Information about size and shape of particles produced in various manufacturing processes is very important for process and product development because design of downstream processes as well as final product properties strongly depend on these geometrical particle attributes. However, recovery of particle size and shape information in situ during crystallisation processes has been a major challenge. The focused beam reflectance measurement (FBRM) provides the chord length distribution (CLD) of a population of particles in a suspension flowing close to the sensor window. Recovery of size and shape information from the CLD requires a model relating particle size and shape to its CLD as well as solving the corresponding inverse problem. This paper presents a comprehensive algorithm which produces estimates of particle size distribution and particle aspect ratio from measured CLD * Corresponding author data. While the algorithm searches for a global best solution to the inverse problem without requiring further a priori information on the range of particle sizes present in the population or aspect ratio of particles, suitable regularisation techniques based on relevant additional information can be implemented as required to obtain physically reasonable size distributions. We used the algorithm to analyse CLD data for samples of needle-like crystalline particles of various lengths using two previously published CLD models for ellipsoids and for thin cylinders to estimate particle size distribution and shape. We found that the thin cylinder model yielded significantly better agreement with experimental data, while estimated particle size distributions and aspect ratios were in good agreement with those obtained from imaging.

Quality by design (ICH-Topic Q8) requires a prospective summary of the desired quality characteristics of a drug product. This is known as the Quality Target Product Profile (QTPP), which forms the basis for the design and development of the product. An analogous term has been established for analytical procedures called the Analytical Target Profile (ATP). The ATP, in a similar fashion to the QTPP, prospectively summarizes the requirements associated with a measurement on a quality attribute which needs to be met by an analytical procedure. Criteria defined in the ATP relate to the maximum uncertainty associated with the reportable result that is required to maintain acceptable confidence in the quality decision made from the result. The ATP is used to define and assess the fitness of an analytical procedure in the development phase and during all changes across the analytical lifecycle. One or more analytical procedures can meet the requirements of an ATP. The ATP can be applied to any quality attribute across any pharmaceutical modality where an analytical procedure is used to generate a reportable result, and this paper provides examples from three of these modalities: small molecules, oligonucleotides, and vaccines. Some key performance characteristics will be discussed for each ATP, namely specificity, accuracy, and precision, taking into account the expected range of the analyte. The combination of accuracy and precision into a combined uncertainty characteristic is also discussed as a more holistic approach. The use of the ATP concept will help focus attention on the properties of a method which impact quality decisions rather than method descriptions and may enable greater regulatory flexibility across the lifecycle using established conditions based on method performance criteria as proposed in the Step 2 version of ICHQ12. The revision of ICHQ2(R1) and development of the new ICHQ14 guideline (Analytical Procedure Development) will provide a golden opportunity to harmonize the definition of new QbD concepts such as the ATP.A nalytical technology, method development, validation, and technical transfers are encountered across many manufacturing industries, including the pharmaceutical, fine

Analysis of needle-shaped particles of cellobiose octaacetate (COA) obtained from vacuum agitated drying experiments was performed using three particle size analysis techniques: laser diffraction (LD), focused beam reflectance measurements (FBRM) and dynamic image analysis. Comparative measurements were also made for various size fractions of granular particles of microcrystalline cellulose. The study demonstrated that the light scattering particle size methods (LD and FBRM) can be used qualitatively to study the attrition that occurs during drying of needle-shaped particles, however, for full quantitative analysis, image analysis is required. The algorithm used in analysis of LD data assumes the scattering particles are spherical regardless of the actual shape of the particles under evaluation. FBRM measures a chord length distribution (CLD) rather than the particle size distribution (PSD), which in the case of needles is weighted towards the needle width rather than their length. Dynamic image analysis allowed evaluation of the particles based on attributes of the needles such as length (e.g. the maximum Feret diameter) or width (e.g. the minimum Feret diameter) and as such, was the most informative of the techniques for the analysis of attrition that occurred during drying.

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