PHARMACEUTICALS real-time degradation rates at longterm stress conditions . Computational methods for accelerated stability assessment programme ( ASAP ) studies are powerful tools for predicting product shelf life and packaging options for tablets , capsules , softgels , intermediates , granules , blends , solutions and suspensions , quickly and accurately
ASAP studies use an isoconversion approach , looking at time to edge of failure from the point when samples are exposed to elevated temperatures and humidity levels . By leveraging a modified Arrhenius equation that accounts for both temperature and humidity , product shelf life and packaging can be predicted by backcalculating from that point .
Typical ASAP studies can be completed in three to four weeks , as opposed to two years for traditional stability programmes . A particular advantage of this approach is that it enables the selection of appropriate packaging components without the need for multiple package-screening
PHASE
DISCOVERY AND PRECLINICAL
PRECLINICAL
INPUT
• 2D structure
• Melting point
• Available physicochemical data
• Experirm1ntal physicochemical properties
• Experimental dissolution data
• In vitro ADME data
• In vivo animal PK studies ( IV and oral formulation )
• Experimental physicochemical properties
• Experimental dissolution data
• Measured in vitro AOME data
• In vivo human PK studies
Table 1 – ADME-PK modelling in different clinical stages
SEP / OCT 2023 studies . The shelf-life predictions based on these analyses can be used to inform storage recommendations and to justify use of material .
From a regulatory perspective , predictive stability modelling is widely accepted globally for early clinical trials ( INDs and IMPDs ). The data is also used in new drug approval applications for the following purposes :
• Demonstrating the validity of models against ICH data
• Bridging clinical-tocommercial changes
• Justifying specification limit , formulation or process changes
• Selecting commercial packaging
• Defining critical quality attributes
Post-approval applications include justification for reduced-protection packaging and acceptance of aftershipping excursions .
Material science , compaction simulation & process modelling
A quality by design ( QbD ) approach to developing drug dosage forms
OUTPUT
• Prediction of physicochemical properties
• Prediction of BCS / DCS / ECCS classification
• Prediction of absorption , metabolism , and excretion
• Technology / excipient selection for oral formulation
• Prediction of dose number and food effect
• Assessment of formulation impact on PK
• Compartmental PK analysis of animal data
• Pl3PK modeling of IV and oral animal studies
• Evaluation of animal bioavailability and PK
• Human PBPK models for FIH PK and clinical dosing strategy
• Pl3PK modeling for humaniS
• Evaluation of human bioavailability and PK
• Assessment of PK guided-dose escalation studies
• Assessment of variability among special populations requires careful characterisation and understanding of the properties and limitations of the product and process . In silico process modelling offers advanced technologies like compaction simulation , discrete element modelling ( DEM ), and computational fluid dynamics ( CFD ) for applications ranging from material characterisation and formulation development to process scale-up and tech transfer .
With respect to oral solid dosages , tablets are the most common and are typically the least expensive vehicle for dosing APIs . Early tablet development is hampered , however , by the limited quantity and prohibitive cost of API available for lab testing and manufacturing process scale-up .
Further , because of the complex powder mechanics involved in tableting , process changes that increase the speed and the duration or force of compression may keep a tablet formulation from working on new equipment . Similarly , even minor changes in tooling design can impact powder compaction proprieties and lead to tablet failure from capping or lamination .
A rational manufacturing decision tree system offers a materialsparing option for addressing these challenges , both for formulation development and for prediction of behavior upon scale-up . To assess processability and manufacturability , the critical decision tree inputs are compaction behavior and powder flow properties .
The compaction behaviour of materials can be evaluated using compaction simulation and analytical techniques . Compaction simulators are computer-controlled devices programmed to mimic precisely the cycle of any tableting process in real time and record the parameters , enabling the evaluation of tablet properties ( strength , disintegration , dissolution ) under identical manufacturing conditions , as well as basic compaction mechanisms , scale-up parameters , material build-
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