The pharmaceutical industry and the US Food and Drug Administration have come to realize that testing quality into a final product can inhibit the rate of introducing new drugs to the market. Since 2003, FDA has been working to modernize pharmaceutical manufacturing and encouraging the use of process analytical technology (PAT) and quality by design (QbD) under its Pharmaceutical CGMPs for the 21st Century initiative (1). The goal of the initiative is to enable manufacturers to produce drug products more efficiently and with higher quality. To achieve this goal, manufacturers must specify critical process parameters (CPPs) and control them within predefined limits of the so-called "design space" (2). These specifications, however, must be developed with laboratory experiments using PAT tools that have the capability to measure CPPs with acceptable accuracy (3). With freeze-drying, in particular, the use of PAT in the laboratory is more focused on process understanding, whereas PAT in production-scale freeze-drying is necessary for process control and may expedite scale-up. The "SMART" freeze-dryer concept (FTS Systems, Stone Ridge, NY) which is based on manometric temperature measurement (MTM), is a new PAT tool that allows accurate product temperature determination at the ice sublimation interface (T p) and the collection of product resistance data (R p) during primary drying (4–6). In addition, SMART technology provides an optimized cycle recipe during the first laboratory experiment for a given formulation. This article describes an approach to evaluate the robustness of a product based on a few simple laboratory experiments for the purposes of scaling-up and to study the impact of a potential T p excess during primary drying.
Materials and methods
Based on an optimized cycle recipe for 50 mg/mL sucrose, shelf temperature and pressure settings were varied to simulate potential worst-case conditions during a production scale run. T p and R p data were collected during the laboratory experiments using an auto-MTM procedure and correlated with the product's appearance. The sucrose purchased from Sigma-Aldrich (Munich) was of analytical grade and used as received. Solutions of 50, 100, and 200 mg/mL were prepared with double-distilled water from an all-glass apparatus.Freeze-drying procedure. Freeze-drying was performed with a "FTS Lyostar II" laboratory-scale freeze dryer with the latest version of SMART freeze-dryer software, which also collects MTM data for a user-predefined recipe (Auto-MTM). Three milliliters of solution were filled into 112 20-mL serum tubing vials (Wheaton, Millville, NY) (vial inner area: 5.74 cm2). Vials were placed hexagonally on the middle shelf of the freeze dryer, using one row of empty vials for shielding. Aluminum foil was placed adjacent to the front door inside the chamber to minimize radiation effects. The first cycle used SMART software to obtain a cycle recipe for the product and experimental conditions (T c= –32 °C, safety margin: 2 °C). The cycle recipe obtained from the SMART run was adjusted to facilitate scale-up conditions (constant shelf temperature over time profile during primary drying). Subsequent runs were performed based on this improvement and then modified for shelf temperature (T s ± 5 °C), chamber pressure (Pc: 62–200 mTorr), and solute concentration (50–200 mg/mL). T p and R p data were recorded and analyzed to describe the influence of the process variations and total solid content on the product morphology.