and which contains an active ingredient substance or combination of substances". This parent concept acts both to scope the domain and, in the future, will separate medicinal products from other products in a larger Products hierarchy, which may include medical devices and certain other products such as foods and cosmetics.

The last model diagram below shows multi-ingredient medicinal products, and therefore, has increased complexity. It again shows the three groups (MP, MPF and CD) with MP classes shown in shades of blue, MPF classes in shades of yellow and the CD class in green; each with two single active ingredient representations (X and Y) and one multi-ingredient representation (X + Y) and then the relationships between these. It shows how the single ingredient "containing" classes (the open world classes) subsume the appropriate multi-ingredient class, whereas the single ingredient "containing only" classes (the closed world classes) do not subsume the multi-ingredient class. The optional MP Precise Only class is present but is not shown with any multi-ingredient products, to limit complexity. MP Precise Only multi-ingredient products are discussed later in the .

Examples: oral solutions, suspensions, emulsions, syrups

This is a variation on the metered dose presentation; the unit of presentation supplied by the manufacturer to provide the “metered dose” is the 5mL spoonful, since this represents “the quantity of product that is administered by filling a single spoon administration device” [EDQM]. Strength is expressed as “per one unit of presentation” (per 5 mL [spoonful]) BUT the presentation strength and the concentration are NOT the same, since these are continuous liquids, so the concentration strength of “per 1 mL” will usually be a different value. Note that explicit representation of the medicine spoon would be as an administration device, and is therefore out of scope of the international Medicinal Product hierarchy. National extensions may wish to represent the inclusion of a medicine spoon (or indeed any other administration device such as an applicator) in the package description (as in IDMP, for example) should the use case(s) require.

Example: A bottle of 125 mL of aciclovir oral suspension 200mg/5mL

The following sections discuss the attribute concepts used to represent the ingredient substances of concepts in the medicinal product hierarchy.

Ingredient Substances

Figure: Ingredient role attributes

The diagram above shows the relationship of the various attribute roles that a substance can play in the definition of MP, MPF and CD description of medicinal products. Any concept from the Substance hierarchy may play one or more of these roles within a product. In all of the descriptions below, when the phrase "a set of substances" is used, the set may have only one member.

Has ingredient

A medicinal product concept has a set of substances that are combined to manufacture the medicinal product that can be described using the "has ingredient" attribute. However, each substance(s) in the "has ingredient" set will have more specific ingredient role that should be described using that more specific concept. Therefore, this is a grouping concept that is not used for definition of medicinal product concepts in the medicinal product hierarchy; it is a parent concept and it provides scope for further child concepts to be added to support future use cases, such as the description of inactive/excipient ingredient substances in products in a national extension. The physical presence or otherwise of an ingredient substance in the finished product may not explicitly be necessary for it to be part of the product's substance description; for example substances that play a role in the manufacturing process, such as solvents etc. are deemed "ingredients" for the product; their presence may or may not remain in the manufactured item. As such, basis of strength substance could be considered as a child concept of the Has ingredient concept, although it is not modeled in that way currently.

Has active ingredient

A medicinal product concept has a set of active ingredient substance(s) responsible for providing the therapeutic effect of the medicinal product and which are described using the clinically relevant part or whole of the substance that is intended to have a therapeutic action on or within the body. In the majority of cases, this description excludes modifiers such as esters, salts or other non-covalent derivatives (such as a complex, chelate etc.), but may include them in the minority of cases when clinically significant (e.g. liposomal substances). This is therefore usually an abstract representation of the active ingredient substance(s) and is used in more abstract representations of medicinal products, such as MP (containing).

Note that "clinical significance" can be described as "something that has a practical, demonstrable effect on the treatment and condition of the patient". For example: different modifiers of a particular active moiety have clinical significance if they affect the potency of the therapeutic action of the moiety (and therefore have an affect on the dose quantities to be used). See Kazdin, E The Meanings and Measurement of Clinical Significance Journal of Consulting and Clinical Consulting 67 (3): 332–9. This is the attribute role that is used in the definition of the MP concept (containing and only) and the MPF concept. Examples of substances playing the role of active ingredient in a medicinal product:

• azithromycin where the precise active ingredient may be azithromycin hemiethanolate, azithromycin isopropanolate

• haloperidol where the precise active ingredient may be haloperidol hydrochloride, haloperidol decanoate, haloperidol lactate

• esomeprazole where the precise active ingredient may be esomeprazole magnesium, esomeprazole sodium

• oxybutynin where the precise active ingredient may be oxybutynin chloride or oxybutynin xinafoate

A medicinal product concept has a set of precise active ingredient substance(s), those substance(s) that provides the therapeutic effect of the medicinal product and which are described using the fullest and most specific description of the substance as it is used in the product(s) that the concept represents (as they are presented by the manufacturer in the manufactured dose form, before any dilution or transformation). The precise active ingredient substance may include various modifiers, such as salts, esters and/or polymers (e.g. pegylation); not all substances, even when used as the precise active ingredient substance, have a modification (see axitnitib). This is the attribute role that is used in the definition of the MP (precisely) concept, and in the definition of the CD (precisely). Examples:

• haloperidol decanoate

• oxybutynin chloride

• dexamethasone sodium phosphate

• sorafenib tosylate

The precise active ingredient attribute will use the Substance hierarchy as a flat list (without role chaining), so that a Clinical Drug containing a modified substance is not subsumed under a clinical drug containing the unmodified substance, thereby unintentionally adding more recursion to the clinical drug class (for example: so that a morphine (base) precise clinical drug does not subsume a clinical drug containing precisely morphine sulphate). This highlights the difference between the semantic of "contains precisely" which explicitly and exclusively describes the full modified substance in the medicinal product concept and "contains only" which inclusively describes the therapeutically active moiety which may be manifest in one or more substance modifications of itself.

Examples:

• "contains dexamethasone only" means that a product will contain only dexamethasone as its active ingredient; but that dexamethasone may be present as dexamethasone base, as dexamethasone phosphate, dexamethasone sodium phosphate, as dexamethasone acetate, as dexamethasone palmitate etc.

• "contains dexamethasone phosphate only" means that a product can contain either dexamethasone phosphate or dexamethasone sodium phosphate (which is a modification of dexamethasone phosphate) as its active ingredient; but it will not contain dexamethasone acetate or dexamethasone palmitate etc.

• "contains dexamethasone phosphate precisely" means that a product will contain exclusively dexamethasone phosphate; dexamethasone sodium phosphate will not be present

See also the subsection below "Using the ingredient roles" which provides a diagram further describing the use of role chaining with the active ingredient role and that there is no role chaining for the precise active ingredient role.

A medicinal product clinical drug concept has one or more substances that have the role of being the substance against which the strength quantity(s) of the product(s) are measured. There will be a basis of strength substance stated for each active ingredient substance present in a multi-ingredient clinical drug product.

Examples:

• azithromycin - in an oral suspension containing azithromycin hemiethanolate, where the strength is 100 mg per 5 mL of azithromycin

• haloperidol in a solution for injection containing haloperidol decanoate, where the strength is 250 mg per 5 mL of haloperidol

• esomeprazole - in a prolonged release tablet containing esomeprazole magnesium, where the strength is 20 mg per tablet of esomeprazole

• oxybutynin chloride – in an oral tablet containing oxybutynin chloride, where the strength is 5 mg per tablet of oxybutynin chloride

Almost always, the basis of strength substance is either the active ingredient substance or the precise active ingredient substance; very occasionally products are licensed using a "reference" basis of strength substance (e.g. a product containing diclofenac diethylammonium as its precise active ingredient substance having its strength expressed in terms of diclofenac sodium).

The Medicinal Product and Medicinal Product Form use the active ingredient attribute, which will have a role chain attached to it, so that it can use the Substance hierarchy as a hierarchy through the "is modification" relationship. This allows the classifier to make the appropriate relationships between MPs, MPFs and CDs based on their active ingredient substances. The role chain is a characteristic that is not inherited, so the precise active ingredient attribute does not inherit this characteristic. The Clinical Drug uses the precise active ingredient attribute/relationship which will use the Substance hierarchy as a flat list without role chaining, so that a clinical drug containing a modified substance is not subsumed under a clinical drug containing the unmodified substance, thereby unintentionally adding more recursion to the clinical drug class (for example: so that a morphine (base) precise clinical drug does not subsume a clinical drug containing precisely morphine sulphate).

Ingredient role is a specific attribute in ISO 11615 in IDMP, but no vocabulary/value set was specified in the conceptual standard for the ingredient roles. Examples that have been given include "active", "inactive" and "adjuvant". This supports the regulatory listing of all the substances present in a product, with their basic role (therapeutic or otherwise).

The explicit use of ingredient roles in the medicinal product model is compatible with the IDMP conceptual model; however, the relationship of ingredient role to substance strength is still being elucidated in IDMP. Note that the concept of "basis of strength substance", in the very few cases where it is not actually a substance present in the product, is managed by the use of the Reference Substance class in IDMP. See also .

To correctly interpret "one countable instance of a whole of medicinal product ", it is important that this is seen in the context of the overall description of a medicinal product, which is always presented from the manufacturer as a "packaged medicinal product". Note that description of packaged medicinal products is outside the scope of the international release but may be included within a national extension. The IDMP Medicinal Product model describes this, showing how the Manufactured Item is related to the Packaged Medicinal Product via the Package Item (Container). This is a recursive class that represents both the package as supplied by the manufacturer (and, for example, labelled with the GTIN, the batch number and the expiry), and through a recursive relationship, with any sub-packages inside the outer pack.

By describing the various standard patterns of products with their basic dose forms and intimate containers, consistent representation of strength based on unit of presentation can be maintained.

Examples: vials, ampoules, sachets, containing solid dose forms such as powders or granules which may or may not be dissolved before administration

The unit of presentation usually either uses the same word (even though it is a different concept) as the (package item) container, or the (package item) container is a more granular concept and the unit of presentation uses a less granular term. Strength is expressed as "per one unit of presentation" and the presentation strength and the concentration are exactly the same.

Example: Pack of 10 vials each containing 2g cefotaxime powder for solution for injection

Examples: various tablets, capsules, cachets, pessaries, suppositories, tampons

The unit of presentation is usually a less granular term than the manufactured dose form, and often corresponds to the basic dose form. Strength is expressed as "per one unit of presentation" and the presentation strength and the concentration are exactly the same.

When authoring in this domain, these are the approved attributes and allowable ranges.

See also respective Templates.

Domain Information for Pharmaceutical/Biologic Product

Examples: various inhalers, nasal sprays, some cutaneous sprays/foams

The unit of presentation is the actuation, the “single operation of a metered-dose pump, valve or other equivalent dosing mechanism” [EDQM].

Strength is expressed as “per one unit of presentation” and the presentation strength and the concentration are exactly the same.

Example: Single inhaler containing a total of 200 actuations worth of salbutamol, 100 micrograms per actuation, packaged in a box

The following sections describe the attribute concepts that are used to represent the ingredient counts for all concepts represented using the "closed world view" (the "only" and "precisely" concepts) in the medicinal product hierarchy.

Ingredient count is the mechanism that the SNOMED CT concept model is using as a proxy to implement a "closed world" view of medicinal products such that a medicinal product concept can be represented as containing only substance X as its active ingredient, and that all more granular child medicinal product concepts also containing only substance X subsume under the correct parent concept(s).

Three count attributes are available for use, but only one is mandatory for all only concepts; i.e. MP (only), MP (precisely), MPF (only) and CD). The additional ingredient counts have to be applied iteratively, if and when they are required based on the presence of multi-ingredient concepts which contain active ingredient substances that have modifications of the same base. For new concepts, the count attribute is first authored for Clinical Drug concepts, which have their precise ingredient substance described; the more abstract classes can then be populated upwards using the base (or parent) active ingredient substance if different.

This count is the number of base (or root or main parent) active ingredient substance(s) (as described in the SNOMED CT Substance hierarchy) present in the medicinal product. Base ingredient substances can be identified from their modifications through the relation "is modification of", traversed iteratively if necessary, until reaching a substance that is not a modification of any other substance.

Examples: parenteral solutions, unit dose nebuliser solutions

The unit of presentation usually either uses the same word (even though it is a different concept) as the (package item) container, or the (package item) container is a more granular concept and the unit of presentation uses a less granular term. Presentation strength is expressed as "per the amount of liquid bounded by the unit of presentation" but concentration strength is per mL (and therefore is often different).

The following sections describe the attribute concepts used to represent the ingredient strength of concepts in the medicinal product hierarchy.

"Medicinal product strength" is not well defined in standards. It is closely aligned with "potency" which in pharmacology describes the measurement or calculation of the therapeutic activity of the medicine; this is expressed in terms of the amount of medicine required to produce an effect of given intensity. Strength is a ratio type concept: expressing the amount of something against another amount of something, which in practical terms is expressed fractionally using the numerator and denominator quantities and their relevant units. The numerator represents how much of the active ingredient substance there is, and the denominator represents the "whole" that the numerator amount is present in.

For a medicinal product, therefore, the strength is:

• the amount of (active) substance (in the form of) the basis of strength substance in one instance of "a whole" of medicinal product

It is the "one instance of 'a whole' of medicinal product" that causes the difficulty. It is not possible to have a single pattern for what this means for all types of medicinal products. Therefore, the consensus for all medicinal product terminology is to define the pattern for each type of product and apply it consistently. In addition, because historically, there has been a difference in how to develop and apply these patterns, a differentiation has developed between two types of representation "presentation strength" and "concentration strength", which are best expressed explicitly.

Examples: bulk parenteral solutions, insulins, patches

The unit of presentation usually either uses the same word (even though it is a different concept) as the (package item) container, or the (package item) container is a more granular concept and the unit of presentation uses a less granular term. However, although presentation strength is expressed as "per one unit of presentation", the clinically relevant strength is the concentration strength, as almost all are used in individually calculated and variable amounts. Note that the unit of presentation is likely to be useful in description of the medicinal product concept at some level; insulin presented in a multi-dose vial will be used/administered differently from insulin presented in a cartridge for use within a "pen device".

Example: A pack of 5 cartridges each containing 1.5mL soluble human insulin 100 units/mL solution for injection

Examples: bulk powders and granules, bulk liquids, semi-solids

These presentations are not particularly bound by their container in any way that is meaningful in terms of their use or administration; the Manufactured Item is a continuous presentation and almost all are used in individually calculated and variable amounts.

For example,

• Hydrocortisone cream for cutaneous use is contained in a tube, but its use is based on how much is squeezed out and applied to the skin.

• Chloramphenicol eye drops are presented in a dropper bottle, but they are administered drop by drop and although the dropper bottle aims to deliver a roughly uniform sized drop to the eye, they are not "metered dose containers" in the way that containers with valves are.

A unit of presentation is not usually given for these products. The pack size (not relevant for SNOMED international model) is given as the Manufactured Item quantity. Strength is expressed as a concentration and as such the presentation strength and the concentration are exactly the same.