(W0930-11-60) Case Study Approach of an Excipient Compaction Assessment to Support Dual Sourcing

Purpose: In recent years, many Pharmaceutical companies have moved to dual sourcing to protect themselves against unplanned supply interruptions. This risk-mitigation effort needs to be anticipated and documented to assess the potential impact on the finished product CQAs. This case study presents an approach to establish a dual sourcing strategy, with a material sparing technology, and assess potential impact of inter-supplier variability. In this example the objective was to assess the feasibility of switching from the lactose grade Sheffield™ 310 (80M) to either the lactose Pharmatose™ 125M or Sheffield™ 310 (60M), using a compaction assessment-based approach. The current process is dry granulation and compression of the granules into tablets.

Methods: The Styl’One® EVO was used for this case study. The work consisted in conducting on the pure lactose, with only 5 to 10g, both, a compaction study (Heckel Analysis), which is an evaluation of the volume reduction mechanism under the compression force, or deformation behaviour. A known weight of lactose was compacted on the compaction simulator to theoretical zero porosity using a single flat faced punch diameter 11.28mm. The data was analysed by the Compaction Analysis software programme to generate values for yield pressure (Py) using the Heckel equation = - ln (1/1-D) = k . P + A ⁽¹⁾. The main data obtained from the Heckel analysis were: Yield pressure (Py) Slow speed and Yield pressure (Py) Fast speed; Strain Rate Sensitivity (SRS%) <sup>(2), allowing to place the properties of the different lactose on the following graph f (Py Slow) = SRS%; a compression study based on the USP < 1062 >, which is the characterization of the material’s intrinsic compaction behaviour (tabletability, compactibility, compressibility). Five compression points were generated between compression pressures of 100 to 300MPa. Additional complementary tests were performed (not presented in this presentation) such as particle size distribution testing and shear Cell (FFc) by FT4.

Results: The compaction assessment-based approach results are the following: 1- Compaction study: The Heckel analysis classified the three lactose grades as presenting moderately hard/brittle compression properties and being expected to deform predominantly by brittle fracture. Similar yield pressures: 118, 142 and 152 MPa, were obtained at a low punch speed of 3 mm/s. The three grades of lactose were consequently placed on the Heckel color map (figure 1). 2- Compression study: The complementary compression evaluation showed that lactose tabletability curves (Figure 2) displayed differences between grades Sheffield™ 310 (80M), Pharmatose™ 125M and grade Sheffield™ 316 (60M), showing a significantly higher bondability for tablets from grade Sheffield™ 310 (60M). Therefore, lactose grade Sheffield™ 310 (60M) was not selected as being the good candidate for dual sourcing the initial grade Sheffield™ 310 (80M). In addition, grade Pharmatose™ 125M was shown to have the same: Tabletability properties (figure 2): same ability to withstand handling and processing; Compressibility properties (figure 3), meaning that the same force is required to achieve the tablet recommend Solid Fraction (SF) of 0.85-0.95 SF and reach acceptable tablet properties. Tablet SF is a critical quality attribute since high SF is linked to capping issues and long dissolution times as the low porosity prevents liquid from penetrating; Compactibility properties (figure 3): meaning that the binding forces are equivalent

Conclusion: This case study illustrates how to perform a first screening evaluation of several grades of excipients with a material sparing application and provides examples of main quality attributes to characterize. The results revealed that one specific grade of lactose matched the current lactose deformation properties and intrinsic compaction behaviour. Therefore, this first assessment allows to conclude that switching lactose from the Sheffield™ 310 (80M) to the Pharmatose™ 125M grade, has a low risk of impacting the finished product CQAs. To carry-out a more in-depth study, a full testing on a finished product would be necessary to completely validate the dual sourcing options. This case study also highlights that identifying multiple excipients with similar properties is not straightforward and requires a detailed data driven analysis. In order to mitigate risks, this dual sourcing approach should be anticipated at the outset of the formulation development. The methodology illustrated here has been shown to be a valuable analytical tool to support Pharmaceutical companies in this early-stage sourcing of multiple excipients.

References: (1) R.W. Heckel. Trans. Metall. Soc. AIME 221 (1961) 1001-1008
(2) R.J. Roberts and R.C. Roe, Chem. Eng. Sci. 42 (1987) p903</sup>