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Combating Alcohol Adduct Impurity in Immunosuppressant Drug Product Manufacturing: A Scientific Investigation for Enhanced Process Control

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Abstract

Objective

This research aims to elucidate critical impurities in process validation batches of tacrolimus injection formulations, focusing on identification and characterization of previously unreported impurity at RRT 0.42, identified as the tacrolimus alcohol adduct. The potential root causes for the formation of new impurity was determined using structured risk assessment by cause and effect fishbone diagram. The primary objective was to propose mitigation plan and demonstrate the control of impurities with 6 month accelerated stability results in development batches.

Methods

The investigation utilizes method validation and characterization studies to affirm the accuracy of quantifying the tacrolimus alcohol adduct. The research methodology employed different characterization techniques like rotational rheometer, ICP‒MS, MALDI-MS, 1H NMR, 13C NMR, and DEPT-135 NMR for structural elucidation. Additionally, the exact mass of the impurity is validated using electrospray ionization mass spectra.

Results

Results indicate successful identification and characterization of the tacrolimus alcohol adduct. The study further explores the transformation of Tacrolimus monohydrate under various conditions, unveiling the formation of Tacrolimus hydroxy acid and proposing the existence of a novel degradation product, the Tacrolimus alcohol adduct. Six-month data from development lots utilizing Manufacturing Process II demonstrate significantly lower levels of alcohol adducts.

Conclusions

Manufacturing Process II, selectively locates Tacrolimus within the micellar core of HCO-60, this prevent direct contact of ethanol with Tacrolimus which minimizes impurity alcohol adduct formation. This research contributes to the understanding of tacrolimus formulations, offering ways to safeguard product integrity and stability during manufacturing and storage.

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Data Availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the supplementary materials. Upon request, and subject to review and legal requirements, Pfizer may provide the data that support the findings of this study.

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Acknowledgments

The authors would like to thank RK, Ramachandran, Dorwat, Anand, and Srinivasu, Polisetty from Pfizer, External Supply, Operation and Category Management, for their external collaboration. All the authors would like to thank Gland Pharma Limited, Hyderabad, India, for their collaboration and for making the PV batch at their manufacturing site. Sekar Vasanthakumar would like to thank M.D. Raja, Senior Scientist, SID, Chennai, India for the final review and comments. Authors would like to thank Vicki Morris, Senior Manager Biostatistics, Medicinal Science, Pfizer, Mulgrave, Australia for the simulation data plot and review.

Funding

This work is part of regular project in Pfizer Healthcare, India Pvt Ltd., Chennai, India.

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Authors and Affiliations

  1. Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113

    Vasanthakumar Sekar, Devarajan Vedhachalam, ArunKumar VB, Sivananthan Sivaraman, Venkatakrishnan Janakarajan & Sai Sethuraman

  2. Pfizer, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 375 North Field Drive, Lake Forest, Illinois, 60045, USA

    Sandeep G. Shiroor & Jean-Marie M. Geoffroy

Authors
  1. Vasanthakumar Sekar
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  2. Devarajan Vedhachalam
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  3. ArunKumar VB
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  4. Sivananthan Sivaraman
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  5. Venkatakrishnan Janakarajan
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  8. Jean-Marie M. Geoffroy
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Contributions

Study Design, Development and Analysis: Sekar Vasanthakumar, Devarajan V, VB, ArunKumar and Sivaraman, Sivananthan.

Data analysis and Interpretation: Sekar Vasanthakumar, Devarajan V, VB, ArunKumar, Janakarajan, Venkatakrishnan, Sethuraman, Sai, and Geoffroy, Jean-Marie M.

Project management and administration: Sivaraman, Sivananthan, Sethuraman, Sai, Shiroor, Sandeep G, Geoffroy, Jean-Marie M, Sekar Vasanthakumar and Devarajan V.

Manuscript conceptualization: Sekar Vasanthakumar, Devarajan V, VB, ArunKumar, Sivaraman, Sivananthan Sethuraman, Sai, Shiroor, Sandeep G, Geoffroy, Jean-Marie M.

Manuscript writing: Sekar Vasanthakumar.

Manuscript review and editing: all the authors.

Corresponding author

Correspondence to Vasanthakumar Sekar.

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Sekar, V., Vedhachalam, D., VB, A. et al. Combating Alcohol Adduct Impurity in Immunosuppressant Drug Product Manufacturing: A Scientific Investigation for Enhanced Process Control. Pharm Res (2024). https://doi.org/10.1007/s11095-024-03695-1

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