Process Analytical Technology-Based In-Line Buffer Dilution In Downstream Bioprocessing - Pharmaceutical Technology

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Process Analytical Technology-Based In-Line Buffer Dilution In Downstream Bioprocessing
The authors describe the operational requirements and design of a process-ready PAT-based IBD system.


Pharmaceutical Technology
Volume 34, pp. s18-s22

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.


Figure 5: pH titration curve of 10 mM acetic acid and 10 mM ammonium hydroxide. PAT is process analytical technology.
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).

Discussion

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,
. Shree Jariwala is an undergraduate student intern at Northwestern University.

*To whom all correspondence should be addressed.

References

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.


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