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The following sections discuss the detail of the concepts that are used as attributes for the classes of representation in the Medicinal Product Hierarchy.

Describing Ingredient Substances

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Figure 39: 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 ingredient substances in products in a national extension. The physical presence or otherwise of the ingredient substance in the finished product is not explicitly part of the definition; 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 modelled 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.  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 (some).

Note that "clinical significance" can be described as "something that as 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

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• azithromycin where the precise active ingredient may be azithromycin dihydrate, azithromycin hemiethanolate monohydrate, azithromycin isopropanolate monohydrate
• haloperidol where the precise active ingredient may be haloperidol hydrochloride, haloperidol decanoate, haloperidol lactate
• esomeprazole where the precise active ingredient may be esomeprazole magnesium dihydrate, esomeprazole magnesium trihydrate, esomeprazole sodium
• oxybutynin where the precise active ingredient may be oxybutynin chloride or oxybutynin xinafoate
• diclofenac where the precise active ingredient may be diclofenac sodium, diclofenac potassium, diclofenac diethylamine
• axitnitib where the precise active ingredient substance is also axitinitib

Has precise active ingredient

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, polymers (e.g. pegylation), and/or solvates (including waters of hydration); 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:

• azithromycin hemiethanolate monohydrate
• haloperidol decanoate
• esomeprazole magnesium dihydrate
• oxybutynin chloride
• paroxetine hydrochloride isopropyl solvate
• dexamethasone sodium phosphate
• sorafenib tosylate
• axitinib

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:

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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.

Basis of strength substance

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 monohydrate, 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 dihydrate, 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
• paroxetine – in an oral tablet containing paroxetine hydrochloride isopropyl solvate, where the strength is 10 mg per tablet of paroxetine
• dexamethasone phosphate – in a solution for injection containing dexamethasone sodium phosphate, where the strength is 4 mg per 1 mL of dexamethasone phosphate
• diclofenac sodium – in a gastro-resistant tablet containing diclofenac sodium, where the strength is 25 mg per tablet of diclofenac sodium
• sorafenib – in an oral tablet containing sorafenib tosylate, where the strength is 200 mg per tablet of sorafenib

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).

Using the ingredient role

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 will allow 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).

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Figure 40: Ingredient role chaining

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Figure 41: Ingredient role chaining example

IDMP Compatibility

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describe the attribute concepts used to represent the defining properties of concepts in the medicinal product hierarchy.

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Figure 42: Ingredient role in ISO 11615 of IDMP
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 (Clinical Drug (CD)). See also IDMP Compatibility for Clinical Drug (above).

Ingredient Count

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.

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Figure 43: Ingredient count attributes

Count of base of active ingredient - mandatory for the closed world view

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.

For all single ingredient products and for the majority of multi-ingredient products, this is the only count information that needs to be described in order to support correct subsumption.

Example:

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Figure 44: Ingredient count attributes simple multi-ingredient example

The base count facilitates the correct subsumption relationship between the "Product containing only Amlodipine and Atorvastatin" and the Clinical Drug that contains only Amlodipine and Atorvastatin. It avoids the "Product containing only Amlodipine and Atorvastatin" being incorrectly subsumed by the concept "Product containing only Amlodipine" or by the concept "Product containing only Atorvastatin" since a concept of a base count of 1 will not subsume a product with a base count of 2. Similarly the Clinical Drug concepts containing only Amlodipine or only Atorvastatin, both of which have a base count of 1, are prevented from being subsumed by the "Product containing only Amlodipine and Atorvastatin" which has a base count of 2.

Count of base and modification pair (closed world view) - optional - to be used in certain circumstances

This count is used for multi-ingredient products where the two (or more) active ingredient substances share the same base active ingredient substance. This will only occur when at least one of the active ingredient substances is a modification of a base active ingredient substance.  The count used in addition to the base active ingredient substance count.  The count is of how many pairs of base + modification substances are present in the medicinal product; this draws from the Substance hierarchy where concepts are managed using the pattern of base substance with related concepts being modifications (salts, esters, chelates) of the base substance; each modification is therefore a "pair".

Example:

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Betamethasone sodium phosphate

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Betamethasone + sodium phosphate

Betamethasone + acetate

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Betamethasone sodium phosphate and betamethasone acetate are both modifications of the betamethasone: a phosphorylation and an acetate esterification; however neither are modifications of each other.

The tooling uses these values to produce the correct subsumption hierarchy, as shown diagrammatically below:

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Figure 45: Ingredient count attributes complex multi-ingredient example with multiple modification of a single base active ingredient requiring two ingredient count attributes

Base count alone would not prevent the incorrect subsumption of the "Clinical Drug containing precisely Betamethasone sodium phosophate and Betamethasone acetate" to the parent Medicinal product concepts containing Betamethasone sodium phosophate only (or Betamethasone acetate only - not shown on the above diagram).  By adding in the Count of Base + modification pair, that incorrect subsumption is avoided and the "Clinical Drug containing precisely Betamethasone sodium phosophate and Betamethasone acetate" is correctly subsumed by just the one parent Medicinal Product, that "containing only Betamethasone sodium phosophate and Betamethasone acetate".The (grand)parent medicinal product concept "Product containing betamethasone only" does not (cannot) have a Count of Base + modification pair, since it does not have any active ingredient modification described; therefore it can correctly parent medicinal product concepts containing only Betamethasone sodium phosophate, containing only Betamethasone acetate (not shown) and containing "only Betamethasone sodium phosophate and Betamethasone acetate", because they all share a Base count of 1, relating to Betamethasone.

Count of active ingredient (closed world view) - optional - to be used in certain circumstances

This count is used for the fairly rare cases of multi-ingredient products where the two (or more) precise active ingredient substance(s) share the same base active ingredient substance and one of those precise active ingredient substances is a modification of another; it is used in addition to the base count and the base + modification pair count.   The count is of how many precise active ingredient substance(s) are present in the product (and therefore can be a count of the number of precise active ingredient attributes are present on a concept).

Example:

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Insulin + aspart

Insulin + aspart protamine

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Insulin aspart and insulin aspart protamine are both modifications of insulin; but since Insulin aspart protamine is itself a modification of Insulin aspart, the Base + modification pair count is only equal to 1 (insulin plus 1 modification - the aspart). To get correct subsumption between the Clinical Drug and Medicinal Product concepts in these types of situations, the third count, that of precise active ingredient substance, must be used as well.

The tooling uses these values to produce the correct subsumption hierarchy, as shown diagrammatically below:

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Figure 46: Ingredient count attributes complex multi-ingredient example with multiple modification of a single base active ingredient requiring three ingredient count attributes

Neither base count alone nor base count and base + modification pair count would prevent the incorrect subsumption of the "Clinical Drug containing precisely Insulin aspart and insulin aspart protamine" because both give a count of 1. The differentiation comes from the counting the precise active ingredient substances. This then gives the (optional in the international release) intermediate parent concepts of "Medicinal product containing precisely" either "insulin aspart", "insulin aspart protamine" or "insulin aspart and insulin aspart protamine" with their correct Clinical Drug concepts as children. The MP (precisely) concepts are then correctly subsumed to the (grandparent) MP (only) concept of insulin aspart only, on the basis of the base count of 1.

Describing Dose forms

A Clinical Drug concept has a pharmaceutical dose form, the physical manifestation of a medicinal product that contains the active ingredient substance(s) and inactive ingredient substances that are intended for administration for the patient.  The Clinical Drug concept in the international release is defined by its manufactured dose form, the dose form as the item is presented by the manufacturer into the supply chain.  This may be the same as the administrable dose form, which is the dose form that can be given to the patient after any necessary transformation (such as dissolution or dispersion) has taken place. or it may be different.  Examples of the relationship between manufactured and administrable dose forms and transformation are given below.  Note that both manufactured dose forms and administrable dose forms are types of pharmaceutical dose form.

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The exception to the principle of using the manufactured dose form to describe Clinical Drugs in the international release is for oral antimicrobial liquid products (solutions, suspensions) that are supplied by the manufacturer as powders but that undergo dissolution or dispersion prior to dispensing for administration.  The exception is present because of the need to describe these products using a clinically relevant strength reflecting the concentration of the administered liquid.

See also SNOMED CT Editorial Guide - Pharmaceutical Dose Form.

Describing Medicinal Product Strength - Presentation and Concentration Strength

"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.

Presentation strength

Presentation strength is the amount of the basis of strength substance present in the unit of presentation of or in the volume (or mass) of the single clinical drug being represented.

Concentration strength

Concentration strength is the amount of the basis of strength substance present per unitary amount (volume, mass) of the single clinical drug being represented.

These two options may be used separately, as they are in this international model specification but can also be used together (as may be used in national extensions), thereby producing three patterns for how medicinal product strength can be described. The place of unit of presentation to provide the "bounding" and to support the description of "a whole" for the medicinal product is described in detail in its own section below.

Use of concentration strength and presentation strength

Description of strength is a safety issue. Mindful that SNOMED core is a reference terminology not an interface terminology, it is still important that the description of product strength should be that which is least confusing for national extensions to use and build out from. Presentation strength is deemed by patient safety agencies to be the least confusing for the majority of types of products so should be provided whenever possible.  However, to avoid combinatorial explosion and to have realistic maintenance processes for the international core content, some types of products that could be described with both presentation and concentration strength will be described with concentration strength only.     

Table of Strength Patterns

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Use of Product Strength patterns for Clinical Drug concepts in the international release

Clinical drug concepts using pattern 1 will be present in the international release as will clinical drugs using strength pattern 3.  Clinical drugs using strength pattern 2 may be authored in national extensions. 

IDMP Compatibility

IDMP (and in particular (ISO 11615 section 9.7.2.4) is clear that strength "can be expressed in two ways: strength (presentation) and strength (concentration)" and it uses both in parallel within the standard. Presentation strength is generally required for description of manufactured items, whereas concentration strength may be optionally provided. When describing the strength of a pharmaceutical product that has undergone a transformation (e.g. dissolution or dispersion), the strength is specified as it would occur "when the transformation undertaken exactly in accordance with the regulated product information". It is not clear whether, if the regulated product information provides alternative transformations, more than one pharmaceutical product would be authored. Since the Medicinal Product model does not intend to represent a transformed product using the administrable dose form when this is different, primarily because of this type of uncertainty, this issue can be put aside.
IDMP has the concept of "Reference Strength" to explicitly describe the difference between the precise active ingredient substance and the basis of strength substance, or to support description of strength in alternative units. The Medicinal Product model supports basis of strength substance explicitly, and therefore is compatible with IDMP, and because alternative descriptions (synonyms) are a core part of the SNOMED structure, alternative strength representations could be provided if required (e.g. adrenaline 1:1000 rather than 1 mg per mL).

See also the IDMP Compatibility part of the Clinical Drug section.

Measurement Point

ISO 11615 in IDMP introduces the concept of "measurement point" for strength in some products, usually those with a metered dosage value system, for example the strength of the active ingredient substance in some inhaler products is measured at a particular distance from the point of aerosolisation. Using a strength measurement point is currently something that is country-specific (although regulation may change to make it more standardized as its use becomes more widespread). In the international core, it may become important to specify the measurement point for the strength of some products to allow national extensions to select the correct concept for their use, since it would appear that differences in measurement point between otherwise similar products can be clinically significant.  Measurement point is currently not explicitly described in the international release. This is a developing area and will be kept under review.

Unit of Presentation

A unit of presentation is a qualitative concept that describes a countable entity in which the clinical drug is presented, or in which it is bounded.  It is used to support expression of presentation strength, where it provides the denominator for the strength ratio, and to differentiate different clinical drug products when the "intimate container" (see below) is clinically important (e.g. differentiating pre-filled syringes from ampoules for a solution for injection product).
As described in the Strength section above and detailed further in an Appendix, there are various patterns for describing how unit of presentation and expression of strength relate together, based on whether the unit of presentation relates to the basic dose form or the intimate container (which is therefore the countable unit) of the medicinal product.  As the countable entity for a medicinal product, unit of presentation is also important in describing packages, which although out of scope of the international release, may be of major importance for national extensions describing medicinal products. There are three types of unit of presentation:

• those that are basic solid dosage forms: e.g. tablets, capsules, suppositories, pessaries etc.
  • in this type, the solid dosage form, because of its discrete nature, is the countable unit; it provides the physical boundary in which the active ingredient substance(s) of the medicinal product are presented
• those that are created by metered dosing valves: e.g. the "actuation" of inhalers, sprays etc.
  • in this type, the countable unit is the "actuation" provided by the metering valve; it is the valve that determines (bounds) the physical amount of the active ingredient substance(s) of the medicinal product are presented
• those that are intimate containers: e.g. ampoules, vials, sachets, cartridges etc.
  • see below for detail

Intimate container

The "intimate container" of a medicinal product is the receptacle or vessel used to contain (or bound) liquid and some solid or semi-solid medicinal products into countable entities. A medicinal product presented in an intimate container will almost always have at least one layer of additional packaging added to it in order to make it into a packaged medicinal product; this external packaging is not described in the international release.  For example: an ampoule is an intimate container to present a solution for injection dosage form; the ampoule will always be supplied in a box or a moulded carton, possibly additionally with a blister strip as intermediate packaging. Particularly for liquid parenteral products and for nebuliser liquids, the intimate container/unit of presentation may have clinical significance: providing a patient heparin in a pre-filled syringe is different from supplying that same concentration of heparin in a (multi-dose) vial.  Similarly, hormone replacement gels may be supplied in single dose sachets to provide the correct administration amount.

IDMP Compatibility

In IDMP, the "one countable instance of a whole of medicinal product" is managed through the information model: it is (generally) one instance of the Manufactured Item, with its manufactured dose form and unit of presentation or one instance of the Pharmaceutical Product (with its administrable dose form and unit of presentation). The Manufactured Item is therefore the concept/class that most closely resembles the SNOMED CT Clinical Drug, but both Manufactured Item and Pharmaceutical Product contain the key "unit of presentation" attribute. The unit of presentation in IDMP is what specifies the "real world" units in which the quantity of the manufactured item is described. The unit of presentation can be specified in accordance with ISO 11239 and ISO/TS 20440 and its resulting terminology [implemented through EDQM].  
IDMP goes on to state: "For items where their quantity is a measured quantity of weight or volume, the "unit of presentation" shall not be given since it is the same as the units of that quantity (that is ml, mg or %). For solid dose forms and other items that are measured by counting integer quantities, the unit for quantity shall be "unit" and the "unit of presentation" shall be the item that is counted."
In EDQM, unit of presentation is defined as the "Qualitative term describing the discrete countable entity in which a pharmaceutical product or manufactured item is presented, in cases where strength or quantity is expressed referring to one instance of this countable entity."

EXAMPLE 1: To describe strength: "Contains 100 mg per tablet" ('tablet' is the unit of presentation).
EXAMPLE 2: To describe quantity: "Contains 100 mL per bottle" ('bottle' is the unit of presentation).

Unit of Presentation is therefore sometimes known as "the countable unit".