Variability in delivered dose and respirable delivered dose from nebulizers: are current regulatory testing guidelines sufficient to produce meaningful information?

Ross HM Hatley, Sarah M Byrne Respironics Respiratory Drug Delivery (UK) Ltd, a business of Philips Electronics UK Limited, Chichester, UK Background: To improve convenience to patients, there have been advances in the operation of nebulizers, resulting in fast treatment times and less drug lost to the environment. However, limited attention has been paid to the effects of these developments on the delivered dose (DD) and respirable delivered dose (RDD). Published pharmacopoeia and ISO testing guidelines for adult-use testing utilize a single breathing pattern, which may not be sufficient to enable effective comparisons between the devices.Materials and methods: The DD of 5 mg of salbutamol sulfate into adult breathing patterns with inhalation:exhalation (I:E) ratios between 1:1 and 1:4 was determined. Droplet size was determined by laser diffraction and RDD calculated. Nine different nebulizer brands with different modes of operation (conventional, venturi, breath-enhanced, mesh, and breath-activated) were tested.Results: Between the non-breath-activated nebulizers, a 2.5-fold difference in DD (~750–1,900 µg salbutamol) was found; with RDD, there was a more than fourfold difference (~210–980 µg). With increasing time spent on exhalation, there were progressive reductions in DD and RDD, with the RDD at an I:E ratio of 1:4 being as little as 40% of the dose with the 1:1 I:E ratio. The DD and RDD from the breath-activated mesh nebulizer were independent of the I:E ratio, and for the breath-activated jet nebulizer, there was less than 20% change in RDD between the I:E ratios of 1:1 and 1:4.Conclusion: Comparing nebulizers using the I:E ratio recommended in the guidelines does not predict relative performance between the devices at other ratios. There was significant variance in DD or RDD between different brands of non-breath-activated nebulizer. In future, consideration should be given to revision of the test protocols included in the guidelines, to reflect more accurately the potential therapeutic dose that is delivered to a realistic spectrum of breathing patterns. Keywords: nebulizer, inhalation:exhalation (I:E) ratio, breathing pattern, delivered dose (DD), respirable delivered dose (RDD), testing guideline

Determination of End Point of Primary Drying in Freeze-Drying Process Control

Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer

Emerging Freeze-Drying Process Development and Scale-up Issues

Although several guidelines do exist for freeze-drying process development and scale-up, there are still a number of issues that require additional attention. The objective of this review article is to discuss some emerging process development and scale-up issue with emphasis on effect of load condition and freeze-drying in novel container systems such as syringes, Lyoguard trays, ampoules, and 96-well plates. Understanding the heat and mass transfer under different load conditions and for freeze-drying in these novel container systems will help in developing a robust freeze-drying process which is also easier to scale-up. Further research and development needs in these emerging areas have also been addressed