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With physicochemical data derived from preformulation studies, the formulation scientist can leverage this information to assess initial compatibility of formulation components and begin activities surrounding process design. During this phase of the development, importance is placed on optimization of the formulation development of the final dosage form and process design. Also during this phase, consideration is given to factors affecting scale-up from bench top to pilot scale.

In QbD, this phase is focused on providing a defined design space to meet FDA and ICH guidelines. Within this area of focus, greater detail is developed for Critical Mat erials Attributes (CMA) and Critical Process Parameters (CPP).

Material Characteristic
Influences
Example
Particle Size Bioavailability, Powder Flow, Compaction, Compression, Dissolution, Blend Uniformity, Protein Aggregation In a final crystallization step, particle size is a CQA (critical quality attribute) used to determine design space variables. Particle size distribution also has a direct impact on biologic material performance and processing. It can also be indicative of undesirable protein aggregation.
Particle Shape Bioavailability, Compaction, Critical Element in Solid and Liquid Dispersion Processing Product morphology in addition to size has direct influence on solubility. Inhaled products are based on less than 5 µm  aerodynamic shape to be deposited in the lungs and not upper respiratory areas. Shape can be used as a PAT to define process send points and batch-to-batch variability.
Surface Area Dissolution, Solubility Compaction, Milling, Stability, Lyophilized Products It is apparent that the dissolution rate of a drug can be proportional to the surface area exposed to the dissolution medium. Surface area can provide critical information in lyophilization in regard to ice crystal formation.
Density Roller Compaction-Lubrication Tableting Setting, Segregation, Compaction, Crystallinity API and excipients are blended and typically then granulated or densified to ensure a uniform blend is delivered to the tablet press.  The material is also granulated to aid in material movement as granulations move easier than powder blends. True density can be indicative of how close the material is to a crystalline state or the proportions of a binary mixture.
Porosity Roller Compaction, Tablet Shelf Life, Fragmentation,  Compaction, Content Uniformity/Dissolution Indicator for shelf life and air and moisture penetration. Porosity measurement can evaluate the ability of liquids to penetrate the tablet for dissolution assessment. Can assist in parameter setting for material flow in coating operations. Predictive evaluation for pellet deformation during compression. Tablet crushing strength influenced by pore size distribution.
Inverse Gas Chromatography Powder Surface Energies, Acid/Base/PolarFunctionality of Surfaces, Diffusion Kinetics, Solubility Parameters,  Phase Transition Temperatures Effect of manufacturing process (i.e. compaction, milling, and predictive particle interactions). Measure properties that help calculate Material Cohesivity and Hansen Solubility Parameters.

 

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QbD Quantitive Measurements of CQAS in Solid Dosage Form Unit Operations...

 .. for Porosity | Density | Surface Area »

 .. for Particle Size | Material Segregation-Flow | Vapor Sorption »

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