Mark Copley of Copley Scientific answers questions about upcoming changes to nebulizer testing requirements.
Q: What are the new nebulizer testing requirements, and when do they come into force?
A: Both the United States Pharmacopoeia (USP) and the European Pharmacopoeia (Ph. Eur.) are introducing new monographs relating to the testing of nebulizers within the next six months. The new monographs are USP 1601, which is coming into force in a few days, in August 2011, and Ph. Eur. 2.9.44, which takes effect in January 2012.
Q: How do the new testing methods differ from past methods?
A: Essentially, in the past, nebulizers have been considered as medical devices and tested as such, rather than as a combined product with a specific formulation. The new monographs harmonize testing with the approach adopted for other OINDPs, which is to test the device and formulation together.
Each of the harmonized monographs covers both dose uniformity and aerodynamic particle size distribution (APSD) measurement.
Key points to note are:
• Greater emphasis on use of the Next Generation Impactor (NGI) for APSD measurement
• The new monographs require testing using breathing profiles for neonates, infants, and/or children where appropriate for assessing dose delivery (active substance delivery rate and total active substance delivered).
• More detail on test methodology than either the European Committee for Standardization (CEN) or ISO standards that have been in effect.
Q: What other changes will the new monographs introduce?
A: Because the new monograph focuses on the use of the NGI, it also includes some detail on the need for impactor cooling for measurement of certain formulations.
The NGI is well-suited to the measurement of APSD for nebulizers because it has calibrated performance at 15 L/min, which reflects the mid-tidal flow rate of a typical adult user, and because it is well established as the impactor of choice for the testing of other orally inhaled drug products. However, droplet evaporation due to heat transfer from the NGI can lead to inaccuracies in the determination of the APSD for many inhalation formulations, especially where the drug is in solution. The new monograph points to the importance of cooling the impactor at 5°C for at least 90 minutes prior to testing to prevent this problem, unless method development has indicated that cooling is unnecessary.
Q: How prepared are most labs for the new testing methods? Is everyone affected aware of the changes?
A: This is of course difficult to judge with any certainty, but the proposed monographs have been in discussion for some time – they were first drafted in 2006 and published in Pharmacopeial Forum and Pharmeuropa.
Equipment suppliers have been gearing up for the change ahead of the final monographs being published, so there has been the opportunity to begin to modify testing methods ahead of their introduction. The research work published on NGI cooling would suggest that people have been actively reviewing their protocols for some time, and many may already have switched to the NGI following its calibration specifically for nebulizer testing at 15 L/Min, which occurred in 2004.
Q: Will laboratories need to upgrade their testing equipment to comply with the new requirements?
A: The original CEN methodology was based on the Marple 298X impactor, which was originally designed as a sampler for monitoring aerosols in the work environment and which operates at 2L/min. Despite the fact that its design necessitates sampling from the 15 L/Min flow applied to the nebulizer during testing and other limitations, including capacity, some people are no doubt still using a Marple 298X for nebulizer testing and will need to upgrade to an NGI.
For anyone who is developing nebulized products specifically for the adult market , their existing breath simulator will be sufficient since the conditions recommended for testing of products destined for adult use remain unchanged. Both the CEN and ISO standards specify the application of a sinusoidal wave with a tidal volume of 500 ml, an inhalation to exhalation ratio of 1:1 and a frequency of 15 breaths per minute, all of which is retained in the new monographs.
However, anyone testing products suitable for pediatric use will now need a breath simulator capable of applying the different breathing profiles defined for neonate, infant, and child. Taken in combination with the adult breathing profile the requirement is now for a breathing simulator with greater flexibility, and some older models may not be up to the task.
For situations where a particular inhalation solution formulation requires cooling of the NGI in order to obtain accurate APSD measurements, it may be possible to get by using standard laboratory refrigeration facilities. Laboratories looking for a more efficient alternative that ensures temperature stability throughout testing may wish to purchase an NGI Cooler specifically designed for that purpose.
Q: Were there any changes proposed that did not make it into the final versions? Anything that may change in the future?
A: One topic discussed during the development of the monograph was the need for cup coating to prevent particle re-entrainment within the impactor. The superior aerodynamic performance of the NGI and its high jet velocities increases the risk of particle bounce, but tests have shown that bounce is rarely an issue with suspension- and solution-based products such as those used with nebulizers. The monograph reflects these findings suggesting that cup coating will rarely be required.
To my knowledge there is no other ongoing work that will change the testing methods in the near future, so I wouldn’t anticipate further changes at this stage.
