Although lyophilization as a practice of preservation has existed for many years, perfecting the science continues to be a
highly sought after objective of parenteral drug manufacturers. The strong push for increasing the number of protein-based
therapeutics and other injectable products through development has contributed to the need for leaner, more cost-efficient
freeze-drying methods without compromising quality. Boosting quality involves identifying vulnerable critical process parameters.
To address the needs for safety, reduced risk, and better control, industry has designed solutions for use in the three areas
of the lyophilization process well known to be highly susceptible: stopper placement, lyophilizer loading and unloading, and
(ILLUSTRATION BY M. MCEVOY. IMAGES:BAXTER PHARMACEUTICAL SOLUTIONS LLC AND DON FARRAL/GETTY IMAGES)
PAT and QbD: drivers of innovation
The US Food and Drug Administration's efforts to cultivate better understanding and control into many sectors of the process
development cycle, including lyophilization, are evident.
"A lot of the emphasis has been spent in the past couple of years on identifying the limits of the freeze-drying process,"
says Heinrich Meintrup, managing director of GEA Pharma Systems (Hurth, Germany). "The basis is having to identify the weak
points. The efforts in lyophilization are going toward trying to get a closer understanding of what is going on in a big installation,
across all the vials, and within individual vials. How can we eliminate variability of the results in individual vials and
how do we improve the design of the equipment to reduce this variability? It comes from better capturing the process conditions
Solutions for monitoring lyophilizer shelf temperature and chamber pressure over time has involved the implementation of radio-frequency
transitioned data, process analytical technology (PAT)-inspired wireless sensors, manometric temperature measurement approaches,
and "smart" vials (1). Other methods include barometric temperature measurement (BTM).
This approach measures the broad temperature barometrically without the need for placing a real sensor. The strategy is especially
advantageous in fully automated systems in which it may be difficult to first place a real sensor in a vial and then downstream
to remove this single vial.
Figure 1. (ALL FIGURES ARE COURTESY OF W.L. GORE & ASSOCIATES.)
"It is a method that is based on physics ... now integrated into the control system as part of the PAT initiative," says Meintrup.
"If you look at what has been driven by PAT, so clearly it is about temperature distribution, having clear information about
what stage the process is at any time inside of the freeze dryer. Because it is a big chamber closed under vacuum conditions,
you cannot take a sample, there is nothing you can see from outside other than frozen vials." Measuring equipment added to
freeze dryers provides a level of understanding of what is going on in the chamber as well as some justification of the particular
stage of the freeze-drying process.
Shrinking the cleanroom
For contract facilities or clinical-trial material processes, innovative solutions must take place within a limited space.
These facilities may not have the resources to set up and maintain large expensive cleanrooms and must rely on other means
to control contamination at critical points. One of these process points is stopper placement. Traditionally, sterile split-stoppers
are placed only part way down the vials, allowing vapor to escape during lyophilization. After lyophilization, under vacuum
or atmospheric conditions, the stopper is pushed into its final position by the freeze-dryer shelves to seal the vials. However,
industry researchers point out that the semi-open vials are at risk of being exposed to potential contaminants.
At the 2008 American Association of Pharmaceutical Scientists annual meeting, W.L. Gore and Associates of Elkton, MD, introduced
a bicomponent material technology to seal vials off from external environments (Gore Lyoguard vial isolator). The system incorporates
a microporous vent to protect the product inside the vial, which effectively shrinks the cleanroom to a one-vial size. The
unit provides a level of filtration such that the product can be freeze-dried through the membrane.