Impact of Different Saccharides on the In-Process Stability of a Protein Drug During Evaporative Drying: From Sessile Droplet Drying to Lab-Scale Spray Drying.

OBJECTIVES: Solid biopharmaceutical products can circumvent lower temperature storage and transport and increase remote access with lower carbon emissions and energy consumption. Saccharides are known stabilizers in a solid protein produced via lyophilization and spray drying (SD). Thus, it is essential to understand the interactions between saccharides and proteins and the stabilization mechanism. METHODS: A miniaturized single droplet drying (MD) method was developed to understand how different saccharides stabilize proteins during drying. We applied our MD to different aqueous saccharide-protein systems and transferred our findings to SD. RESULTS: The poly- and oligosaccharides tend to destabilize the protein during drying. The oligosaccharide, Hydroxypropyl ß-cyclodextrin (HPßCD) shows high aggregation at a high saccharide-to-protein molar ratio (S/P ratio) during MD, and the finding is supported by nanoDSF results. The polysaccharide, Dextran (DEX) leads to larger particles, whereas HPBCD leads to smaller particles. Furthermore, DEX is not able to stabilize the protein at higher S/P ratios either. In contrast, the disaccharide Trehalose Dihydrate (TD) does not increase or induce protein aggregation during the drying of the formulation. It can preserve the protein's secondary structure during drying, already at low concentrations. CONCLUSION: During the drying of S/P formulations containing the saccharides TD and DEX, the MD approach could anticipate the in-process (in) stability of protein X at laboratory-scale SD. In contrast, for the systems with HPßCD, the results obtained by SD were contradictory to MD. This underlines that depending on the drying operation, careful consideration needs to be applied to the selection of saccharides and their ratios.

Best Practices and Guidelines (2022) for Scale-up and Technology Transfer in Freeze Drying Based on Case Studies. Part 2: Past Practices, Current Best Practices, and Recommendations.

Scale-up and transfer of lyophilization processes remain very challenging tasks considering the technical challenges and the high cost of the process itself. The challenges in scale-up and transfer were discussed in the first part of this paper and include vial breakage during freezing at commercial scale, cake resistance differences between scales, impact of differences in refrigeration capacities, and geometry on the performance of dryers. The second part of this work discusses successful and unsuccessful practices in scale-up and transfer based on the experience of the authors. Regulatory aspects of scale-up and transfer of lyophilization processes were also outlined including a topic on the equivalency of dryers. Based on an analysis of challenges and a summary of best practices, recommendations on scale-up and transfer of lyophilization processes are given including projections on future directions in this area of the freeze drying field. Recommendations on the choice of residual vacuum in the vials were also provided for a wide range of vial capacities.

Best Practices and Guidelines (2022) for Scale-Up and Tech Transfer in Freeze-Drying Based on Case Studies. Part 1: Challenges during Scale Up and Transfer.

The freeze-drying process scale-up and transfer remain a complicated and non-uniform practice. We summarized inefficient and good practices in these papers and provided some practical advice. It was demonstrated that using the same process set points/times in laboratory and commercial scale dryers may lead to loss of product quality (collapse or vial breakage). The emerging modeling approach demonstrated practical advantages. However, the upfront generation of some input parameters (vial heat transfer coefficient, minimum controllable pressure, and maximum sublimation rate) is essential for model utilization. While the primary drying step can be transferred with a high degree of confidence (e.g., using modeling), and secondary drying is usually fairly straightforward, predicting potential changes in product behavior during freezing remains challenging.

The need for new control strategies for particulate matter in parenterals.

An undesirable characteristic in lyophilized parenteral products is the potential presence of particulate matter in the final product, which may affect patient safety. In this study, quality risk management tools described in the International Conference on Harmonization Guideline Q9 were used to estimate the risks for a pharmaceutical manufacturing line, based on three critical quality attributes: (1) visible particulate matter; (2) lyo-cake collapse traces; and (3) lyo-cake melt-back traces. Together with a Process Failure Mode Effect Analysis (PFMEA), an input-output analysis of the individual unit operations identified seven major material classes of extrinsic particulate matter. In addition to the process assessment, an experimental investigation of the location of impurities in lyophilized products was performed. To that end, intentionally contaminated vials were examined to locate the particulate matter and its possible migration. The results emphasize the importance of a full transmission mode release testing since the particles may enter the interior of the lyo-cake. A theoretical explanation of the observed impurity locations is provided.

Lyophilizer Leak Rate Testing - An Industry Survey and Best Practice Recommendation.

The vacuum integrity of freeze dryers is critical for attaining adequate process control and maintaining confidence in sterility assurance which is key for the manufacture of sterile pharmaceutical products. Although discussions on the topic have been published, there is no industry standard established that is based on empirical data or that has a justifiable scientific rationale. This article provides a review of the scientific literature in the public domain and most importantly, a perspective from 14 Pharmaceutical companies on the leak rate specifications commonly used in industry. Using this information we recommend a best practice for the lyophilizer leak rate test which includes detailing necessary preparation activities following Steam-In-Place (SIP) sterilization, defining a period of stabilization to eliminate pressure and temperature fluctuations and details of the test conditions and the test period. We conclude that for routine manufacturing practice the operational leak rate should not exceed 20 µbar L/s and we provide additional guidance for large volume and older lyophilisation equipment.

X-ray imaging: A potential enabler of automated particulate detection and cake-structure analysis in lyophilized products?

The presence of particulate matter in parenteral products is a major concern since it affects the patients' safety and is one of the main reasons for product recalls. Conventional quality control is based on a visual inspection, which is a labour-intensive task. Limited to clear solutions and the surface of lyophilised products, it cannot be applied to opaque containers. This study assesses the application of X-ray imaging for detecting the particulate matter in a pharmaceutical lyophilized product. The most common types of particulates (i.e., steel, glass, lyo stopper, polymers and organics in different size classes) were intentionally spiked in vials. After optimizing all relevant parameters of the X-ray set-up, all classes of particulates were detected. At the same time, due to contrast enhancement, the inherent structures of lyophilized cake became obvious. This work addresses the potential and limits of X-ray technology in that regard, paving the way for automated image-based particulate matter detection. Moreover, this paper discusses using this approach to predict critical quality attributes (CQAs) of the drug product based on the cake structure attributes.

Multivariate Monitoring Workflow for Formulation, Fill and Finish Processes.

Process monitoring is a critical task in ensuring the consistent quality of the final drug product in biopharmaceutical formulation, fill, and finish (FFF) processes. Data generated during FFF monitoring includes multiple time series and high-dimensional data, which is typically investigated in a limited way and rarely examined with multivariate data analysis (MVDA) tools to optimally distinguish between normal and abnormal observations. Data alignment, data cleaning and correct feature extraction of time series of various FFF sources are resource-intensive tasks, but nonetheless they are crucial for further data analysis. Furthermore, most commercial statistical software programs offer only nonrobust MVDA, rendering the identification of multivariate outliers error-prone. To solve this issue, we aimed to develop a novel, automated, multivariate process monitoring workflow for FFF processes, which is able to robustly identify root causes in process-relevant FFF features. We demonstrate the successful implementation of algorithms capable of data alignment and cleaning of time-series data from various FFF data sources, followed by the interconnection of the time-series data with process-relevant phase settings, thus enabling the seamless extraction of process-relevant features. This workflow allows the introduction of efficient, high-dimensional monitoring in FFF for a daily work-routine as well as for continued process verification (CPV).