On the Influence of Raw Material Attributes on Process Behaviour and Product Quality in a Continuous Wet Granulation Tableting Line

Solid oral dosage forms remain the preferred dosage forms due to their convenience, low manufacturing costs, non-sterile production and high patient compliance (Qiu et al., 2016). Tablets comprise about 90% of all oral solids (Kirtane et al., 2022) and, according to the Manufacturing Classification System Working Group, 40% of all tablets are manufactured via a wet granulation intermediate step (Leane et al., 2018). Although there is a trend towards direct compaction, wet granulation will remain an important manufacturing route, at least for “difficult” APIs that have low density, segregate easily or charge electrostatically. However, most oral solids are still manufactured in the batch mode, which has several economical and technical disadvantages (Khinast et al., 2017), e.g., resource-consuming scale-ups, equipment down times, supply chain issues, no real-time quality assurance, high floor space requirements, operator risks and increased material waste (Junnila et al., 2022, Portier et al., 2020a). A continuous powder-to-tablet manufacturing process, including a wet granulation step, makes it possible to overcome these shortcomings and minimize the number of manufacturing steps and the time required to release the drug product to the market.

Continuous manufacturing of oral solids is a complex process that is affected by the critical material attributes (CMAs), the formulation composition and the critical process parameters (CPPs), which can introduce variability and inconsistencies in the process. To reduce the risk and guarantee a stable continuous process with the specified drug product quality, a correlation between CMAs, formulation composition and CPPs must be explored and the critical quality attributes (CQAs) must be identified (Charoo, 2020, Rustomjee, 2016). This makes sure that the process is in a state of control.

To date, several studies have dealt with evaluating CMAs and CPPs of individual parts of a continuous manufacturing line for oral solids, i.e., feeding (Bekaert et al., 2022), twin-screw wet granulation (TSWG) (Kumar et al., 2016, Portier et al., 2021, Vandevivere et al., 2022), fluid bed drying (FBD) (Rehrl et al., 2021, Rehrl et al., 2020, Ryckaert et al., 2021), milling (Chablani et al., 2011, Vercruysse et al., 2015), in-line blending and tableting (de Backere et al., 2022). For instance, (Portier et al., 2020a) evaluated the effect of formulation composition and intrinsic active pharmaceutical ingredient’s (API) properties, such as the grade, micrometrics, the particle size and lipophilicity, on TSWG and, subsequently, the granule quality and processability. Four formulations with different APIs and drug loadings were compared in terms of their influence on the liquid-to-solid ratio (L/S ratio) and the screw speed. It was shown that the liquid-to-solid ratio was a CPP. Selecting a proper ratio of lactose and microcrystalline cellulose (MCC) as excipients minimized the effect of raw materials on the process.

Other studies evaluated the influence of drying conditions (i.e., the drying temperature, drying time and drying air flow) in a six-segmented FBD on the granule breakage and attrition, as well as their effect on granule conveying between TSWG and FBD (Ryckaert et al., 2021). In addition, granule attrition was compared between horizontal and vertical manufacturing set-ups (De Leersnyder et al., 2018). Furthermore, an extended continuous full-line run of 5 h under constant process conditions was performed for a model formulation composed of two APIs, powdered cellulose, maize starch, pregelatinized starch and sodium starch glycolate (Vercruysse et al., 2013). The CQAs of granules (i.e., residual moisture, particle size distribution and friability) and tablets (i.e., weight, hardness, thickness, friability, disintegration time and dissolution profile) were compared for three batches, for which consistent product quality and stable process conditions were demonstrated. However, few studies evaluated the influence of CMAs and CPPs on the intermediate and final product’s CQAs throughout a complete continuous manufacturing line.

The aim of this study was to evaluate the influence of raw material attributes on the processability and the product quality in a wet-granulation continuous manufacturing line. Four formulations with two APIs in different drug loadings (2.5% w/w vs. 25% w/w) and biopharmaceutical classification system (BCS) classes I vs. II were processed under three contrary process conditions. BCS classifies drugs into four classes based on aqueous solubility and intestinal permeability. Class I drugs show high solubility and high permeability, class II low solubility and high permeability (Amidon et al., 1995). Furthermore, the ability of microcrystalline cellulose (MCC) and lactose in 1:1 ratio to compensate intrinsic API powder properties like lipophilicity, wettability and flowability in a continuous process was evaluated. The intermediate granule CQAs “loss on drying” (LOD) and “particle size distribution” (PSD) were determined as well. In addition, the tablets were characterized in terms of hardness, disintegration time, contact angle, surface area and pore width.

Materials

Paracetamol (semi-fine powder, Type 0081, Mallinckrodt, USA) and ibuprofen (ibuprofen-25, BASF, Germany) were used as APIs. Additional components of the tablet formulations were microcrystalline cellulose (MCC) (Avicel PH 101, JRS Pharma, Germany), lactose monohydrate (AlphaTab 150 DC, Alpha Nutrition, Netherlands) and magnesium stearate (Parteck LUB MST, Merck KGaA, Germany). The raw material properties are listed in Table 1. The formulation compositions are summarized in Table 2.