Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness.

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to manage the batch-to-batch variability of an active pharmaceutical ingredient (API) in a high drug loaded formulation on a continuous line was investigated to obtain consistent tablet CQAs. As the ultimate goal of continuous manufacturing is to produce 24/7, current study also aimed at guaranteeing long term stability of the process. To do so, previously identified API critical material attributes (CMAs) were varied together with granulation, drying and milling critical process parameters (CPPs) in a screening design of experiments to understand the influence of these factors upon product CQAs and process stability. To evaluate the factors affecting the process stability with a reduced amount of materials, process deviations recorded by process sensors were used. While product CQAs only depended on process CPPs, process stability was strongly affected by API CMAs. The effect of API batch-to-batch variability on process stability could nonetheless be managed by applying suitable granulation conditions. Therefore, appropriate ranges of CPPs were defined to ensure both product CQAs and process stability. By studying the fully integrated continuous manufacturing line, it was possible to highlight the interactions between the different unit operations and the API CMAs and to design a robust process.

Managing API raw material variability during continuous twin-screw wet granulation.

Very few studies have investigated the impact of raw material variability upon the granule critical quality attributes (CQAs) produced via twin-screw wet granulation (i.e., granule size distribution, density, flowability). In this study, the impact of the raw material variability of an active pharmaceutical ingredient (API) in a high dose formulation on the twin-screw wet granulation process and on the resulting granule quality attributes was investigated. In a previous study (Stauffer et al., 2018), eight API batches were characterized to determine the API batch-to-batch variability. Principal component analysis (PCA) was then used to analyse the raw material property differences between the API batches and to determine the causes of the batch-to-batch variability. In current study, the three principal components from that PCA model were used as factors together with twin-screw granulation process parameters (i.e., screw speed and liquid-to-solid ratio) in a D-optimal screening design of experiments to understand the influence of these factors upon the granule CQAs. It was found that the API particle size distribution and related properties (e.g., density, agglomeration profile) were critical for the granule CQAs. In a next step, the significant factors from the screening design results were used to determine the design space of the twin-screw granulation process for the studied formulation via a D-optimal optimisation design, herewith controlling the risk of failure for the potential API raw material variability. The possibility to obtain suitable granule CQAs with a risk of failure of 1% for all API batches was demonstrated. It was thus possible to identify a combination of process parameters that can manage the API batch-to-batch variability leading to granules with pre-defined suitable CQAs.

Managing active pharmaceutical ingredient raw material variability during twin-screw blend feeding.

Continuous powder feeding is a critical step in continuous manufacturing of solid dosage forms, as this unit operation should ensure the mass flow consistency at the desired powder feed rate to guarantee the process throughput and final product consistency. In this study, twin-screw feeding of a pharmaceutical formulation (i.e., blend) existing of a highly dosed very poorly flowing active pharmaceutical ingredient (API) leading to insufficient feeding capacity was investigated. Furthermore, the API showed very high batch-to-batch variability in raw material properties dominating the formulation blend properties. Formulation changes were evaluated to improve the flowability of the blends and to mitigate the impact of API batch-to-batch variability on the twin-screw feeding. Herewith, feeding evaluation tests and an extensive material characterization of the reformulated blends were performed to assess the impact of the formulation changes upon continuous twin-screw feeding. The transfer of the glidant from extra-granular to intra-granular phase allowed to improve the flowability of the blends. A sufficient feeding capacity for the downstream process and a mitigation of the impact of batch-to-batch variability of the API upon twin-screw feeding of the blends could be achieved. No effect of the formulation or of the API properties on the feeding stability was observed. The material characterization of the blends allowed identifying the material attributes which were critical for continuous twin-screw feeding (i.e., bulk density, mass charge and powder cohesiveness).

Raw material variability of an active pharmaceutical ingredient and its relevance for processability in secondary continuous pharmaceutical manufacturing.

Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients.

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC0₋360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.