What are the requirements for the graduation of measuring devices for medicinal products for human use that are administered to patients as liquid preparations, in particular in relation to the suitability of the graduation of the measuring device regarding dosing accuracy and precision, and the suitability of the measuring device for its intended use? H
November 2018 question reworded and response supplemented with guidance on the measurement of small volumes
The points discussed below are applicable to new Marketing Authorisation (MA-)applications or fully reformulated existing medicinal products. These points should be considered when referring to the graduation of a measuring device for a liquid preparation for human use in the Common Technical Document section 3.2.P.2: pharmaceutical development. They should form part of the justification of the suitability of the graduation of the measuring device for dosing the preparation under application. The measuring device shall comply as well with the relevant parts of the Essential Requirements given in Annex I of the Medical Device Directive 93/42/EEC, or with the General Safety and Performance Requirements given in Annex I of the Medical Device Regulation (EU) 2017/745, as and when applicable, and with International Organization for Standardization (ISO) standards.
Measuring devices may be required to deliver a variety of liquid preparations to patients through different routes of administration, e.g. oral, parenteral, nasal, vagin*l and rectal. The related medicinal products may already be a liquid upon marketing (e.g. ready to use solutions, suspensions, emulsions) or the products may be marketed as a solid or a concentrate where the liquid preparation needs to be prepared prior to use. The measuring device can be marketed together with the medicinal product (e.g. syringes without needles to administer oral liquid preparations, measuring cups, spoons or beakers, pipette applicators) or can be incorporated as integral part of the medicinal product (e.g. prefilled syringes).
In general, the minimum volume of a liquid measured with any measuring device should not be lower than 10% of the maximum capacity (e.g. 0.10 ml for a 1 ml syringe). However, this percentage may not be acceptable in situations where dosing accuracy and precision are considered to be critical, e.g. for active substances with a small therapeutic range. When the minimum volume that is measured increases up to 25% of the maximum capacity (e.g. 0.25 ml for a 1 ml syringe), usually no issues with regards to accuracy and precision are expected. This should be confirmed during pharmaceutical development.
The recommendation of the minimum volume of a liquid to be measured (in milliliters) is not applicable to devices that measure insulin as they are graduated in insulin units.
Manner of graduation
The graduation should be applied to the measuring device in such a manner that accurate and precise dosing is guaranteed. The graduation can be embossed or debossed on the measuring device, or printed on it.
This precision and accuracy of dosing should be guaranteed from release throughout storage until the end of shelf life, and also during the use of the particular measuring device under the conditions recommended in the Summary of Product Characteristics and Package Leaflet (SmPC/PL). Attention should be paid to the possibility of the printing ink fading. Gluing of a label with a printed graduation to the measuring device is not generally favoured, because of the potential for dislocation of the glued label during storage and use. If a glued label is used, the effectiveness of the adhesive / label system under normal conditions of storage and use should be demonstrated.
Graduated scale
The graduated scale should correspond with the way the dose or product strength is declared in the SmPC/PL. Generally, graduation in ‘ml’ is preferred as commonly available measuring devices are most often graduated in units of volume and as in many regions, health care professionals are more familiar with this type of graduation. This applies in principle to all measuring devices. For example, attention should be paid to the following:
- The possibility of the measuring device to deliver the minimum and maximum dose per single administration (nominal capacity);
- The suitability of the scale intervals of the measuring device in relation to the posology of the medicinal product or to the dose range when the posology is stated per kilogram bodyweight or square meter body surface;
- The ease of interpretation of the graduated scale: readability of the graduation numbers and the graduation lines, and distinction between the intervals of the scale.
European or international standards (European Committee for Standardization or ISO) may be available, e.g. for syringes recommendations are given on tolerances, graduated capacity, and graduated scale in ISO standards. These recommendations can be applied without further justification.
Suitability of a measuring device for a liquid preparation derived from/of a medicinal product: The suitability of the measuring device should be addressed. Attention should be paid to the following:
- The dosing accuracy and precision in relation to the therapeutic window of the active substance;
- The risk of overdosing in relation to the measuring device. If possible, overdosing should be prevented. If the risk of overdosing cannot be avoided, appropriate measures should be taken to prevent overdosing, e.g. the use of a device with a different scale interval;
- The physical characteristics of the liquid preparation in relation to the measuring device, such that accurate and precise dosing is assured. For example, considerations should be given to the needle diameter and the particle size of suspensions in injectables, the hom*ogeneity (re-suspendability) of suspensions and emulsions prior to use and during the application of the measuring device, or residual amounts of liquid preparation in the measuring device after administration of the dose to the patient.
Furthermore, the suitability of the measuring device and its graduation for the intended patient population should also be taken into account.
Acceptance criteria
The graduation of the measuring device should be suitable to meet the acceptance criteria of the dose of the liquid preparation derived from/of the medicinal product under application, as measured with the measuring device under application. These acceptance criteria should be in line with European Pharmacopoeia (Ph. Eur.) requirements, if applicable (for example Ph. Eur. 2.9.27: uniformity of mass of delivered doses from multi-dose containers), or other accepted pharmacopoeias. For single-dose containers where only a portion of the content needs to be administered to the patient, the same requirements can be applied as for multi-dose containers.
Measuring small volumes
Liquid preparations are intended to be administered with a measuring device that is commonly available in the European Union. If this is not the case, a measuring device should be supplied with the product by the MA-holder.
In order to ensure accurate dosing, the maximum capacity (size) of a measuring device should be appropriate for the volume to be dosed. For example, the smallest size of syringes that are graduated in ml and that are commonly available in hospitals and pharmacies throughout the European Union are 1 ml syringes with 0.01 ml dosing increments. Where commonly available 1 ml syringes are not considered suitable for dosing a liquid preparation with sufficient accuracy and precision, the company should develop an alternative administration strategy that would enable the use of a 1 ml syringe, e.g. a lower strength product. Where this approach is not an option, it is expected that (a) suitable dedicated measuring device(s) will be co-packed with the product and that the company will demonstrate acceptable accuracy and precision with such (a) device(s).
If the volume is too small to be measured accurately, (serial) dilution may be considered. However, this practice is prone to error. If dilution is considered necessary, this must be justified in the development pharmaceutics. In addition, and to avoid error, the dilution steps should be described in the SmPC/PL.
