QbD In Dry Powder Inhaler Development

Comprehensive Quality by Design in Pharmaceutical Development and Manufacture
2011 AIChE Annual Meeting
AIChE Annual Meeting
October 19, 2011 - 8:00pm

Summary

Developing products comprising un-bound fine cohesive powders throws up significant challenges. Dry powder inhalers present a prime example. Why? Because the behaviour of fine cohesive particle behaviour is notoriously complex, and notably more so than any single phase solid, liquid or gaseous material (1): where powders can exhibit the behaviour of solids, liquids or gases- and sometimes all three. Furthermore, the complexity is compounded by the need to match the nature of such a complex powder, with a small dispersion device with aerodynamically complex air flow channels intended to create some form of dispersion energy, as well as the reliance on bringing the function together by the complex and variable inspiration pattern of the patient as they inconsistently inhale through these air channels to actuate the system (2).

A few have ventured to computationally model and even develop measurement or theoretically based strategies to try to predict performance of a powder within a given device. It is proposed that none can claim success, in a way that captures effective predictive capability. Product development in this area consequently remains largely based on empirical controls of the formulation, and consequently QbD implementation in its true sense remains out of reach. Successful current development is therefore largely based on parametric control of both input materials and processes, but where the influence of parameters are not fully known, they are selected without a fundamental scientific basis, and do not yield a true design space, nor any predictive capacity. Furthermore, it is also proposed here that outcomes of the measurement of basic surface properties of real (as opposed to model and ideal) materials is either too simplistic, based on unrealistic “isolated” measurements or even beyond current scope of practical technology- for example, single particle adhesion force-contacts, electrostatic charge measurement, surface rugosity, and probing molecular surface structure cannot be either usefully or effectively measured for real pharmaceutical powders. Hence the subtitle of this paper- is a provocative challenge that past research has suffered by too great a focus much on the measurement, rather than as a problem-centred approach.

In this paper, a number of case studies will be used to illustrate apparent contradictions and failures to develop even a simple predictive capability from such measurements.

However, we have on the market highly successful and effective DPI products, and progress in understanding is ongoing. Some semi-empirical approaches have also had qualified success, such as the Cohesive-Adhesive Balance approach (CAB), despite its flaws (3). This paper will then focus on some more recent problem-driven and bulk scale approaches to make more pragmatic and hopefully effective powder property measurements and models.

References

1. Igwe GJI, 1991. “Powder technology and multiphase systems: Gas permeametry and surface area measurement”. New York: Ellis Horwood Ltd, Preface.

2. Morton, DAV, Staniforth, JN, 2005. “The Challenge of the New: Device-Formulation Matching in Dry Powder Inhaler Systems.” Pharm. Manuf. Packing Sourcer, Spring, pp. 80–83.

3. Begat P, Morton DAV, Staniforth JN, Price R, 2004. “The cohesive-adhesive balances in dry powder inhaler formulations. I: Direct quantification by atomic force microscopy.” Pharm Res 21:1591–1597.

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