![]() ![]() This capability curve can vary widely between laboratory and production scale. One of the boundaries of the graphical design space is the equipment capability curve or the maximum sublimation rate supported by the equipment as a function of chamber pressure. Understanding equipment capability or performance is a point of emphasis in the Quality by Design (QbD) regulatory paradigm, and has taken on increased visibility in light of the development of a graphical design space approach to optimization of the primary drying phase of a freeze-drying cycle. It is important to know which factor, or factors, limits performance, as well as the maximum sublimation rate supported by a given freeze dryer. ![]() Any freeze dryer has performance attributes that limit the sublimation rate it will support-refrigeration capacity, condenser surface area, the upper temperature limit of the heat transfer fluid circulating through the shelves, system geometry such as vapor duct length and diameter, or the dynamics of vapor flow from the chamber to the condenser. The underlying cause of the failed scale-up lot was a phenomenon known as choked flow, which we will not elaborate on here, but this event is a good example of the importance of understanding equipment capability. The failed scale-up run caused a significant delay in the product development timeline. ![]() In response to the pressure drop, the heating elements turned on again, resulting in a pressure rise to the upper limit, and the cycle repeated. As a result, the sublimation rate decreased and the chamber pressure dropped to the lower limit. When the pressure reached the upper alarm limit, the power to the heating elements in the heat transfer fluid was cut off. Pressure in the freeze dryer chamber could not be controlled, but rather oscillated between alarm limits. The scale-up batch did not go according to plan. A contract manufacturer was chosen and a scale-up batch was prepared using the suggested cycle conditions. The development scientists at the biotech company tried to take advantage of the robustness of the formulation by recommending aggressive cycle conditions that resulted in a relatively short freeze-dry cycle. It was known that the formulation itself was very robust that is, it could be freeze-dried under very aggressive conditions without compromising any quality attribute of the product, such as cake appearance, reconstitution time, recovery of original activity, or residual moisture level. At the time, the development scientists had no clear idea of where scale-up and, ultimately, production scale operations would take place. The formulation was to be freeze-dried, and formulation development, as well as early process development, was carried out by development scientists at the biotech company. Graphical AbstractĪ few years ago, a big pharmaceutical company entered into a joint development agreement for a large molecule therapeutic agent with a small biotech company. These specific procedural recommendations are based on calculations, measurements, and experience to provide useful process and equipment knowledge. Finally, guidelines for systematic leak rate testing criteria for a freeze dryer are presented. Furthermore, merits and demerits of thermal conditions maintained on the cooled surfaces of the freeze dryer condenser have been discussed identifying the specific influence of the condenser surface temperature on the process conditions using experimental data to support the guidelines. In all the guidelines provided, much attention has been paid to identifying the balance between obtaining useful process knowledge, logistical challenges associated with testing in the production environment vs that at laboratory scale, and the frequency of the testing necessary to obtain such useful information. 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. ![]() Specific guidelines for performing shelf temperature mapping, freeze dryer equipment limit testing (the capability curve), and condenser performance metrics have been provided. 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. ![]()
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