The Impactor Sub-Team of the European Pharmaceutical Aerosol Group (EPAG), a consortium of pharmaceutical companies that develop pulmonary and intranasal drugs, has focused its attention on the potential benefits of the abbreviated impactor method (AIM), a fast screening technique to provide a good estimate of the potentially respirable and non-respirable fractions of a pharmaceutical aerosol that uses as few as two impactor stages.
The MSP Fast Screening Impactor
AIM can provide aerodynamic particle size information for pharmaceutical aerosols when the full particle size distribution provided by multi-stage cascade impactors is unnecessary, as in product quality control or for drug formulation screening and optimization, for example. The technique may save up to 50% of the time required to perform full multi-stage cascade impactor testing and also requires significantly less solvent for sample recovery, a significant consideration, given the increasing importance of the “green chemistry” movement, which promotes sustainable industry.
Over the past few years, several manufacturers have begun offering commercial AIM instruments based on the Andersen cascade impactor (ACI) and the Next Generation Cascade Impactor (NGI), and scientists from various companies have also been experimenting with modifying the NGI and exploring other potentially useful apparatuses, including the twin-stage liquid impinger, which is already a compendial apparatus in the European Pharmacopoeia.
At DDL 21 last month, EPAG sponsored a workshop on AIM featuring presentations of data from seven companies that have been experimenting with AIM, followed by a panel discussion focusing on the hurdles remaining for implementation and the compendial and regulatory implications of the application of this new technique.
After the workshop, sub-team members Steve Nichols, an industry consultant, and Jolyon Mitchell of Trudell Medical International sat down with OINDPnews to provide an update about EPAG’s efforts related to AIM.
Gathering AIM data
An EPAG survey that asked whether EPAG member companies would consider using AIM either in QC or in the development environment found that all the companies responding said that they were either currently using or were considering using AIM during development. The vast majority said they would consider using the technique in a QC environment once the technology has been proven and accepted. Mitchell estimates that approximately 25-30 companies have experimented with AIM to date.
The Westech FPD impactor
EPAG is encouraging all companies to test their products with one or more of the commercially available AIM apparatuses, to compare that data with equivalent measurements from the full multi-stage cascade impactor, and to publish the results. “It’s not an exclusive club; it’s an opportunity for people to bring their science and their data to the table,” notes Mitchell; “this is a very, very open discussion, and we want as many people involved as possible.” It would be very useful, they say, if companies will at minimum post their observations or comments or questions to EPAG via the “contact us” button on the EPAG web site.
In addition, says Mitchell, “We also want to hear the stories where it doesn’t work because that’s an important learning tool and may reveal a scientific issue that needs further investigation.” For companies worried about protecting data on proprietary formulations, Nichols and Mitchell suggest just calling the drug “formulation X”; they are interested only in how their AIM data compare with the full multi-stage cascade impactor data.
For anyone wanting to learn how to collect AIM data in order to participate in the EPAG efforts, they suggest that the company begin by contacting one of the three companies selling the commercial versions of the AIM apparatus: Copley Scientific, MSP Corporation, and Westech Instruments.
Companies can also apply to join the EPAG impactor sub-group at no cost without having to join the EPAG consortium itself. Impactor sub-team member companies need not be located in Europe; a number of North American companies are already participating, and those located on other continents are encouraged to join as well.
Reporting the data
The EPAG-sponsored workshop on AIM at DDL 21 had as one of its goals to “provide data led practical examples of AIM “ and included presentations of data from Pfizer, PARI, AstraZeneca, Aptar, MAP Pharmaceuticals, Trudell Medical International , and Novartis involving various types of AIM apparatus and different delivery devices. All of the presentations from the workshop are posted in the “Public Documents” area on the EPAG web site.
EPAG has also been liaising with the cascade impactor working group of the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) to evaluate the AIM technique in conjunction with the use of efficient data analysis (EDA). While EPAG has focused on apparatus and methodology development, IPAC-RS is taking the lead on EDA and will include an AIM/EDA workshop at its upcoming conference in March 2011.
IPAC-RS is coordinating with RDD Online for a session at RDD Europe called “Efficient Data Analysis in Quality Assessment Data." Also at that meeting, which will be in in Berlin this coming May, EPAG will present a poster describing key issues identified during the panel discussion of the DDL 21 AIM workshop. Then at the ISAM 2011 conference in June, Mitchell will present a talk titled, “Relating inhaler aerosol size measurement to clinical data utilizing the Abbreviated Impactor Concept,” covering possibilities for apparatuses to provide measurements most relevant to deposition in the human respiratory tract.
The regulatory situation
According to Nichols and Mitchell, both of whom have been involved in informal discussions with US and European regulators and the corresponding pharmacopoeial committees, the FDA, EMA, USP, and Ph. Eur. have all expressed interest in learning more about AIM and EDA. “It’s a win-win situation,” they suggest; “the regulators win because if they use EDA they get a less chance of a bad batch; the producer also wins because there is less chance of a good batch getting rejected.”
Mitchell, who will soon become chair of the USP aerosol subcommittee, and Nichols, a member of the European Pharmacopoeia Inhalanda working group, emphasize that they intend to work with both organizations to harmonize impactor testing requirements, with the goal of “a common understanding on both sides of the Atlantic so that it will make life easier for pharmaceutical companies compiling product approval submissions.”
Both agree that the regulators will require rigorous data to support the use of these techniques and that, as a result, regulatory acceptance is still a number of years away. Nichols points out that before proposals can be submitted, scientists must show that AIM “demonstrates a benefit, that we have suitable apparatuses available, methods that are validated, and calibration data that are publicly available.” Then, he notes, “apart from the time required to get these technical aspects “fit for purpose,” you then have the cycle of the review, so 2015 is probably about the right sort of time scale for the acceptance of AIM and EDA.”
Some of the issues that must be addressed derive from the differences in data that have been produced for DPIs using AIM compared to data produced with the full multi-stage cascade impactor. These differences likely stem from the start-up behavior in the test apparatuses as flow increases from zero to steady state. For MDIs and nebulizers, where flow rate remains steady at a pre-determined value throughout the duration of the measurement, data have proved more consistent between AIM and full multi-stage cascade impactors.
Other issues relate to the fact that assessment requirements for quality control applications and new drug submissions differ, so strategies for the use of AIM throughout the product life cycle must be developed. Finally, It is conceivable that compendial monographs dealing with AIM may be among the few that specify multiple apparatuses, and they may need to specify different cut point sizes for different situations.
Potential additional applications
Once the initial QC and product development applications for AIM and EDA have proven themselves, the EPAG sub-team will move forward in looking at possible additional uses, including a combination of aerodynamic particle size and dose content uniformity determination in a single apparatus and the possibility of in vivo/in vitro correlation. At DDL 21, IPAC-RS presented a poster demonstrating a concept for a combined impactor and dose content apparatus, and that apparatus should be available for experimental use in the coming months, once its design has been finalized.
“If the early potential of AIM and EDA, where needed, can be realized and demonstrated,” say Nichols and Mitchell, “this simplified approach could prove a major success for pharmaceutical science, industry and regulators.”
