(W0930-05-27) Compaction Simulation as a Risk Mitigation Strategy for Dual Sourcing on Commercial Drug Products

Purpose: Dual sourcing is a strategy adopted by Drug Product (DP) manufacturers to reduce supply chains risks ensuring uninterrupted availability of critical therapies. Dual sourcing for common excipients used on Oral Solid Dosage (OSD) development has been often studied. However, when it comes to the Drug Substance (DS), the impact of having two different manufacturers needs to be carefully assessed to guarantee meeting same DP Quality Attributes (QA). This case study presents a risk mitigation strategy for validating a DS dual sourcing on a commercial product.

Methods: A DP was developed under the form of film-coated tablets by direct compression for an orphan indication. This DP is currently manufactured for clinical and commercial purposes for the US, European and Asian market. Aiming to validate a commercial dual sourcing for the DS, a comprehensive assessment of the DS (16 % w/w of the formulation) and DP properties was performed. First, raw DS from both suppliers were compared using a powder rheometer (FT4®) to study their bulk, dynamic flow and shear properties. A laser diffraction analyzer (Mastersizer 2000®) was used to compare their particle size distributions (PSD). A compaction simulator (Styl’One®) was used to determine their deformation behavior during compression (Heckel model), and their compaction properties (as per the USP < 1062 > recommendations) in terms of tabletability, compactibility and compressibility. Second, a characterization of the final blends mechanical properties (using both DS suppliers) was conducted. For this, a blending process scale-down was performed from commercial (75 Kg in a 300 L blender) to R&D scale (0.28 Kg in a 1L blender). Their deformation behavior was determined by the Heckel model. To compare their compaction properties at R&D scale, the Styl’One was set to mimic the commercial rotary press profile (Kilian S500) and throughput (100 Ktab/h) using the commercial tablet tooling. Finally, the risk mitigation approach was confirmed at commercial scale where a 75 Kg batch using the new DS supplier was manufactured respecting the validated process parameters and specifications for the current commercial DP. This included: blending and lubrication on 300 L blender, compression on a Kilian S500 tablet press and coating (8% weight gain) on 70 L Perfima® perforated pan. To complete this assessment, a whole set of analytical FP release testing was performed to eliminate any impact of introducing a new DS supplier on the current commercial process from a processability and analytical perspective.

Results: On raw DS: both DS had similar PSD: D₁₀ at 3 µm; D₅₀ at 16-18 µm and D₉₀ at 49-57µm. FT4® results showed that new DS supplier had more mechanical interlocking and friction between particles. Flow Function Coefficient ranked DS as free flowing (current supplier) and easy flowing (new supplier). Yield pressures calculated from the Heckel model were of 76 – 77 MPa for both DS, being therefore classified as soft/ductile materials. Pure DS tablets from new supplier presented: slightly lower Solid Fractions (SF) at same pressure and lower Tensile Strength (TS) at same SF. As well, TS was lower at same pressure (Fig.1). Overall, DS from both suppliers showed poor tabletability properties. On final blends at R&D scale: blends containing both DS suppliers showed similar yield pressures (95- 100 MPa) and were ranked as moderately brittle/ductile. Both blends resulted in tablets with: similar SF at same pressure (compressibility); similar TS at same SF (compactibility) and similar TS at same pressure (tabletability) (Fig. 2). Therefore, differences observed on the raw DS, with poor tabletability properties, were most probably mitigated by the other excipients present in the formulation (as microcrystalline cellulose: 64.8 % w/w). The results at small scale indicate that a DS dual sourcing might not have an impact on tableting at larger scale. On DP at commercial scale: Final blend using the new DS supplier had similar bulk/tapped densities and flow properties than the validated commercial batches. During compression, the validated commercial specifications for tablet breaking force (4.6 to 5.6 kP) could be achieved at compression forces (mean at 7.4 kN) comprised within the commercial design space as illustrated in Fig. 3. This confirms the predictability of the results obtained at R&D scale. All other compression in-process-controls were also compliant to the validated specifications. Tablet coating was conducted at the commercial process parameters without any issue. Finally, analytical testing confirmed that the FP using the new DS supplier was compliant to all specifications and was consistent to analytical results obtained during the validation campaign of batches using the current DS supplier.

Conclusion: Compaction simulation was leveraged as a material-sparing risk mitigation approach for the introduction of a DS dual sourcing on a commercial DP for an orphan indication. A quality-by-design comprehensive study of the DS and DP mechanical properties allowed to de-risk the introduction of a new DS supplier on a commercial manufacturing process. A validation campaign using this new supplier will be conducted.


Raw DS Tabletability and Compactibility


Final blends Tabletability and Compactibility


Manufacturability at R&D and Commercial scale