Freeze dryer capabilities can change with different designs, which is imperative when transferring cycles from lab-scale to commercial-scale. Each freeze dryer has limitations and it is important to understand them in order to avoid the risk of product failure when upscaling production.
Dr. Jayasree M. Srinivasan, Baxter BioPharma Solutions, recently presented a webinar discussing the measurement and comparison of equipment capabilities in lab-scale and production-scale freeze dryers for the definition of optimum design space parameters. The webinar is summarized here and includes a selection of questions from the Q&A session.
Determining Design Space for Optimal Product Lyophilization
Defined by boundaries representing the limitations of freeze-drying conditions, optimal product and processes can be represented graphically. One boundary is the critical product temperature required before collapse occurs and the second boundary is equipment capability.
The area underneath the boundaries is the design space and guarantees that the product is safely produced (Figure 1). The plot of chamber pressure and sublimation rate depends on the vial heat transfer coefficient (Kv) and product resistance (Rp), which establishes the relationship between the controlled parameters and product temperature.
Figure 1: Design space of the freeze-drying process. A multidimensional representation of equipment capability limit and product knowledge.
Variations the design or function of the freeze dryer or any process deviations can change the freeze-drying cycle properties and lead to product failure. Process deviation can be caused by fluid problems in refrigeration and varying dynamics of water vapor flow from the chamber to the condenser. Sublimation requires consistent and homogenous heat controlled by the shelf temperature, regulating the freeze-drying, and any discrepancies in shelf temperature can result in uncontrolled freeze-drying.
Product parameters are vital in early-stage development, pilot clinical stages, or commercial manufacturing. However, transferring from one stage to another might require repeated optimization if the freeze dryers are not fully characterized.
Comparative Freeze Dryer Capability Study
Dr. Srinivasan examined the capability of two lab-scale freeze dryers (LyoStarTM II, SP Scientific) (Figure 2) and three production-scale freeze dryers (one LyoMax® 9 and two LyoMax® 20s, IMA Group). Several methods exist that determine the mass flow rate during sublimation, the easiest being tunable diode laser absorption spectroscopy (TDLAS).
Figure 2: LyoStar 3 (the next generation to LyoStar II).
The studies described in this article utilized a TDLAS as the flow meter for mass flow determination. Measuring the maximum mass flow rate recognizes the choked point (the limit of velocity of water vapor that flows through the spool piece [duct] between the freeze dryer chamber and condenser).
Compatible Capabilities of Laboratory and Production Freeze Dryers
After increasing the shelf temperature at each pressure point, maximum sublimation rates were measured as a function of chamber pressure, until the chamber pressure was no longer in control (“choked” flow). Comparing two LyoStar II freeze dryers showed that the capability curves of sublimation rates were superimposable, which represented equivalent performance.
Comparing the LyoStar with the two LyoMax freeze dryers showed that the production freeze dryers (LyoMax 9 and 20) had more capability than lab-scale freeze dryers and maintained higher sublimation rates. Lab-to-production technical transfer would therefore be quite achievable (Figure 3). LyoMax 9 capability was, therefore, better than the LyoMax 20 due to the smaller shelf surface area.
Figure 3: Comparison of Capabilities of LyoStar II® and LyoMax® Freeze-dryers.
Comparable Lyophilization between Lab and Product Freeze Dryers Using the same Cycle Conditions
The scalability from LyoStar to LyoMax was demonstrated by Dr. Srinivasan. Lyophilization was carried out using an amorphous API (124.2 mg/mL) and mannitol (32 mg/mL) formulation, as well as batches of 300 vials in the LyoStar II and 11,000 vials in the LyoMax freeze dryers. The same cycle conditions that were developed with the LyoStar II were utilized in both freeze dryers.
Good agreement in mass flow rate data (collected using TDLAS) between the two freeze-dryers was shown and the maximum rate achieved during this study for both the LyoStar II and the LyoMax freeze dryers. This indicated that they were operating at 20% and 30% of their maximum capability, respectively, implying that they will not reach the choke point under the process conditions used.
The reproducibility of two batches using the same formulation and lyophilization cycle conditions was measured in the LyoMax 9, which found that the maximum flow rates and the time taken to reach them were quite similar (1.37 g/sec and 1.33 g/sec, respectively, after 0.5 hours).
For their equipment capabilities, two lab-scale (LyoStar II) and three production-scale freeze dryers (LyoMax) were likened. The LyoMax 9 and 20 were more capable than the LyoStar II with all the freeze dryers operating at 20–30% capability, which suggested that the lyophilization process can be scaled up between a lab- and production-scale freeze dryer.
Providing further evidence of thorough equipment functionality for both freeze dryers, equipment capabilities, and batch reproducibility was established in the LyoStar II and LyoMax 9, respectively. This information can be graphically illustrated on a design space plot, which identifies the safe zone where cycle conditions produce an enhanced product. Deviance into areas outside this region can lead to choked flow rates and product breakdowns.
- What is the ratio of the duct diameter to chamber volume or mass flow where the choked flow becomes impossible?
We have not determined that ratio.
- Would you favor dm/dt via TDLAS vs MTM to fill up the Pikal equation and Kv determination?
We at Baxter routinely use the TDLAS for mass flow rate determination. We prefer this technique due to its ease of use and the non-destructive nature of the measurements.
- Can you explain why it has to be -45°C for water freezing?
We typically use -40°C to -45°C to freeze formulations to ensure batch uniformity so all vials are frozen completely prior to sublimation.
- Why does your example lyo cycle start pulling vacuum at -15°C during thermal treatment, rather than -45°C?
If the primary drying shelf temperature is warmer than -15°C (or any annealing temperature), it is not necessary to freeze the formulation back down to -40°C before pulling a vacuum. You can initiate vacuum at the annealing temperature. Freezing it to -40°C would only extend the cycle time.
- Has Baxter WW standardized on TDLAS for pilot equipment, even in Belgium?
No, we have not. Bloomington is the only Baxter facility that has the TDLAS capability.
- Why do you need to know the weight of the water when using TDLAS for choke limit determination?
The TDLAS estimates the total mass flow rate data. We also measure the weight loss gravimetrically (weights before and after drying) as a way to check the accuracy of the TDLAS. A variance of 3-5% is typical.
- How full do we need to fill the tray with H2O?
For lab-scale freeze dryers, we use 1.5-2 L of Milli-Q water for each lyo tray.
About SP Scientific Products
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