Delivered-dose uniformity

Currently the U.S., European, and British pharmacopeias specify different requirements for delivered dose uniformity. Table 5 describes these requirements as well as proposed FDA expectations [33]. The Japanese pharmacopeia does not speeify a delivered dose uniformity requirement. Current compendia should be eonsulted as referenees. 

Of the four pharmacopeias, the U.S. pharmacopeia (USP) has the strietest requirements for delivered dose uniformity. Although the British pharmaeopeia (BP) allows the same performance range, the USP defines the range around the label claim and the BP defines the range around the average value. The FDA expeetation for delivered dose uniformity is currently tighter than that stated in all the pharmaeopeias. 

Various dry powder attributes are assessed at release and on stability. These include physieal eharaeteristies sueh as appearance, content uniformity, delivered dose uniformity, and partiele size distribution. Chemieal attributes that may be assessed include drug eontent, purity, and identity, as well as the water content. Dry powders may also undergo mieroseopie evaluation for foreign particulate matter, unusual agglomeration, and partiele size. Mierobial limits should also be examined, including the total aerobie, yeast, and mold eounts. The presence of specific pathogens should be ruled out. The dry powders may be dissolved to test for pH. 

In addition, eertain eompendial requirements for content and delivered dose uniformity should be measured. The USP and EP propose that the total aerobic count not exceed 100 CFU/g (colony-forming imits) that the total yeast and mold counts not exceed 10 CFU/g and that no specific pathogens be detectable. Specifications for the other attributes should be based on the intended use and the historical performance of the product. As with other dosage forms, specifications must be met throughout the intended shelf life of the product. 

Dose Content Uniformity/Delivered-Dose Uniformity.335... 

IPAC-RS (2001) A parametric tolerance interval test for improved control of delivered dose uniformity in orally inhaled and nasal drag products. 

Data should be provided on uniformity of delivered dose using the Ph Eur method. Products should be able to attain a range of nominal 20% or better. The specification should be based on data from satisfactory clinical batches of product, taking into account the tolerances of the device and the batch variability for lots used in clinical studies. 

Two critical attributes characterize the performance of DPIs the uniformity of the delivered dose and the... 

Table 16 Dose uniformity of a NCE delivered EHD pulmonary drug delivery device...

MDI products are subject to batch control and acceptance tests similar to those for other pharmaceutical dosage forms, that is, active drug identification, dose delivery, and dose uniformity. Additional special tests unique to inhalers, e.g., characterizing the particle size distribution of the delivered aerosol, are also applied. Typical tests are shown in Table 3. 

Brown D, Ford JL, Nunn AJ, et al. An assessment of dose-uniformity of samples delivered from paediatric oral droppers. J Clin Pharm Ther 2004 29 521-529. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

Important for aU different preparations and delivery devices is that they meet the requirements for uniformity of the delivered dose and the number of deliveries per inhaler for multidose inhalers. Also the fine particle dose has to be tested and calculated, but there are no... 

Nasal sprays with a declared amount of active substance for each puff (so called metered-dose sprays), should comply with the requirements on the variation in this amount. In practice, this is only seen in licensed medicines. For solutions the test for uniformity of mass is sufficient. Suspensions should comply with the test for uniformity of dosage units (see Sect. 32.7.2.4), or, where justified and authorised, with the test for uniformity of delivered dose. In this test, specially meant for metered-dose sprays, the allowed range of variation is much broader than for oral preparations. 

Topical aerosols and nasal sprays rely on pump systems to deliver the API in the form of finely dispersed mist or as coarse spray or stream of semisolid. Because of their design, aerosol and nasal products are usually under very high pressure, and this makes it difficult to obtain suitable samples for analysis. In spite of that, a number of very specialized tests which include pressure test, minimum fill, number of discharges per container defivered dose uniformity, delivery rate, leak test, spray pattern and plume geometry test, assay, and microbial enumeration test (MET) have been devised to test the integrity of the aerosol package and the device used to defiver the dose. ... 

Pharmaceutical scientists have developed improved suspension dosage forms to overcome problems of poor physical stability and patient-perceived discomfort attributed to some active ingredients. An important development aspect of any suspension is the ability to resuspend easily any settled particles prior to instillation in the eye and ensure that a uniform dose is delivered. It would be ideal to formulate a suspension that does not settle since the patient may not always follow the labeled instructions to shake well before using. However, this is usually not feasible or desirable since the viscosity required to retard settling of the insoluble particles completely would likely be excessive for a liquid eyedrop. The opposite extreme, of allowing complete settling between doses, usually leads to a dense layer of agglomerated particles that are difficult to resuspend. 

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