The University of Connecticut’s Michael Pikal, PhD, has researched pharmaceutical freeze-drying for decades, having helped to develop and patent various leading technologies, including the Smart Freeze-Dryer (see, for example, “PAT Advances Freeze Dryer Control”).

Among Pikal’s latest work is exploring controlled ice nucleation as a means of monitoring and controlling heat and mass transfer parameters during process scale-up. Pikal believes that techniques such as controlled ice nucleation are a critical component of applying Quality by Design principles to lyophilization and ensuring consistency in moving from lab to plant. We spoke with Pikal recently about this topic and more.

PhM: Pharmaceutical freeze-drying has traditionally been time-consuming and costly. Are we making progress in this regard? Are Quality by Design principles a pathway to continued improvement?

M.P: My view is that anything that is poorly understood tends to be classified as “time consuming and costly”. I do not believe freeze drying is currently poorly understood, although I would freely admit that not every organization that does freeze drying has experts in the area, and therefore not every freeze drying development and manufacturing organization is taking full advantage of what has been developed over the past several decades. I would also admit that we have much more to learn, but I would also assert that we are learning!

Therefore, I would argue that we have made remarkable progress in the 30 years or so I have been involved with freeze drying, and the pace of progress continues at a moderate rate. Acceleration of that progress would require more emphasis on “technology development” in industry and more support of freeze drying research in academia. Quality be Design principles are useful, in particular the systematic approach to risk assessment for the purpose of defining what aspects are potential problem areas and which are not and can be simply addressed by historical knowledge and “common sense”. In fact, it is my view that most aspects of “QbD” have been long practiced, even if not with the current protocol, by at least the best of the scientists/engineers with the best companies. Quality by Accident has never been acceptable

PhM: What’s your assessment of the PAT technologies currently available for lyo process monitoring in general? Are good technologies available and on the market, or do you hope to see some advances?

M.P.: There have long been good PAT technologies, particularly for determining the end point of primary drying, which is one of the main issues arising from scale-up differences in proceeding from the laboratory to manufacturing. The use of comparative pressure measurement, Pirani vs. Differential Capacitance Manometer, to evaluate vapor composition in the chamber and therefore to determine the end point of primary drying was first suggested to me by Steve Nail, then of Upjohn, almost 30 years ago. [Note: See “At Baxter, Testing the Limits of Lyo Processes and Equipment,” for an interview with Nail and colleague Lisa Hardwick.] It now appears that some companies are taking advantage of this simple, cheap, and very effective technology.

We still have difficulty measuring meaningful product temperature. It has long been known that placing temperature sensors in product vials gives very misleading and often useless information. Fortunately, there are emerging technologies (MTM, or Manometric Temperature Measurement; TDLAS, or Tunable Diode Laser Absorption Spectroscopy) that show promise, even for manufacturing environments.

Finally, I would like to emphasize that while a large number of sophisticated techniques have been studied in the laboratory, most of these techniques are useless in manufacturing as PAT even though they may be extremely useful in designing a formulation and/or process in the laboratory. We (Dr. Sajal Patel and I) recently reviewed this area, and I would refer the interested parties to the literature for more detail. [Note: Here is one recent article by Pikal, Patel, and Doen—registration required.]

PhM: Manufacturers continue to have many heat and mass transfer scale-up issues regarding lyophilization. You suggest that “one may minimize the freezing difference between laboratory and manufacturing by annealing in the frozen state.” How easily is this done?

M.P.: In principle, it is rather easy. You simply investigate a “design space” of temperature between the Tg’ and the onset of the ice melt endotherm and a range of times from a few hours to the upper limit of what is practical, likely about six hours. Here, a DoE can be useful. The problem is that annealing will require more time and may facilitate degradation problems, particularly if the buffer system is prone to crystallize and shift pH. Generally, degradation is not an issue, but clearly the development scientist needs to very carefully evaluate the impact of annealing on stability, including storage stability.

PhM: Another solution is controlled ice nucleation. Given that ice nucleation is, as you’ve said, normally “random” and uncontrolled, how is the control achieved and maintained through scale-up?

M.P.: Controlled ice nucleation involves cooling the entire batch of vials, whether in development or manufacturing to a given selected temperature below the equilibrium freezing point but yet above the temperature at which spontaneous heterogeneous nucleation may occur. This is usually in the range of -5°C to -10°C. Next, the super-cooled solution is nucleated (or seeded) with ice crystals, by whatever technique is used. In reality, although many methods have been proposed, there are only two methods that I have confidence will work in both laboratory and manufacturing (ice-fog and the Praxair depressurization technique).