The graphical design space for the primary drying phase of freeze Drying: Factors affecting the dried product layer resistance.

An emerging approach to process development of a lyophilized pharmaceutical product is to construct a graphical design space for primary drying as an aid to process optimization. The purpose of this paper is to further challenge the assumption in earlier work that the maximum values of the resistance of dried product layer, R, is approximately constant and is independent of process conditions within the "acceptable" region of the design space. Three model formulations containing bovine serum albumin as the model protein were chosen to represent: (a) an amorphous system, (b) a crystalline system, and (c) a mixed system where both an amorphous and a crystalline component were present.

Mannitol hemihydrate in lyophilized protein formulations:Impact of its dehydration during storage on sucrose crystallinity and protein stability.

The high propensity of mannitol to crystallize in frozen solutions along with its high eutectic temperature enabling higher primary drying temperatures makes it a good bulking agent. In protein formulations, addition of a sugar (sucrose) that has the ability to remain amorphous throughout processing as well as storage is imperative to retain the protein in its native state. It is well known that in the presence of amorphous excipients and protein, mannitol can crystallize as a mixture of anhydrous polymorphs - α-, β- and δ-forms and a hemihydrate form [mannitol hemihydrate (MHH); CHO·0.

Recommended Best Practices for Lyophilization Validation 2021 Part II: Process Qualification and Continued Process Verification.

This work describes the lyophilization process validation and consists of two parts. Part one (Part I: Process Design and Modeling) focuses on the process design and is described in the previous paper, while the current paper is devoted to process qualification and continued process verification. The goal of the study is to show the cutting edge of lyophilization validation based on the integrated community-based opinion and the industrial perspective.

Correction to: Recommended Best Practices for Lyophilization Validation-2021 Part I: Process Design and Modeling.

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Recommended Best Practices for Lyophilization Validation-2021 Part I: Process Design and Modeling.

This work describes lyophilization process validation and consists of two parts. Part I focuses on the process design and is described in the current paper, while part II is devoted to process qualification and continued process verification. The intent of these articles is to provide readers with recent updates on lyophilization validation in the light of community-based combined opinion on the process and reflect the industrial prospective.

Equipment Capability Measurement of Laboratory Freeze-Dryers: a Comparison of Two Methods.

The objective of this investigation was to evaluate two methods for measuring the maximum sublimation rate that a freeze-dryer will support-the minimum controllable pressure method and the choke point method. Both methods gave equivalent results, but the minimum controllable pressure method is preferred, since it is easier, faster, and less subjective. The ratio of chamber pressure to condenser pressure corresponding to the onset of choked flow was considerably higher in this investigation (up to about 20:1) than in previously published reports.

Freeze-Dryer Equipment Capability Limit: Comparison of Computational Modeling With Experiments at Laboratory Scale.

The equipment capability curve is one of the bounding elements of the freeze-drying design space, and understanding it is critical to process design, transfer, and scale-up. The second bounding element of the design space is the product temperature limit beyond which the product collapses. The high cost associated with freeze-drying any product renders it crucial to operate using the most efficient cycle within the limits of the equipment and the product.

Process and Formulation Effects on Protein Structure in Lyophilized Solids Using Mass Spectrometric Methods.

Myoglobin (Mb) was lyophilized in the absence (Mb-A) and presence (Mb-B) of sucrose in a pilot-scale lyophilizer with or without controlled ice nucleation. Cake morphology was characterized using scanning electron microscopy, and changes in protein structure were monitored using solid-state Fourier-transform infrared spectroscopy, solid-state hydrogen-deuterium exchange-mass spectrometry, and solid-state photolytic labeling-mass spectrometry (ssPL-MS). The results showed greater variability in nucleation temperature and irregular cake structure for formulations lyophilized without controlled nucleation.

Pre-filled syringes: a review of the history, manufacturing and challenges.

Pre-filled syringes are convenient devices for the delivery of parenteral medications. They are small which makes them easy to carry and are dependable for delivering a precise dose of medication. These and many other reasons are leading to their growth in the pharmaceutical market.

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study.

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state.

Practical fundamentals of glass, rubber, and plastic sterile packaging systems.

Sterile product packaging systems consist of glass, rubber, and plastic materials that are in intimate contact with the formulation. These materials can significantly affect the stability of the formulation. The interaction between the packaging materials and the formulation can also affect the appropriate delivery of the product.

Thermal analysis of frozen solutions: multiple glass transitions in amorphous systems.

Frozen aqueous solutions of sucrose exhibit two "glass transition-like" thermal events below the melting endotherm of ice when examined by DSC, but the physical basis of these events has been a source of some disagreement. In this study, a series of sugars, including sucrose, lactose, trehalose, maltose, fructose, galactose, fucose, mannose, and glucose were studied by modulated DSC and freeze-dry microscopy in order to better understand whether sucrose is unique in any way with respect to this behavior, as well as to explore the physical basis, and the pharmaceutical significance of these multiple transitions. Double transitions were found to be a common feature of all sugars examined.

Rapid determination of vial heat transfer parameters using tunable diode laser absorption spectroscopy (TDLAS) in response to step-changes in pressure set-point during freeze-drying.

The purpose of this study was to perform a rapid determination of vial heat transfer parameters, that is, the contact parameter K(cs) and the separation distance l(v), using the sublimation rate profiles measured by tunable diode laser absorption spectroscopy (TDLAS). In this study, each size of vial was filled with pure water followed by a freeze-drying cycle using a LyoStar II dryer (FTS Systems) with step-changes of the chamber pressure set-point at to 25, 50, 100, 200, 300, and 400 mTorr. K(cs) was independently determined by nonlinear parameter estimation using the sublimation rates measured at the pressure set-point of 25 mTorr.

Identification of physical-chemical variables affecting particle size following precipitation using a supercritical fluid.

The physical-chemical processing variables affecting particle size following precipitation using the supercritical antisolvent (SAS) method were investigated by varying both the composition of the feed solvent and the structure of the solute, using a series of steroids. The key factor influencing particle size in these studies appears to be the solubility of the drug in the organic solvent/supercritical fluid mixture, where relatively high solubility causes a lower degree of supersaturation in the precipitation vessel, resulting in a relatively large particle size. Higher operating pressures result in larger particle sizes, probably through the effect of pressure on solubility.

Identification of critical process variables affecting particle size following precipitation using a supercritical fluid.

The critical processing parameters affecting average particle size, particle size distribution, yield, and level of residual carrier solvent using the supercritical anti-solvent method (SAS) were identified. Carbon dioxide was used as the supercritical fluid. Methylprednisolone acetate was used as the model solute in tetrahydrofuran.