Purpose: There are several models described in scientific literature that estimate the effect of particle size changes of an active substance on individual quality attributes, such as dissolution, granule uniformity and dissolution. However, the interplay of the effects has been less studied and described. The purpose of this study was to evaluate the impact of API PSD on the main CQA’s defined using QbD approach (mainly dissolution and content uniformity). The goal is to justify an API PSD specification taking into account all the potential quality attributes that are influenced. Before the experiments were set-up model predictions were used to estimate the magnitude of the risks, select the appropriate API lots for the study and to be able to compare the final results with these predictions The evaluation is performed on final drug product, using scale-down approach (1/5th ) for a high-potent product.
Methods: The high shear granulation process was scaled-down from GEA PMA 300 (62.5kg batch size) to GEA PMA 30 (10kg batch size) in order to evaluate the impact of 3 different API PSD (D50 =2µm-16µm-32µm) on the main CQAs identified during Risk assessment/ FMEA. Scale down rational was based on constant tip speed for the different mixing steps, homothetic equipment for blenders and same granulation time / water amount, for granulation.
Granules were then tableted on IMA synthesis 500 WIP at two different strength (1 mg and 20mg) to cover the whole range of strengths developed for the product, and finally coating in IMA perfirma lab contained, coating pan 10L.
The main CQAs were used to validate the scale down and assess the impact of API PSD:
- Particles size distribution of granules and API content of sieved fractions
- Content uniformity by stratified sampling on core tablets
- Dissolution / assay on coated tablets
Results: The scale down approach of the granulation process used for the study was verified since results show comparable granule size and API content distributions between pilot scale and small scale (figure 1). Also all the results for the small-scale batch manufactured within current API PSD specification (D50=2µm) was aligned with large scale, for both tablet size at minimal and maximal dosage strength.
A significant impact of API PSD for coarse particle (D50=32µm) was demonstrated on content uniformity by stratified sampling with evidence of unexpected high content (figure 2). The effect is particular significant when dose strength is low. The coarse API did not pass Bergum assessment (ASTM E2709/E2810) for content uniformity, whereas Fine and middle did pass.
Dissolution method demonstrated a good discriminating power with regards to API PSD specification. Fine API (D50=2µm) passes statistical assessment using ASTM guideline E2709 at Q=85% 30min, whereas MIDDLE (D50=15µm) failed at Q=75% 30min, and COARSE (D50=32µm) failed at Q=70% 30min (figure 3):
Conclusion: Using QbD scale-down approach for the high shear granulation process, it was possible to demonstrate the critical impact of API PSD with regards to CQAs, such as dissolution or uniformity of dosage units. The importance of an advanced micronization of the API but also the discriminating powder of dissolution method were demonstrated. Based on these data, API PSD specification could be justified and risks related to the API particle size can be mitigated. The data also confirmed the expectations from the models when it relates to granule uniformity and dissolution. However, the predictions on content uniformity where less critical, only an increase in variations than the observed results for the coarse particle, where OOS results were obtained. This difference might be related to the determination of the API particle size.
Complementary studies are on going to fine-tune the maximum limit between for D50 between 5µm and 16µm.
Berne Remi– Technical project leader, Patheon, Bourgoin Jallieu
Marylène Dubois– Analytical Project leader, Patheon Pharmaceuticals, Inc., Bourgoin jallieu, Rhone-Alpes
Kaspar Van Den Dries– Senior Director Formulation Sciences, solid dosage soft gels, Patheon Pharmaceuticals, Inc., Tilburg, Noord-Brabant
BERNE Rémi– Patheon, Bourgoin Jallieu