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Purpose <p>Aluminum hydroxide adjuvant is widely used in vaccine production, yet its washing process still depends on qualitative, operator-dependent assays such as Nessler’s reagent and barium chloride tests. This study aimed to validate a conductivity-based Process Analytical Technology (PAT) method for real-time and non-destructive endpoint determination during aluminum hydroxide adjuvant washing.</p> Methods <p>The adjuvant was synthesized from ammonium aluminum sulfate and ammonia. Thirty-seven process samples from three production batches were analyzed using in-line pH and conductivity probes. Residual ammonium and sulfate ions were quantified using spectrophotometric reference assays. Linear regression models were developed between conductivity and ion concentrations, and specificity was evaluated through controlled pH shifts (pH 5–8) followed by dilution.</p> Results <p>Conductivity demonstrated strong linear correlations with residual ammonium (R<sup>2</sup> = 0.9946) and sulfate (R<sup>2</sup> = 0.9963). A conductivity threshold of 250 µS/cm consistently indicated attainment of target residual ion limits (≤ 50&#xa0;ppm NH₄⁺ and ≤ 100&#xa0;ppm SO₄<sup>2</sup>⁻), eliminating the need for colorimetric assays. The PAT approach removed approximately three redundant washing cycles per batch, reducing deionized water consumption and processing time by ~ 25%. Continuous-mode integration further reduced deionized water usage by up to 33% and shortened the overall washing process to a single working day.</p> Conclusions <p>Conductivity-based PAT provides a robust, safe, and efficient alternative to conventional endpoint assays, enabling automated real-time control and eliminating hazardous reagents. The validated method aligns with Quality by Design (QbD) and Real-Time Release Testing (RTRT) principles and advances aluminum adjuvant manufacturing toward Industry 4.0.</p>

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Real-Time endpoint monitoring in aluminum hydroxide adjuvant washing using process analytical technology: toward smarter vaccine manufacturing

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月22日

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  • Mohammad Zali,
  • Mohammad Reza Halvagar,
  • Sara Zali,
  • Mahdieh Najafi Mobarra,
  • Tara Adimi,
  • Marjan Sadat Bozorgvar

摘要

Purpose

Aluminum hydroxide adjuvant is widely used in vaccine production, yet its washing process still depends on qualitative, operator-dependent assays such as Nessler’s reagent and barium chloride tests. This study aimed to validate a conductivity-based Process Analytical Technology (PAT) method for real-time and non-destructive endpoint determination during aluminum hydroxide adjuvant washing.

Methods

The adjuvant was synthesized from ammonium aluminum sulfate and ammonia. Thirty-seven process samples from three production batches were analyzed using in-line pH and conductivity probes. Residual ammonium and sulfate ions were quantified using spectrophotometric reference assays. Linear regression models were developed between conductivity and ion concentrations, and specificity was evaluated through controlled pH shifts (pH 5–8) followed by dilution.

Results

Conductivity demonstrated strong linear correlations with residual ammonium (R2 = 0.9946) and sulfate (R2 = 0.9963). A conductivity threshold of 250 µS/cm consistently indicated attainment of target residual ion limits (≤ 50 ppm NH₄⁺ and ≤ 100 ppm SO₄2⁻), eliminating the need for colorimetric assays. The PAT approach removed approximately three redundant washing cycles per batch, reducing deionized water consumption and processing time by ~ 25%. Continuous-mode integration further reduced deionized water usage by up to 33% and shortened the overall washing process to a single working day.

Conclusions

Conductivity-based PAT provides a robust, safe, and efficient alternative to conventional endpoint assays, enabling automated real-time control and eliminating hazardous reagents. The validated method aligns with Quality by Design (QbD) and Real-Time Release Testing (RTRT) principles and advances aluminum adjuvant manufacturing toward Industry 4.0.