Integration of PAT in Biopharmaceutical Research: A Case Study - Pharmaceutical Technology

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Integration of PAT in Biopharmaceutical Research: A Case Study
This case study describes the implementation of process analytical technology on the cultivation process step of a whole-cell vaccine against whooping cough disease.


Pharmaceutical Technology
Volume 33, Issue 7

Conclusion

The principles of PAT can be applied to biopharmaceutical products, not just small-molecule drugs. Biopharmaceutical processes, particularly the cultivation process step, are intrinsically more complex than processes used to make chemical drugs. By applying a sound scientific approach for development of process understanding and by using the appropriate sensors and monitoring techniques, a biopharmaceutical process can become as stable and capable as any world-class manufacturing process.

The ultimate benefits of PAT application are mitigation of risks (failures) during manufacturing, flexibility in process optimization, and safer and more pure products. The effort to understand the process will be rewarded when scale-up, process changes, or even medium optimizations are more easily implemented throughout the product's manufacturing lifetime. Furthermore, on-line monitoring of product quality and subsequent adjustment to the optimal trajectory will lead to fewer failed runs and a more consistent product of high quality. Real-time quality assurance will lead to shorter cycle times and fewer stockpiles. This case study shows that monitoring cell cultivation, combined with process understanding condensed in chemometrical models, allows the optimal harvest point to be determined, and thereby allows the monitoring of product quality throughout the batch, opening the possibility for real-time product release. This increased process understanding leads to shorter production times and faster detection of batch failures, reduces cost and increases productivity.

These benefits have encouraged FDA to make PAT application the mandatory backbone of future pharmaceutical process development and manufacturing. This case study demonstrates that it can even be applied to a complex and undefined product such as a whole-cell vaccine, which means it should also be feasible for any pharmaceutical or biopharmaceutical product currently on the market. The PAT initiative can therefore help to increase the safety and efficacy of medicines while reducing the time-to-market for new products and the operational costs of manufacturing. This situation is good news for regulatory inspectors, manufacturers, and patients.

Kjell François, PhD,* is senior PAT consultant for Siemens NV, Curie Square 30, 1070 Brussels, Belgium,
. Mathieu Streefland, PhD, is project leader of the PaRel project at The Netherlands Vaccine Institute (NVI). Rebecca Vangenechten is a consultant for business and project development life sciences USA, and Leo Hammendorp is director of business and project development for global life sciences, both at Siemens NV.

*To whom all correspondence should be addressed.

References

1. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, 2004), http://www.fda.gov/cder/guidance/6419fnl.pdf.

2. M. Streefland, "From Process Understanding to Process Control: Application of PAT on the Cultivation of Bordetella pertussis for a Whole Cell Vaccine," (Doctoral thesis, Wageningen University, The Netherlands, 2009).

3. ICH, Q8 Pharmaceutical Development (Geneva, Switzerland, 2005), http://www.ich.org/LOB/media/MEDIA1707.pdf.

4. FDA, "Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products; Notice of Pilot Program," Federal Register 73, 37972–37974 (Rockville, MD, 2008).

5. M. Streefland et al., "PAT for Vaccines: The First Stage of PAT Implementation for Development of a Well-Defined Whole-Cell Vaccine Against Whooping Cough Disease," Vaccine, 25 (16), 2994–3000 (2007).

6. C.A. Cummings et al., "Species- and Strain-Control of a Complex, Flexible Regulon by Bordetella BvgAS," Jrnl. Bacteriol. 188 (5), 1775–1785 (2006).

7. D. Hot et al., "Differential Modulation of Bordetella pertussis Virulence Genes as Evidenced by DNA Microarray Analysis," Mol. Genet. Genomics 269 (4), 475–486 (2003).

8. M. Streefland et al., "Evaluation of a Critical Process Parameter: Oxygen Limitation During Cultivation Has a Fully Reversible Effect on Gene Expressions of Bordetella pertussis," Biotechnol. Bioeng. 102 (1), 161–167 (2009).

9. M. Streefland et al., "Gene-Expression Based Quality Scores Indicate Optimal Harvest Point in Bordetella pertussis Cultivation for Bacterial Vaccine Production," Biotechnol. Bioeng., 103 (5), 900–908 (2009).

10. M.M. Nakamura et al., "Growth Phase- and Nutrient Limitation-Associated Transcript Abundance Regulation in Bordetella pertussis," Infect. Immun. 74 (10), 5537–5548 (2006).

11. E.N.M. van Sprang et al., "Manufacturing Vaccines: An Illustration of Using PAT Tools for Controlling the Cultivation of Bordetella pertussis," Qual. Engin., 19 (4): 373–384 (2007).

12. ICH, Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System, http://www.ich.org/cache/compo/363-272-1.html.

13. D.C. Montgomery, "Experimental Design for Product and Process Design and Development," Jrnl. Roy. Stat. Soc. 48 (2), 159–177 (2001).


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