Ammonium hydroxide (10 mM) was delivered from pump P001 to mix with acetic acid (20 mM) from pump P002. In mass-flow blending,
the frequency of both pumps was tuned for the pH to start at around 5. A gradual increase of base over 30 min afforded a final
pH of 10. Simply blending weak acid and weak base by mass-flow obtained a typical sigmoid curve (see Figure 5). The steep
rise of pH from 6.5 to 9 in less than 2 min was typical of mass-flow control. The pH of the resulting solution followed the
acid-and-base titration curve.
The goal for this experiment was to generate a linear pH gradient from 5 to 9. To control the sigmoid change in pH and to
obtain a linear pH gradient, acidity adjustment and control through a PAT-based system is necessary. Accordingly, ammonium-hydroxide
solution (100 mM) was delivered from pump P102. Initially, three pumps were properly tuned to start at a pH of approximately
5.0. The authors programmed the process-control software with a linear pH gradient from 5 to 9 over 30 min. During the run,
the acidity of the resulting solution in the loop was constantly adjusted to meet the set point in accordance with the signal
from the process-control feedback loop. As a result, a linear pH gradient was obtained (see Figure 5).
Figure 5: pH titration curve of 10 mM acetic acid and 10 mM ammonium hydroxide. PAT is process analytical technology.
Pharmaceutical companies still suffer from excessive re-work and discarded product because of out-of-specification processes.
PAT-based IBD has the potential to account for and to reduce the impact of raw-material variability when diluting concentrate
solutions. Thus, IBD can reduce the amount of out-of-specification products that must be reprocessed or discarded. PAT-based
control can be applied to chromatographic separations so that consistent and reproducible gradients are produced, regardless
of the starting materials. Furthermore, PAT control also can enable the use of linear pH gradients for different applications
normally not available from a mass-flow control system.
The ability of an IBD system to monitor and manipulate the state of a process and actively manipulate it to maintain a desired
state was supported by both the conductivity and the linear pH gradient experiments (1). FDA's QbD initiative incorporates
PAT as a crucial tool for designing and optimizing manufacturing processes. The PAT-based IBD system described in this article
successfully implements the principles of this guidance and minimizes variability by adaptively correcting the quantity of
raw materials around a set point.
Michael Li, PhD,* is manager of process sciences, Vivek Kamat is senior engineer, Hiroyuki Yabe is manager of science and technology, and Tomo Miyabayashi is vice-president of science and technology, all at Asahi Kasei Bioprocess, 1855 Elmdale Ave., Glenview, IL 60026, tel. 847.556.9716,
fax 800.293.5059, firstname.lastname@example.org
. Shree Jariwala is an undergraduate student intern at Northwestern University.
*To whom all correspondence should be addressed.
1. FDA, PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, Sept. 2004).
2. T. Matthews et al., Pharm. Manuf.
8 (4), 36– 41 (2009),
http://www.pharmamanufacturing.com/articles/2009/046.html accessed Sept. 21, 2010.
3. T. Malone and M. Li, Bioprocess Int.
8 (1), 40–44 (2010).
4. T. Brown, H. LeMay, Jr. ,and B. Bursten, Chemistry: The Central Science (Prentice Hall, Englewood Cliffs, NJ, 5th ed., 1991), pp. 607–615.