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Report on the workshop on drug delivery
J. Aerosol Sci., Vol. 24, No. 1, pp. 115 116. 1993. Pergamon Press Ltd. Printed in Great Britain.
REPORT ON THE WORKSHOP ON D R U G DELIVERY Held during the 1992 European Aerosol Conference, Oxford, September 1992 Chairman: Prof. D. Ganderton
Currently, the European Pharmacopoeia is assessing a number of devices designed to analyse the dose of drug emitted by propellant-based metered-dose inhalers. These are designed to measure the magnitude of the emitted dose, its reproducibility, and assess a quality of the emitted flume which can be related to the amount of drug delivered to the lungs, normally its inertial behaviour. This area is under worldwide review at present, with other test methods being proposed, including multi-stage liquid impingers and cascade impactors. The objective of this Workshop was to discuss the findings of a multi-centre study, each using the same range of test methods on the same batch of products. Five laboratories took part in this study: four were from the pharmaceutical industry (Astra, Boehringer Ingelheim, Fisons and Glaxo), and one from academia (ClermontFerrand), which unfortunately was unable to be represented at the Workshop. Each laboratory assessed the inhalers using four techniques: (a) a two-stage liquid impinger, operating at 60 lpm, with an intermediate cut-off size of 6.4 pm; (b) a two-stage impactor, with an upper stage which can be immersed in liquid to minimize particle bounce, also operating at 60 lpm to give an intermediate cut-off size of 9.4 #m; (c) a four-stage liquid impinger operating at 60 lpm to give a cut-off size for the bottom two stages of 6.8 #m and (d) an Andersen impactor operating at 28 lpm, where penetration below stage 2 gives a cut-off size of 5.8 pm. Entry conditions to these devices are critical, since the initial flume velocity is well above the air velocity in each device, preventing complete entrainment and thereby introducing error into the quoted cut-off sizes. For all but apparatus (b), the same glass inlet throat was used. This attempts to simulate the distance from the inhaler orifice to the back of an adult human throat. Two operators from each laboratory measured the same three inhalers (from a single manufacturing batch) using standard operating procedures for all four methods. In general each laboratory felt most comfortable using test methods which were routinely in use. All agreed that the cascade impactor was the most difficult to use, and this showed most variability in the data produced. To some extent, this may reflect the sharper cut-off characteristics. Another important aspect demonstrated was that the design of the inlet has a significant influence on the degree of penetration to the lower stages of the apparatus. Thereafter, parameters such as residence time have little effect on the measured size of the aerosol. As this is controlled by the inertial properties of the whole flume, rather than particle size alone, the value of the additional data generated by the cascade impactor was questioned. From analysis of variance, the variability in the data generated showed least dependence on which of the three inhalers was measured. Operator variability tended to be lower on methods in routine use at the laboratory, than on unfamiliar techniques. Further, there was a significant component of variability between the different laboratories, despite all working to standard operating procedures. Temperature in the different laboratories was controlled, but not relative humidity. In addition, there was no standardization on the training given on each of the procedures. This serves to illustrate a potential pitfall, even with carefuly controlled methodology. None of the four methods give results which are in agreement with in vivo studies using radioactive traces. A paper presented elsewhere in the conference (D. L. Swift) demonstrated much closer agreement when the inlet is in the form of a cast of the human oropharynx. However, the need for realism in a quality control method is different to that 115
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Workshop Report
in a pharmacokinetic or research tool. Thus, there may be a need for different levels of sophistication, perhaps including velocity analysis, in different applications. The findings of this study group will be collated and formally published. However, the collaboration will not finish there; it is planned to repeat the exercise with a higher dosage strength product. Thereafter, a similar group will investigate the problems associated with setting standard test methods for powder inhalers. J. N. PRITCHARD
REPORT ON THE WORKSHOP ON D R U G DELIVERY Held during the 1992 European Aerosol Conference, Oxford, September 1992 Chairman: Prof. D. Ganderton
Currently, the European Pharmacopoeia is assessing a number of devices designed to analyse the dose of drug emitted by propellant-based metered-dose inhalers. These are designed to measure the magnitude of the emitted dose, its reproducibility, and assess a quality of the emitted flume which can be related to the amount of drug delivered to the lungs, normally its inertial behaviour. This area is under worldwide review at present, with other test methods being proposed, including multi-stage liquid impingers and cascade impactors. The objective of this Workshop was to discuss the findings of a multi-centre study, each using the same range of test methods on the same batch of products. Five laboratories took part in this study: four were from the pharmaceutical industry (Astra, Boehringer Ingelheim, Fisons and Glaxo), and one from academia (ClermontFerrand), which unfortunately was unable to be represented at the Workshop. Each laboratory assessed the inhalers using four techniques: (a) a two-stage liquid impinger, operating at 60 lpm, with an intermediate cut-off size of 6.4 pm; (b) a two-stage impactor, with an upper stage which can be immersed in liquid to minimize particle bounce, also operating at 60 lpm to give an intermediate cut-off size of 9.4 #m; (c) a four-stage liquid impinger operating at 60 lpm to give a cut-off size for the bottom two stages of 6.8 #m and (d) an Andersen impactor operating at 28 lpm, where penetration below stage 2 gives a cut-off size of 5.8 pm. Entry conditions to these devices are critical, since the initial flume velocity is well above the air velocity in each device, preventing complete entrainment and thereby introducing error into the quoted cut-off sizes. For all but apparatus (b), the same glass inlet throat was used. This attempts to simulate the distance from the inhaler orifice to the back of an adult human throat. Two operators from each laboratory measured the same three inhalers (from a single manufacturing batch) using standard operating procedures for all four methods. In general each laboratory felt most comfortable using test methods which were routinely in use. All agreed that the cascade impactor was the most difficult to use, and this showed most variability in the data produced. To some extent, this may reflect the sharper cut-off characteristics. Another important aspect demonstrated was that the design of the inlet has a significant influence on the degree of penetration to the lower stages of the apparatus. Thereafter, parameters such as residence time have little effect on the measured size of the aerosol. As this is controlled by the inertial properties of the whole flume, rather than particle size alone, the value of the additional data generated by the cascade impactor was questioned. From analysis of variance, the variability in the data generated showed least dependence on which of the three inhalers was measured. Operator variability tended to be lower on methods in routine use at the laboratory, than on unfamiliar techniques. Further, there was a significant component of variability between the different laboratories, despite all working to standard operating procedures. Temperature in the different laboratories was controlled, but not relative humidity. In addition, there was no standardization on the training given on each of the procedures. This serves to illustrate a potential pitfall, even with carefuly controlled methodology. None of the four methods give results which are in agreement with in vivo studies using radioactive traces. A paper presented elsewhere in the conference (D. L. Swift) demonstrated much closer agreement when the inlet is in the form of a cast of the human oropharynx. However, the need for realism in a quality control method is different to that 115
116
Workshop Report
in a pharmacokinetic or research tool. Thus, there may be a need for different levels of sophistication, perhaps including velocity analysis, in different applications. The findings of this study group will be collated and formally published. However, the collaboration will not finish there; it is planned to repeat the exercise with a higher dosage strength product. Thereafter, a similar group will investigate the problems associated with setting standard test methods for powder inhalers. J. N. PRITCHARD