Recommended Best Practices in Freeze Dryer Equipment Performance Qualification: 2022.

Best practices for performing freeze dryer equipment qualification are recommended, focusing on identifying methods to quantify shelf thermal uniformity (also known as "shelf surface uniformity"), equipment capability, and performance metrics of the freeze dryer essential to the pharmaceutical Quality by Design paradigm. Specific guidelines for performing shelf temperature mapping, freeze dryer equipment limit testing (the capability curve), and condenser performance metrics have been provided. Concerning shelf temperature mapping and equipment capability measurements, the importance of paying attention to the test setup and the use of appropriate testing tools are stressed.

The Influence of Mannitol Hemihydrate on the Secondary Drying Dynamics of a Protein Formulation: A Case Study.

The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where "bursts" of water vapor release were observed during secondary drying as detected by comparative pressure measurement. "Thief" samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in a stepwise fashion. These samples were examined by X-ray powder diffraction and thermal analysis.

A proposed rationale and test methodology for establishment of acceptance criteria for vacuum integrity testing of pharmaceutical freeze dryers.

A scientific rationale is proposed for the establishment of acceptance criteria for leak rates in pharmaceutical freeze dryers. A method was developed to determine the quantity of air that could leak into any lyophilizer from the outside while still maintaining Class 100/Grade A microbial conditions. A lyophilizing product is assumed most vulnerable to microbial contamination during secondary drying, when mass transfer of water vapor from product to condenser is minimal.

Two experimental tests of relational models of procedural justice: non-instrumental voice and authority group membership.

In both a laboratory experiment (in Australia) using university as the basis of group membership, and a scenario experiment (in India) using religion as the basis of group membership, we observe more favourable respect and fairness ratings in response to an in-group authority than an out-group authority who administers non-instrumental voice. Moreover, we observe in our second experiment that reported likelihood of protest (herein called "social-change voice") was relatively high following non-instrumental voice from an out-group authority, but relatively low following non-instrumental voice from an in-group authority. Our findings are consistent with relational models of procedural justice, and extend the work by examining likely use of alternative forms of voice as well as highlighting the relative importance of instrumentality.

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.

Product mass transfer resistance directly determined during freeze-drying cycle runs using tunable diode laser absorption spectroscopy (TDLAS) and pore diffusion model.

The pore diffusion model is used to express the dry layer mass transfer resistance, [Formula: see text], as a function of the ratio r(e)/?, where r(e) is the effective pore radius and ? is the tortuosity factor of the dry layer. Using this model, the effective pore radius of the dry layer can be estimated from the sublimation rate and product temperature profiles measured during primary drying. Freeze-drying cycle runs were performed using the LyoStar II dryer (FTS Systems), with real-time sublimation rate profiles during freeze drying continuously measured by tunable diode laser absorption spectroscopy (TDLAS).

Determination of shelf heat transfer coefficients along the shelf flow path of a freeze dryer using the shelf fluid temperature perturbation approach.

The spatial distribution of local shelf heat transfer coefficients, Ks, was determined by mapping the transient temperature response of the shelf surface along the serpentine internal channels of the shelf while the temperature of the heat transfer fluid was ramped from -40 degrees to 40 degrees C. The solution of a first-order non-steady-state differential equation resulted in a predicted shelf surface temperature as a function of the shelf fluid temperature at any point along the flow path. During the study, the shelf surfaces were maintained under a thermally insulated condition so that the heat transfers by gas conduction and radiation were negligible.

Rapid determination of dry layer mass transfer resistance for various pharmaceutical formulations during primary drying using product temperature profiles.

Mass transfer resistance of the dry layer during the primary drying phase of a lyophilizaton cycle is probably the most important factor affecting maximum product temperature and drying time. Product resistance parameters should be determined for each formulation because of their dependence of formulation composition and concentration. The purpose of this study was to determine the dry layer mass transfer resistance, using a simple and rapid method, for various pharmaceutical formulations during primary drying in a laboratory dryer, using monitored product temperature profiles.

Correlation of laboratory and production freeze drying cycles.

The purpose of this study was to develop the correlation of cycle parameters between a laboratory and a production freeze-dryer. With the established correlation, key cycle parameters obtained using a laboratory dryer may be converted to those for a production dryer with minimal experimental efforts. In order to develop the correlation, it was important to consider the contributions from the following freeze-drying components: (1) the dryer, (2) the vial, and (3) the formulation.

Practical formulation and process development of freeze-dried products.

Freeze-drying science and technology continues to evolve and increase in importance because of the emergence of biotechnology drugs that are too unstable to be commercially available as ready-to-use solutions. As more new drug compounds need to be developed as freeze-dried products, this mini-review article provides practical guidance and commentary on the latest literature articles on formulation and process development of freeze-dried products. This article contains a table that provides the quantitative formulations of all commercial freeze-dried protein pharmaceutical products through 2004.