The good, old-fashioned dose cup . . . you know, that 30ml polypropylene cup that comes shrink-wrapped on top of the cough syrup bottle you picked up at the local pharmacy? The cup is really quite simple to use. Based upon the dose prescribed for the patient, simply pour the medication up to the corresponding line of the dose cup and hand off to the patient. For the five year old, you may be instructed to pour to the 5 ml line and for the 16 year old you pour to the 20 ml line. A very simple concept, and one that any parent can relate to. However, let’s take a moment to discuss how we can develop and test this drug delivery method to ensure the accuracy of the dosing lines meets the intended regulatory requirements for the drug being administered.
The United States Pharmacopeia (USP) general chapter <905> outlines test procedures specific to the “Uniformity of Dosage Units”. The stated objective of these test procedures is clearly outlined at the outset of this chapter: “To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim.” The details of the chapter are very specific to different drug types and outline two variations of testing that may be applicable to your product: Content Uniformity and Weight Variation. In essence, the chapter, which relies heavily on the assay of the drug product, is specific to the product and not the delivery device. When we begin to look at items such as dose cups and metered syringes, which are commonly used in the practice of medicine delivery, we quickly see that the USP <905> chapter does not specifically address or apply quality control test procedures. Yet, it is incumbent upon the manufacturer to ensure that these add-on drug delivery tools are performing exactly as intended.
Testing of a dose cup (or any other device that uses a printed or engraved scale) is a relatively simple process once you begin to understand a few key factors that must not be overlooked. In the development of a dose cup, there are two key stages in which testing may occur.
In the first stage, the cup manufacturer should initiate testing that ensures the printed or engraved lines on the cup are accurately placed. Using the example of a 30 ml total volume cup with lines at 5, 10, 15, 20 and 25 ml levels, it is imperative that each line be placed at precise points corresponding to each volume. Testing at this stage should rely on the use of distilled water (at 25 degrees C) and a video microscope or optical comparator to precisely measure and view the water level at the specific line. Based upon the fact that 1 ml of 25C distilled water will be equal to 1 gram, a water level at the 5 ml line should weigh 5 grams. As each line is tested, the corresponding weight of the distilled water can be measured. If there is a discrepancy, it is at this stage in the manufacturing process that the line can be adjusted (up or down) on the cup side wall.
The second stage of testing typically occurs when the dose cup is assigned to a specific product. Dosing accuracy testing at this stage becomes slightly more complicated because of variations in the product density. Unlike distilled water, which has a density of 1.0, product density can vary greatly. The gravimetric methods may still be applied, but the density factor must be known and used when computing weight adjustments. Thus, the product at the 5 ml line may yield a weight result of 5.65 grams or 4.73 grams – normalizing the result using the density factor is a critical step.
Other factors must also be considered and evaluated when dose testing is being performed with actual product. For example, the residual effect must be calculated to determine the exact amount of product that is actually delivered to the patient. The residual effect is defined as the volume of product that is left in the dose cup after delivery of the product to the patient. In laymen’s terms, this is the product that is left on the cup side wall after the patient has ingested the drug product. A higher than expected volume can mean that the dose delivered may be lower than intended. It is critical that factors like this be identified and tested as part of the qualification test plan.
The USP <905> chapter does not outline or address test procedures for items like dose cups and pre-printed syringes, which are typically used for over-the-counter products. However, the manufacturers have a regulatory responsibility to ensure the quality and accuracy of the drug and its delivery devices. Test plans in this unique area are best developed under a formal protocol process that is specific to the drug product and the delivery method. By using the protocol development approach, all of the unique factors for that product can be outlined and addressed (i.e. the product density). In addition, specific items like residual volume and delivered volume can be calculated.
Over the past five years, we have seen an increase in FDA interest in dose cups and other product delivery devices. Companies have worked to improve the accuracy and develop more stringent internal guidelines that help ensure improved quality for these items. The key to success is the development of a quality control test protocol that is specific to the product and uses sound scientific principles and instruments such as NIST traceable balances, optical comparators, and video microscopes.