4 Preliminary Risk Assessment Critical quality attributes –Content uniformity –Assay –Disintegration –Physical form of API –Physical stability of API –Purity –Chemical stability –Microbiology –Appearance Unit operations –Binder solution preparation –Granulation –Drying –Granulate shipping –Blending –Compression
Example of Failure Mode Table SODRPN EffectCause Effect (CQA) tablets Mechanism of effectScale-upUnit opCause Disintegration Homogeneity of HPCxBlendingInadequate blending Physical form API Hydrate formation during ProcessingxGranulationTime as wet mass The (CQA) test is out of specification because (mechanism of effect). The source of the problem is in (Unit operation) and is caused by (Cause1), caused by (Cause2), caused by (Cause3).
Histogram of all Failure Modes Assessed (RPN values) Medium High High: > 60 Medium: = 60
Preliminary RPN Results: Risks sorted by Unit Operation Binder solution preparation –Number of risks assessed:11 –No high or medium risk failure modes Granulation –Number of risks assessed:75 –High risk failure modes:13 /75 –Medium risk failure modes:20 /75 Fluid bed drying –Number of risks assessed:30 –High risk failure modes:3 /30 –Medium risk failure modes:16 /30
QbD Approach to Formulation Optimization The original HPC grade (Klucel EXF, fine PSD) was sensitive to small changes in water content (lacking robustness) A second HPC grade (Klucel EF, larger PSD) was more robust. Similar PSDs were achieved using Klucel EF at 5.5% water as with Klucel EXF at 2.5%.
Comparing Granule PSD Produced from Different HPC Grades Particle size distribution Granules formed with EF and 5.5% water were similar to granules formed with EXF and 2.5% water
Drying of Wet Granulations with 2 Different Grades of HPC Water added 5.5%4%3%2.5%2% EF ✔✔ ✔ Little Particle Size Growth ✔ Little Particle Size Growth ✔ Little Particle Size Growth EXF No fluidization ✔✔
Klucel EXF vs. Klucel EF Klucel EXF Klucel EF
FBD Stability Concerns (Example Process Models and Design Space)
Summary of Drying Stability Specs Residual moisture stabilizes granules and blends from lactam formation –Some residual moisture is good to decrease lactam formation, but too much residual moisture has flow and hardness consequences, which could result in content uniformity and disintegration problems. High temperature drying results in higher lactam formation. –There was no improvement in efficiency by drying at higher temperatures due to increased cooling times, so low temperature drying is optimum.
Lab Scale Compression Data (Rotary Press) By changing the extragranular HPC from Klucel EF (larger PS), to Klucel EXF (Fine PS), the crushing strength threshold of 6 kp was achieved.
Additional Assessment Efforts Evaluate all stability data Update design space models at each scale –Develop design space model across scales Identify and document –Risks to product quality –Advantages of current methods for reducing risk Modeling Process monitoring/control