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[Display omitted] As lyophilization continues to be a critical step in the manufacturing of sensitive biopharmaceuticals, challenges often arise during the scale up to commercial scale or the transfer from one manufacturing site to another. While data from the small-scale development of the lyophilization cycle is abundant it is typically much more difficult to extract important information from commercial scale cycles, due to the lack of process analytical technologies available on the commercial line. There is often a reluctance to include wireless temperature or pressure probes during GMP operations due to the additional contamination risk, and retrofitting equipment such as the TDLAS can be prohibitively expensive. Further, as products become more advanced, the cost of consuming the product or even the availability of material may limit the opportunities to run commercial scale trials. This paper presents two novel methods to garner critical cycle information to allow for the evaluation of cycle performance without the need for expensive analytical equipment, costly revalidation and line downtime. Critically, this can be achieved using commonly available temperature and capacitance probes on existing commercial scale equipment. The first method is a calorimetric method, based on quantifying the differences in heat transfer liquid temperature between the shelf inlet and shelf outlet. This change in temperature results from the on-going sublimation, an endo-thermic reaction occurring during lyophilization. The second method uses the differential pressure between the chamber and condenser resulting from the vapor flow from vial to condenser during primary drying. As stated by the authors both methods align well and provide valuable cycle characterization data. [ABSTRACT FROM AUTHOR]

Needle clogging induces several issues during the filling step of injectable drugs, which makes essential to avoiding it to ensure a favorable outcome for the process. The suck-back function, present in peristaltic pumps, is often used empirically to that end. This study aims at describing and understanding the fluid behavior after suck-back application, which provides some quantitative specifications to prevent needle clogging. [ABSTRACT FROM AUTHOR]

Currently, the two technologies primarily used for the manufacturing of nano-crystalline suspensions using top down process (i.e. wet milling) are high pressure homogenization (HPH) and stirred bead milling (SBM). These two technologies are based upon different mechanisms, i.e., cavitation forces for HPH and shear forces for stirred bead milling. In this article, the HPH and SBM technologies are compared in terms of the impact of the suspension composition the process parameters and the technological configuration on milling performances and physical quality of the suspensions produced. The data suggested that both HPH and SBM are suitable for producing nano-crystalline suspensions, although SBM appeared more efficient than HPH, since the limit of milling (d 50 ) for SBM was found to be lower than that obtained with HPH (100 nm vs 200 nm). For both these technologies, regardless of the process parameters used for milling and the scale of manufacturing, the relationship of d 90 versus d 50 could be described by a unique master curve (technology signature of milling pathway) outlining that the HPH leads to more uniform particle size distribution as compared to SBM. [ABSTRACT FROM AUTHOR]

Stirred media milling is the main technology for producing colloidal nanocrystalline suspensions. A number of studies have been reported on the effect of different operating parameters for lab, pilot, and industrial scales. However, typical milling tool box that can be used to support candidate from selection up to phase III clinical supplies can involve different mill configurations. This article describes a parametric study and milling kinetic modelling of the different mills. The impact of active pharmaceutical ingredient (API) type and process parameters on milling kinetics was determined. The milling kinetics were modeled using an empirical model which allows for predicting and simulation of milling kinetics of stirred annular and pin mills. The proposed model was found to accurately fit milling kinetics whatever the API considered, technology employed, and the process parameters used for milling. Moreover, the model was found to be able to ensure the process transfer from one mill to another. [ABSTRACT FROM AUTHOR]

The small particle size of nano-crystalline suspensions can be responsible for their physical instability during drug product preparation (downstream processing), storage and administration. For that purpose, the commercial formulation needs to be sufficiently robust to various triggering conditions, such as ionic strength, shear rate, wetting/dispersing agent desorption by dilution, temperature and pH variation. In our previous work we described a systematic approach to select the suitable wetting/dispersant agent for the stabilization of nano-crystalline suspension. In this paper, we described the assessment of the formulation robustness (stabilized using a mixture of sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone (PVP) and) by measuring the rate of perikinetic (diffusion-controlled) and orthokinetic (shear-induced) aggregation as a function of ionic strength, temperature, pH and dilution. The results showed that, using the SDS/PVP system, the critical coagulation concentration is about five times higher than that observed in the literature for suspension colloidaly stable at high concentration. The nano-suspension was also found to be very stable at ambient temperature and at different pH conditions. Desorption test confirmed the high affinity between API and wetting/dispersing agent. However, the suspension undergoes aggregation at high temperature due to the desorption of the wetting/dispersing agent and disaggregation of SDS micelles. Furthermore, aggregation occurs at very high shear rate (orhokinetic aggregation) by overcoming the energy barrier responsible for colloidal stability of the system. [ABSTRACT FROM AUTHOR]

This paper describes a systematic approach to select optimum stabilizer for the preparation of nano-crystalline suspensions of an active pharmaceutical ingredient (API). The stabilizer can be either a dispersant or a combination of dispersant and wetting agent. The proposed screening method is a quick and efficient way to investigate a large number of stabilizers based on the principles of physical-chemistry and employs a stepwise approach. The methodology has been divided in two main parts; the first part being focused on the qualitative screening with the objective of selecting the best candidate(s) for further investigation, the second part has been focused on quantitative screening with the objective to optimize the ratio and amount of wetting and dispersing agents, based on wettability, surface charges measurement, adsorption evaluation, process-ability evaluation and storage stability. The results showed clearly that SDS/PVP 40/60% (w/w) (sodium dodecyl sulfate/poly(vinyl pyrrolidone)) at a total concentration of 1.2% was the optimum stabilizer composition, at which the resulting nanosuspensions were stable for more than 50 days at room temperature. [ABSTRACT FROM AUTHOR]

Purpose: To predict the crystallization time of amorphous solid dispersions by controlling the combined effect of temperature and moisture content. Methods: The authors exposed amorphous samples of spray-dried API and Hydroxypropylmethylcellulose Phtalate to various temperature and humidity conditions below and above the glass transition temperature (Tg) until crystallization of the API was observed. The crystallization of API was detected by XRPD, while the T and the water absorption by the amorphous dispersion are quantified by mDSC and water sorption analysis. Results: Extrapolation of the data obtained at a temperature above T to conditions below T gives only a qualitative trend. By contrast, in conditions below T the logarithm of onset of crystallization time was shown to vary linearly with the T /T ratio. A statistical analysis shows that the data obtained in the highest temperature/humidity conditions, for which the onset of crystallization is below 3 months, can be extrapolated over 15 months. Conclusions: The proposed methodology can be used as a stress program to predict long-term stability from a relatively short observation period and to design appropriate temperature and humidity conditions for long-term storage to prevent crystallization. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a new approach to model cocrystal phase diagrams is presented. Starting from an initial set of data, the phase diagram is obtained from discontinuous isoperibolic thermal analysis (DITA) and basic thermodynamic data (enthalpies and solubilities). The solubility product constant may then be determined. Since this constant is solvent independent, extrapolation to other solvents is possible. Application of this technique to an active pharmaceutical ingredient and glutaric acid demonstrates good agreement between calculated and experimental data. [Copyright &y& Elsevier]

Abstract: Different physical and mathematical models of non-stoichiometric hydrates derived form previous work in inorganic hydrates are reviewed. A theoretical link between the order of water molecules in the hydrate and the shape of the isotherm is outlined. The comparison of the models with sorption isotherms and structural data of well-known cases from the literature and one in-house case shows that the model can fit many experimental situations and is in good agreement with qualitative assessments of the order in the hydrates. [Copyright &y& Elsevier]

Measurement of heat transfer coefficients (K v) is an important part of freeze-dryers characterization and as well a necessary step for executing any modelling. In most cases only an average value of K v is calculated, or an average value of center and edge vials is provided. Our aim is to go a step further and to describe the overall K v distribution various vial/ freeze drier combinations, whatever the pressure. From an experimental point of view, in this article we propose three methods to calculate the K v value for individual vials based on the ice sublimation gravimetric method. The first method we use is the most usual one, where the K v value is calculated based on the mass of sublimated ice and the product temperature measured in selected vias. In the second method, the average product temperature is estimated for each vial, based on the mass difference before and after sublimation and the K v value is calculated accordingly. In the third method, the K v is estimated by comparison to sublimation results from a simulation. Results from methods 2 and 3 are very similar results and are slightly different from those of method 1. Method 1 was shown to exhibit a systematic bias due to the fact that it is based on the temperature of recording of selected vials only, which are not representative for all positions. Once the individual values of K v have been calculated, it is possible to establish a distribution for each method. It was observed that an overlay of two normal distributions describing the center and the edge vials provides a good representation of the empirical distribution. Furthermore, we propose a holistic model aiming to calculate the K v distribution for any specified pressure. [ABSTRACT FROM AUTHOR]

Abstract: This paper examines fine grinding techniques in current use in the pharmaceutical industry. Experimental results are given for fine grinding of vitamin C, chosen as a model substance representative of pharmaceutical products, using eight different grinding mills chosen amongst those in current use in the pharmaceutical industry. The results are evaluated in terms of product quality expressed as particle size and distribution and also in terms of operating criteria applicable in the pharmaceutical industry such as ease of setting up, ease of cleaning, and investment cost. The main conclusion reinforces and quantifies current practice of using pancake mills that are preferred for ultra fine grinding as they are simple to use, can treat high feed rates and are easy to clean. [Copyright &y& Elsevier]

Fill & finish manufacturing processes of biologics drug product involve multiple unit operations. In particular they often include a mixing step to reduce non-uniformities in fluids by eliminating gradients of concentration and pH may occur during freezing. This step should be conducted carefully to avoid any degradation of the protein under mechanical stress. This study was aimed at characterizing disposable vessels of square cross-section such as Levmixer® from Sartorius Stedim in terms of fluid dynamics and mixing in turbulent regime. The investigation included two tree large vessels (50, 200 & 650-l) and one 4-l vessel designed in house. For that purpose, the impact of stirrer speed, filling volume and duration of mixing on product quality attributes were studied, using a surrogate. Moreover, a scale-up rule, based on first principle, was established and allows prediction of the mixing time as a function of stirring speed and filling volume. A lab-scale test, using drug product, was performed at the same stress intensity but for a much longer duration than the commercial operation and did not reveal any trend to aggregation. Finally, based on the correlation, lab scale stress test and a single verification test at large scale, a design space within which the product can be processed without altering product quality was proposed [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) for RNA and DNA delivery have attracted considerable attention for their ability to treat a broad range of diseases and to vectorize mRNA for COVID vaccines. LNPs are produced by mixing biomolecules and lipids, which self-assemble to form the desired structure. In this domain, microfluidics shows clear advantages: high mixing quality, low-stress conditions, and fast preparation. Studies of LNPs produced in micromixers have revealed, in certain ranges of flow rates, a degradation in performance in terms of size, monodispersity and encapsulation efficiency. In this study, we focus on the ring micromixer, which is well adapted to high throughput. We reveal three regimes, side-by-side, transitional and highly mixed, that control the mixing performance of the device. Furthermore, using cryo-TEM and biochemical analysis, we show that the mixing performances are strongly correlated to the characteristics of the LNPs we produce. We emphasize the importance of the flow-rate ratio and propose a physical criterion based on the onset of temporal instabilities for producing LNPs with optimal characteristics in terms of geometry, monodispersity and encapsulation yield. These criteria are generally applicable. [ABSTRACT FROM AUTHOR]

[Display omitted] Surfactants are commonly used in biotherapeutic formulations to prevent the formation of aggregates and protect proteins from denaturation. Among them polysorbates are the most widely used. However, they are known to be prone to degradation, mainly via enzymatic hydrolysis and oxidation. In this study, the impact of different conditions and factors on the oxidation of polysorbate 80 (PS80) and of a monoclonal antibody (mAb) was evaluated. In particular, the role of different formulation components (e.g., mAb concentration, pH, buffer, surfactant grade, chelators) was investigated in the presence of iron as transition metal contaminant. The results of our studies demonstrated that PS80 oxidation was accelerated even in the presence of iron levels as low as 20 ppb. In addition, the results showed that the oxidation of a specific solvent-exposed mAb methionine increased with PS80 oxidation, in particular under accelerated stress conditions and that the oxidation phenomenon was hindered in absence of iron or after addition of EDTA. Our results showed that PS80 "all oleate" (PS80-AO) was more sensitive to oxidative degradation than PS80 "multi-compendial" (PS80-MC). Contrary to acetate and citrate buffers, the results showed that the kinetics of PS80 oxidation was pH-dependent in presence of histidine buffer. It was also demonstrated that, when increasing its concentration, the mAb exhibited a protective effect against metal catalyzed PS80 and methionine oxidation. Our systematic studies on the role of the formulation components and potential contaminants (i.e., iron) demonstrated the complexity of the oxidative mechanism and the importance of different competitive systems, including pro-oxidant factors (e.g., iron, pH, PS80 quality) and antioxidant factors (e.g., protein concentration, EDTA, citrate) that may occur in biologic formulations containing PS80. [ABSTRACT FROM AUTHOR]

[Display omitted] This article is presenting completely new observations linked to Polysorbate 80 (PS80) oxidation in biologics drug product. Indeed, we observed that, in the drug product exposed to long contact time (∼ 1 h) in platinum-cured silicon tubing during the filling, the oxidation of PS80 is dramatically accelerated compared to short contact time. The phenomenon was observed in presence of iron traces (20 ppb), but not in absence of iron (< 2 ppb) or in presence of a chelator like EDTA. Electron Paramagnetic Resonance (EPR) measurements demonstrated the presence of radicals formed during the oxidation. It was deduced that platinum-cured silicon tubing is leaching some radical initiators, most probably peroxides decomposed by the iron. Alternative filling sets made of ThermoPlastic Elastomer (TPE) were investigated, both for the impact on PS80 stability and the filling performance using a peristaltic pump. The results showed that these filling sets were indeed not causing accelerated PS80 degradation but the process was not robust enough; these filling sets being too rigid for the constraints of the peristaltic pump rollers. These results show that there is no practical tubing alternative to platinum silicone cured tubing. To avoid the impact on PS80 oxidation the potential remediations presented in the article are to avoid any trace of iron or to add a chelating agent, or to discard the vials having experimented a filling stop (> 5 min). [ABSTRACT FROM AUTHOR]

The viscosity of high-concentration protein solutions can lead to a range of challenges in drug product manufacturing and administration. Accurately modeling the viscosity of biologics solutions in response to changes in the formulation and surrounding environment is of significant interest and remains a challenge. Here, we show a practical method of modeling the viscosity of a therapeutic solution in response to changes in temperature and protein concentration. Our viscosity model consists of a Ross-Minton model of concentration dependence and a modified Arrhenius temperature dependence. We measured the viscosity as a function of concentration and temperature of 4 therapeutic antibodies in a range of potential clinical formulations. With these data, our model shows surprising generality, proving effective with different types of antibodies, formulations, and a range of more than 2 orders of magnitude in viscosity. Our approach is built on existing theory but provides a practical approach to modeling the viscosity of formulated drug product over the range of process-relevant concentrations and temperatures to better mitigate challenges in the drug manufacturing process. [ABSTRACT FROM AUTHOR]

Within the framework of routine application of image analysis in a pharmaceutical laboratory, a compromise should be established between the number of particles, the analysis time and the accuracy of the results. In the case of nonacicular particles, 500 particles constitute the minimal set to be analysed to get basic information on size and shape distributions. The best choice is 1000 to 1500 particles. As complex shapes should be described by a set of parameters, statistical data mining techniques allow to globally compare samples from the point of view of their size and morphology. For acicular particles, frequently seen in pharmaceutical powders, an algorithm based on the Hough transform and the Euclidian Distance Map transform has been developed: it allows to estimate the length and the breadth of the particles, even when they are in (limited) contact with one another. [Copyright &y& Elsevier]