Skip to main content
SpringerLink
Log in

Application of PAT Probes in Aluminum Phosphate Adjuvant Manufacturing

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

This study is focused on monitoring process parameters and quality attributes of aluminum phosphate (AlPO4) using multiple in-line probes incorporated into an industrial-scale adjuvant suspension manufacturing unit.

Methods

The manufacturing of aluminum adjuvant suspension was monitored at manufacturing scale using conductivity, turbidity, infrared, and particle sizing and count probes to follow the continuous evolution of particle formation and size distribution, and the reaction kinetics during the synthesis of AlPO4.

Results

The data showed that AlPO4 forms large particles at the early stages of mixing, followed by a decrease in size and then stabilization towards the later stages of mixing and pH adjustment. The results provided a complementary view of process events and assisted in optimizing several parameters, e.g., flow rate of reactants AlCl3 and Na3PO4 solutions, mixing rate, pH, and conductivity of AlPO4, as well as adjuvant quality attribute such as particle size, thus streamlining and shortening the process development stage.

Conclusion

The results of this study showed the usefulness of the in-line probes to automate continuous assessment of AlPO4 batch-to-batch consistency during in-house adjuvant production at the industrial scale.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Hem SL, Hogenesh H. Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Rev Vaccines. 2007;6:685–98.

    Article  CAS  PubMed  Google Scholar 

  2. Kalbfleisch K, Deshmukh S, Mei C, Ore M, Williams W, Durowoju I, et al. Identity, Structure and Compositional Analysis of Aluminum Phosphate Adsorbed Pediatric Quadrivalent and Pentavalent Vaccines. Comput Struct Biotechnol J. 2019;17:14–20. Available from: https://www.sciencedirect.com/science/article/pii/S2001037018301156. Accessed 13 Dec 2023.

  3. Process Analytical Technology. European Pharmacopeia 10.4, Chapter 5.25. 04/2021.

  4. FDA Guidance for Industry. PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 2004.

  5. Mei C, Deshmukh S, Cronin J, Cong S, Chapman D, Lazaris N, Sampaleanu L, Schacht U, Drolet-Vives K, Ore M, Morin S, Carpick B, Balmer M, Kirkitadze M. Aluminum Phosphate Vaccine Adjuvant: Analysis of Composition and Size Using Off-Line and In-Line Tools. Comput Struct Biotechnol J. 2019;17:1184–94. https://doi.org/10.1016/j.csbj.2019.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Razani M, Gerzon G, Patt M, Dhaliwal S, Hunter HN, Sheng Y, Kirkitadze M. Near Infrared Spectroscopy - A Real-Time Method to Measure Aluminum Content and Protein Concentration in Adsorbed Vaccines. J Vaccines Immunol Immunopathol. 2022;7:167. https://doi.org/10.29011/2575-789X.000167.

    Article  Google Scholar 

  7. Carmona P, Rodriguez ML. Hydrogen bonding between phosphate and amino acid side chains. J Mol Struct. 1986;143:365–8. https://doi.org/10.1016/0022-2860(86)85278-4.

    Article  ADS  CAS  Google Scholar 

  8. General notices. European Pharmacopeia 10.0, p.5371–5373.

  9. Synchronised Total Quality (synTQ) PAT knowledge manager. https://www.syntq.com. Accessed 13 Dec 2023.

  10. Redman T, O’Grady D, Improve Products and Processes with In-line Particle Analysis, AIChE 2017; August:47–55. https://www.aiche.org/resources/publications/cep/2017/august/improve-products-and-processes-inline-particle-analysis.

  11. Aluminum Compounds Used as Adjuvants in Vaccines. Shirodkar S, Hutchinson RL, Perry DL, White JL, Hem SL. Pharma Res. 1990;7:1282-1288. https://doi.org/10.1023/a:1015994006859.

  12. Yan S, Gu W, Xu ZP. Re-considering how particle size and other properties of antigen-adjuvant complexes impact on the immune responses. J Colloid Interface Sci. 2013;395:1–10. https://doi.org/10.1016/j.jcis.2012.11.061.

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Haer M, Payne J, Strahlendorf K, Jung R, Xiao E, Kowal P, Gemmiti G, Cronin J, Gable T, Park-Lee K, Drolet-Vives K, Balmer M, Kirkitadze M. PAT Solutions to Monitor Adsorption of Tetanus Toxoid with Aluminum Adjuvants. J Pharm Biomed Anal. 2021;198: 114013. https://doi.org/10.1016/j.jpba.2021.114013.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors would like to thank Kira Li, Yu Chen Lin, Wayne Williams, and Madeline Patt for their support with LD measurements over the course of the study, Olivier Level and Pascale Gonnet for discussions, and Jean-Sébastien Bolduc (Sanofi) for editorial assistance.

Funding

This study was funded by Sanofi.

Author information

Authors and Affiliations

  1. Analytical Sciences, Vaccine CMC Development and Supply, Sanofi, Toronto, ON, M2R 3T4, Canada

    Przemyslaw Kowal, Ginny Fung & Marina Kirkitadze

  2. Manufacturing Sciences, Analytics and Technology, Sanofi, Toronto, Canada

    Gabriel Gemmiti & Liliana Sampaleanu

  3. Mettler Toledo AutoChem Inc., Columbia, MD, USA

    James T. Cronin

Authors
  1. Przemyslaw Kowal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ginny Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriel Gemmiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liliana Sampaleanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James T. Cronin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marina Kirkitadze
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors substantially contributed to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work, and provided final approval of the version to be published. P.K., G.F., and M.K. contributed to drafting the work and revising it critically for important intellectual content.

Corresponding author

Correspondence to Marina Kirkitadze.

Ethics declarations

Conflicts of Interest

Przemyslaw Kowal, Ginny Fung, Gabriel Gemmiti, Liliana Sampaleanu, and Marina Kirkitadze are employees of Sanofi and may hold shares and/or stock options in the company. James T. Cronin is an employee of Mettler Toledo and has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kowal, P., Fung, G., Gemmiti, G. et al. Application of PAT Probes in Aluminum Phosphate Adjuvant Manufacturing. Pharm Res 41, 375–385 (2024). https://doi.org/10.1007/s11095-023-03642-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03642-6

Keywords

Search

Navigation