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Process Design and Pilot Scale Up

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During this phase of development, emphasis is placed on evaluating options available to manufacture, purify, and charac-terize the final formulation by focusing on how Critical Quality Attributes (CQA) can impact Critical Process Parameters (CPP). Using the principles of QbD and experimental design, a design space with proven acceptable processing ranges is created that will produce a rugged, robust control strategy to meet estab-lished Quality Target Product Profiles and may allow for paramet-ric (real-time) product release.

Process Analytical Technology (PAT) is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.

Material Characteristic
Influences
Example
Particle Size Powder Flow, Compaction, Compression, Blend Uniformity, Protein Aggregation. Fines Production API particles are of varying sizes and distribution and can potentially affect stability, solubility, and efficacy. PAT Compatible at line
Particle Shape Bioavailability, Compaction, Critical Element in Solid and Liquid Dispersion Processing Product morphology in addition to size has a direct influence on solubility. Shape can be used as a PAT to define process end points and batch-to-batch variability. Fragmentation can indicate the robustness of a process from unit to unit. PAT Compatible at line
Surface Area Critical Quality Attribute of  API and Excipients Solubility Compaction, Milling, Stability, Lyophilized Products Surface area can provide critical information in lyophilization in regard to ice crystal formation.
Density Roller Compaction-Lubrication Tableting Setting, Segregation, Compaction Can be utilized as a control parameter for solid dosage tableting uniformity using various tablet presses. PAT Compatible at line
Porosity Roller Compaction,  Fragmentation,  Compaction, Scoring Tablets for Half Dosages Indicator for shelf life and air and moisture penetration. Tablet crushing strength, ability to withstand coating processes, and tablet robustness is influenced by pore size distribution.
Yield Strength of Powders Flowability Characteristics of Powdered or Granular Materials Sample material will flow as long as the force acting upon the sample to cause the flow of the material is higher than the sample’s yield strength.  PAT Compatible at line
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).
Materials Segregation Segregation Mechanisms to Determine Sifting, Angle of Repose, Air Entrapment, Fluidization Provides uniformity index for sample and segregation variance data. PAT Compatible at line

 

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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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