Purpose: The purpose of this work was to develop 5 mg strength immediate release tablet for Phase III clinical trials while applying elements of QbD methodology to ensure the consistent performance of the product.
Methods: The main manufacturing equipment units were: Pharmatech bin Blender (Various bin size), Korsch XL100 rotary (4-8 punches), Manesty 24” Accela-Cota pan coater equipped with 24” pan. DoE data were analysed by Design-Expert® Version 8.0.4.
Results: Initially, the Compound A was formulated to deliver capsules to support Phase I/II clinical supplies in a dose range of 1 mg to 100 mg strengths. The initially selected process was high shear granulation of milled active substance (D90 ≤ 50 µm), drying and encapsulation. Upon successful completion of the early clinical trials, the dose of 5 mg was selected as the final therapeutic dose and a new pharmaceutical form was required to better address market needs. The preliminary Quality Target Product Profile (QTPP) for 5 mg strength, coated tablet was built as per ICH Q8 (R2) [1, 2]. Among Critical Quality Attributes (CQAs) %Claim (Assay), Content of Related Substances, Content of Residual Solvents, Dissolution and Microbial Limits were identified. The relationship between Critical Material Attributes (CMAs) of active substance and excipients onto CQAs was assessed using the three level (colour) risk matrix . Among CMAs of active substance, particle size, particle morphology, polymorphic form, solubility and purity were expected to have the highest impact into CQAs such as Content Uniformity, Dissolution as well as others attributes including tablet hardness and friability. Based on the solubility data in pH 1.2, 4.5 and 6.8, Compound A was classified as BCS class II, hence physical characteristics such as particle size distribution (PSD), particle morphology and polymorphic form were critical to ensure adequate oral bioavailability. The solubility in simulated gastro-intestinal fluids (SGF, FaSSIF, FeSSIF) was also examined and the presence of surfactant(s) was noted to improve the solubility. Due to limited availability of Compound A at the start of development of the new pharmaceutical form, selection of manufacturing process as a first intent was also performed using three level (colour) risk matrix. The Critical Process Parameters were identified for three potential manufacturing processes: 1) blending & direct compression 2) wet granulation (high shear) & compression and 3) dry granulation (roller compaction/milling) & compression in relation to CQAs of required product, 5 mg of Compound A per tablet. The blending and direct compression process was prioritized as first intent due to reduced number of CPPs. Subsequent trials were performed to establish the preliminary formulation composition for uncoated tablets, which was selected to be: 65% of microcrystalline cellulose (Avicel PH200), 23% of mannitol (Pearlitol 200 SD), 5% of sodium starch glycolate (Glycolys), 1% of colloidal silicon dioxide (Aerosil 200 Pharma) and 1% of magnesium stearate (Ligamed MF-2-V). The chosen formulation composition was expected be robust enough since Compound A made 5% of tablet core weight and the control of particle size and solid state was planned through the specification for drug substance, therefore CPPs of manufacturing process were initially challenged at the scale intended for Phase III manufacture (~12 kg). Three main unit operations were identified: blending, compression and coating. After initial experiments (mixing curve, scoping trial for compression and coating), DOE was carried out for each unit operation where statistical significance was found for blending time (moderate), feeder/compression speed (moderate), compression force (moderate) on the CQAs. Overall the selected manufacturing process was found to be robust within the range explored by the DOEs when using the active substance batch with particle size D90 < 25 µm. However, Content Uniformity (blend, tablets) and Dissolution worsen when a coarser active substance batch was used (D90 ~ 300 µm).
QbD principles have been successfully applied to develop a tablet formulation suitable for Phase III clinical trials. The formulation was developed by evaluating the QTPP as a critical starting point, performing a risk assessment to identify the impact of the API properties on the Critical Quality Attributes of the product and executing DoE to propose the design space.  ICH Q8 (R2): PHARMACEUTICAL DEVELOPMENT, Current Step 4 version, dated August 2009.  ICH Harmonised Tripartite Guideline Q6A (1999) specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances.  ICH Q9: QUALITY RISK MANAGEMENT, Current Step 4 version dated 9 November 2005.  FDA, Guidance for Industry, Immediate Release Solid Oral, Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation, November 1995.
Marco Rossetti– Aptuit (Verona) Srl, an Evotec Company, Veneto
Stefano Cagliero– Aptuit (Verona) Srl, an Evotec Company, Veneto
Davide Roveda– Aptuit (Verona) Srl, an Evotec Company, Veneto
Cristiano Boraso– Aptuit (Verona) Srl, an Evotec Company, Veneto