Dose Form for the NTP

The dose form is one of the definitional components of an NTP and therefore its correct description is an essential part of the human readable Formal Name and French Description for the NTP.   The dose form (sometimes also known as the pharmaceutical dosage form) is the physical manifestation (formulation) of a medicinal product that contains the active (and inactive) ingredient substance(s) that are intended to be delivered to the patient.  

Dose Form Types

The manufactured dose form of the product is the formulation as it is supplied by the manufacturer and may require transformation into an administrable dose form.

The administrable dose form of the product is the formulation that is used for administration to the patient.

For the majority of products, the manufactured dose form and the administrable dose form are the same, but for products that undergo transformation prior to administration, they are different (e.g. "powder for suspension for injection" is a manufactured dose form, which after the transformation of addition of a liquid to reconstitute the powder, becomes "suspension for injection" as the administrable dose form).

The dose form for the NTP (and MP) will normally be the manufactured dose form.   

For those products where the manufactured dose form and administrable dose form are different, it is the manufactured dose form that most closely co-ordinates with the description of strength (with one exception, see below).  For example, for injectable Cefotaxime products, the dose form is the manufactured dose form of “powder for solution for injection” because the product strength is described as the mass amount of powder per vial (e.g. 500 mg per vial).

Oral preparations that are reconstituted at the time of dispensing have the administrable dose form for the NTP because the strength of these products is described in terms of the clinically useful strength (e.g.,  amoxicillin 125 mg per 5 mL).  The administrable dose form reflects this liquid preparation: oral suspension, oral solution, etc. (rather than the manufactured dose form of powder for oral suspension, powder for oral solution).

Dose Form Examples

Dose Form Formal Name and French Descriptions

Unit dose forms such as vaginal tablet, oral capsule, suppository, etc., will be stated using the singular form and not the plural.

The dose form description for the NTP should be granular and explicit enough to allow a prescriber to clearly identify the product to be supplied to the patient.  For example: to differentiate between the clotrimazole cream product intended to treat vaginal candidiasis (yeast infection) and the clotrimazole cream product intended to treat tinea pedis (athlete’s foot), there should specific be a specific dose form  – explicitly stating the dose form with its intended site of administration - “vaginal cream” for the product for vaginal use (even if a difference in strength already differentiates the products).

Similarly, for products (usually solid dose oral products) that have undergone modification to change their release characteristics (e.g., prolonged release, extended release); this change needs to be explicitly stated in the dose form description (see below).

The European Directorate for the Quality of Medicines & Healthcare (EDQM)[3], publishes a database of standard terms for dose forms, routes of administration and various other key concepts within the domain.  This was originally created in response to a request from the European Commission, but now is available for wider global use to support the Identification of Medicinal Products (IDMP) initiative and to support description of medicines in both regulatory processes and in healthcare generally[4].   A relevant subset of the EDQM dose forms (based on the product scope of the Canadian Clinical Drug Data Set), with their definitions, forms the basis of the NTP dose form terminology.  Some specific adjustment of individual concepts within the subset has been undertaken; for example, for prescribing use cases, there is no requirement to differentiate between hard and soft gelatin capsules, therefore a single “oral capsule” concept is used in the Canadian Clinical Drug Data Set. 

See also https://www.edqm.eu/sites/default/files/standard_terms_introduction_and_guidance_for_use.pdf

Release Characteristics

For dose forms that have modified release characteristics, the granularity of description of the modification in the EDQM concepts may not be sufficient for the NTP for documentation and interoperability.  For example, for oral solid dosage forms such as tablet and capsule, EDQM does not differentiate between different release rates as there are no pharmacopoeial standards to support this differentiation.  There are concepts for “modified release tablet” (tablet with a rate, a place and/or a time of release different from that of a conventional-release tablet) and “prolonged release tablet” (a tablet with a slower release of the active substance(s) than that of a conventional-release tablet). 

The following release characteristic types will be used for NTPs:

• Modified release: a rate, a place and/or a time of release different from that of a conventional-release.   Modified-release is used only when the more specific terms 'gastro-resistant tablet' or 'prolonged-release tablet' do not apply;
• Prolonged release, (a type of modified release): Solid single-dose preparation showing a slower release of the active substance(s) than that of a conventional-release preparation. Prolonged release is achieved by a special formulation design and/or manufacturing method. Prolonged-release preparations are intended for oral use;
• Orodispersible: Solid single-dose preparation consisting of an uncoated tablet intended to be placed in the mouth where it disperses rapidly in saliva before being swallowed;
• Gastro-resistant: Solid single-dose coated preparation obtained by compressing uniform volumes of particulate solids or by other means such as extrusion or moulding; preparations are intended for oral use to release active substance(s) in the gastrointestinal fluids by a rate depending essentially on the intrinsic properties of active substance(s) (conventional release);
• Chewable: Solid single-dose preparation consisting of an uncoated tablet intended to be chewed before being swallowed. Chewable tablets are intended for oral administration

Examples of Dose Forms with Release Characteristics in the Canadian Clinical Drug Data Set

Some groups of products with the same active ingredient substance are available with more than one “duration” of prolonged release: morphine prolonged release capsules are available for both a twice-daily dosage (e.g. M-Eslon) and a once daily dosage (e.g. Kadian).  These may not be differentiated by the dose form “prolonged release capsule”. Similar considerations apply to transdermal patches whose strength is stated as a rate (amount administered over 24 hours, usually) but whose dosing may be “one patch per 4 days” or “one patch per 7 days”.  Note that the 4-day patch may contain more total active ingredient substance than the 7-day patch, but because of the matrix of the patch, release it reliably only over 4 days.    As there is no pharmacopoeial or pharmacokinetic standard for dose forms with specific durations and no standardised source from which to obtain such information, development of any additional granularity of prolonged-release dose forms based on dosage schedule (e.g. prolonged release (xx-hour recommended)) cannot be supported currently.   This position will be actively reviewed based on user feedback.

Liquid dose forms

For most liquid dose forms, the NTP dose form will use the most granular concepts, as found in the EDQM standard, distinguishing between solutions, suspensions, emulsions and pure liquids; for example: "oral suspension", "emulsion for injection", "cutaneous solution".  For "drops" and "spray" dose forms, the NTP dose form will use a less granular dose form concept than those found in the EDQM standard (e.g. "ophthalmic drops" [rather than "ophthalmic drops, suspension"], "nasal spray" rather than "nasal spray, solution"), with the exception of oral drops, where the more granular concepts will be used (e.g. "oral drops, solution") when DPD has the data to support this.  Oral and parenteral liquids may need to be mixed or administered through narrow tubing (such as a nasogastric tube) so having the formulation information (and therefore a sense of the risk of blocking) can be clinically useful in the NTP.  The formulation of cutaneous liquids can also change their patient acceptability, so again, this information is clinically useful in the NTP.

The "drops" dose forms is used for all products presented with a dropper mechanism, either intrinsic to the container (e.g. an eye dropper bottle) or supplied separately.  Strength for drops dose forms should be expressed as a concentration, either as a percentage or as "per 1 mL" (see also the Substance Strength section).

DPD Dose Form Transformations

In order to undertake generation of the more granular dose forms for the NTP from the DPD dose forms, a set of rules is used, mapping the existing DPD dose form for a product to the NTP dose form.  Examples are given below.  

Example 1: Simple Mapping

DPD dose form = CAPSULE (ENTERIC COATED)

NTP dose form (formal name) = gastro-resistant capsule

Definition: “Solid single-dose, delayed-release preparation contained in a hard or soft shell. The preparation is intended to resist the gastric fluid and to release the active substance(s) in the intestinal fluid. Hard gastro-resistant capsules are usually made by filling capsules with gastro-resistant granules or solid particles made gastro-resistant by coating or, in certain cases, by providing capsules with a gastro-resistant shell. They are intended for oral use.”

Transform:

All products with DPD Dose form = CAPSULE (ENTERIC COATED) (code =14) transform to have the NTP dose form as “gastro-resistant oral capsule”

Example 2: Simple Change

DPD dose form = TABLET (CHEWABLE)

NTP dose form (formal name) = chewable tablet

Definition: “Solid single-dose preparation consisting of an uncoated tablet intended to be chewed before being swallowed. Chewable tablets are intended for oral administration.”
Note: “oral” is not explicitly in the formal name dose form because chewable implies an oral site.

Transform:

All products with DPD Dose form = TABLET (CHEWABLE) (code = 151) transform to have the NTP formal name dose form as “chewable tablet”

Example 3: Transform Using Route of Administration

DPD dose form = CREAM

An NTP with a dose form of “cream” would not be granular enough to identify the correct set of products for prescribing.

EDQM “cream” dose forms include the intended site of use; for example:  

• vaginal cream
  • Definition: “Semi-solid preparation consisting of a cream usually presented in a single-dose container provided with a suitable applicator, intended for vaginal use to obtain a local effect” or
• ophthalmic cream
  • Definition: “Semi-solid sterile single-dose or multi-dose preparation consisting of a cream intended for ocular use. Eye creams may be presented in collapsible tubes fitted with a cannula and having a content of not more than 5 g of the preparation. Eye creams may also be presented in suitably designed single-dose containers. The containers or nozzles of tubes are of a shape that facilitates administration without contamination”
• cutaneous cream
  • Definition: Semi-solid single-dose or multidose preparation of homogeneous appearance consisting of a lipophilic phase and an aqueous phase, one of which is finely dispersed in the other. Active substance(s) are dissolved or dispersed in the basis, which may be hydrophilic or hydrophobic. Creams are intended for cutaneous use. In certain cases, transdermal delivery may be obtained

Use the route of administration information present in the DPD to transform to the more granular dose form:

Where DPD Dose form = CREAM (code =9) and DPD Route of administration = VAGINAL (code = 74) transform to have the NTP dose form (formal name) as “vaginal cream”

Where DPD Dose form = CREAM (code =9) and DPD Route of administration = OPHTHALMIC (code = 55) transform to have the NTP dose form (formal name) as “ophthalmic cream”

Where DPD Dose form = CREAM (code =9) and DPD Route of administration = TOPICAL (code = 70) transform to have the NTP dose form (formal name) as “cutaneous cream”

Note: "Cutaneous" (defined as "administration of a medicinal product to the skin and/or cutaneous wounds and/or nails and/or hair in order to obtain a local effect") is used in preference to "topical" in the formal description of dose forms for the NTP formal name.  This is because there is no good definition of "topical" - it tends to be defined as "not systemic" and definition by exclusion is not recommended.

Example 4: Product Based Transform

DPD Dose form = TINCTURE

Not an EDQM dose form (or anything similar)

Used by two products:

• DIN = 00873195; Product = CETRIMIDE TINCTURE 0.5%
• DIN = 00545279; Product =  FRIAR'S BALSAM BENZOIN TINCTURE

Select an NTP formal dose form appropriate for each product:

Transform DIN = 00873195 to have the dose form of “cutaneous solution”
Transform DIN = 00545279 to have the dose form of “inhalation solution”

(3) https://www.edqm.eu/en/Standard-Terms-590.html

(4)The EDQM dose form terminology was developed on a model originally designed by a team including representatives from HL7, SNOMED CT and regulatory agencies.  It has been adopted for use by a number of organizations around the globe for use in healthcare as well as in the regulatory domain.   It was therefore felt to be a good choice to support the Canadian NTP development and helps Health Canada towards IDMP compliance.