Powder Flow: Identifying CQAs and CPPs: Powder Measurement for QbD

Implementing QbD calls for identification of both critical to quality attributes (CQAs) and critical process parameters (CPPs). CQAs are those that impact key aspects of product performance, such as safety, efficacy and stability. CPPs are the process variables that control CQAs during manufacture. Accurate definition and control of both sets of variables is clearly essential, but requires detailed knowledge of the process and the product. Acquiring this information can present a challenge, especially for particulate systems, but modern multi-faceted powder characterization can help by providing highly relevant data in a cost- and time-effective way.

Consider the requirements for powder characterization imposed by adopting QbD in the development of a particulate product. Formulation demands definition of the powder properties that control product performance (CQAs) and determination of associated specifications for release. Process designers, on the other hand, need to understand how powder characteristics will affect in-plant behavior in order to ensure compatibility between equipment and material, and develop a process that consistently delivers in-spec product. An important part of this is setting appropriate specifications for any powder feeds to the plant, since batch-to-batch variation may affect processability and/or product quality.

It is not possible to capture the complexity of powder behavior with just a single number, particularly when the aim is to correlate measured properties with such different aspects of performance. The characteristics that determine clinical success may not be the ones that influence processability, and even within the process environment different parameters may apply for specific unit operations. A principal benefit of ‘universal’ powder testers that offer a suite of testing methodologies is their ability to rapidly measure an array of shear, dynamic and bulk properties, which together provide the fullest description of powder behavior. The resulting dataset can be used to establish correlations between processing performance and powder properties.

With tablets, for example, content uniformity is usually critical since it determines the consistency of drug delivery. The manufacturing process must be designed and operated to achieve this goal, but requires control of a number of processing steps; blending and discharge from the feed hopper are prime examples. Blending behavior is influenced by properties such as cohesivity and the material’s response to aeration, while flow through the feed hopper is a function of shear properties and powder flowability, particularly under consolidated conditions. Quantifying the tendency of a material to segregate is also very important from the point of view of final product uniformity.

For dry powder inhalers (DPI), fine particle fraction (FPF) is an important parameter because it reflects the amount of active ingredient that will, because of its size, tend to deposit in the lung. FPF is therefore an indication of the effectiveness of drug delivery. With DPI technology the response of the formulation to aeration is especially important because it has an impact on aerosolization behavior during inhalation. Research has shown a direct correlation between aerated flow energy and FPF [1].

All the powder characteristics highlighted in these two examples can be measured reproducibly using a system such as the FT4 Powder Rheometer. This quantifies an array of powder descriptors, facilitating the identification of critical process and product characteristics, and encouraging the successful implementation of QbD.

[1] Shur, J., Price, R., Freeman, T (2008). Fine tuning DPI formulas, Manufacturing Chemist, June 2008, p42-44

Author Biography

Tim Freeman, Managing Director, Freeman Technology

Tim Freeman is Managing Director of powder characterisation company Freeman Technology for whom he has worked since the late 1990s. He was instrumental in the design and continuing development of the FT4 Powder Rheometer® and the Uniaxial Powder Tester. Through his work with various professional bodies, and involvement in industry initiatives, Tim is an established contributor to wider developments in powder processing.

Tim has a degree in Mechatronics from the University of Sussex in the UK. He is a mentor on a number of project groups for the Engineering Research Center for Structured Organic Particulate Systems in the US and a frequent contributor to industry conferences in the area of powder characterisation and processing. A past Chair of the American Association of Pharmaceutical Scientists (AAPS) Process Analytical Technology Focus Group Tim is a member of the Editorial Advisory Board of Pharmaceutical Technology and features on the Industry Expert Panel in European Pharmaceutical Review magazine.  Tim is also a committee member of the Particle Technology Special Interest Group at the Institute of Chemical Engineers, Vice-Chair of the D18.24 sub-committee on the Characterisation and Handling of Powders and Bulk Solids at ASTM and a member of the United States Pharmacopeial (USP) General Chapters Physical Analysis Expert Committee (GC-PA EC).

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