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Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray-Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach

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Abstract

Purpose

To develop a strategy to control benzene, an ICH Q3C Class 1 impurity that may be present in spray solvents at ppm concentration, in amorphous polymer-stabilized spray-dried dispersion (SDD) products.

Methods

Risk assessments included determining the probability for benzene concentration in primary spray solvents, the physical properties of volatiles, and the potential enrichment of benzene from solution to solid. Mechanistic understanding of benzene removal was gained through a benzene-spiked fate and tolerance (F&T) study simulating worst-case spray-drying conditions and application of diffusion models for secondary drying.

Results

The mass ratio of spray solution to solid presented the highest risk of benzene enrichment. With slow spray-drying kinetics, benzene was reduced about 700-fold. Under standard secondary-drying conditions to remove residual solvents, residual benzene was further removed. Using diffusion models, the maximum benzene concentration was approximated for SDDs dried to the in-process control (IPC) limit of primary solvents.

Conclusions

Two critical control points were established to eliminate any risk of residual benzene reaching patients: (1) upstream control of benzene in solvents (≤10 ppm) and (2) IPC of residual solvents in polymer-stabilized SDDs.

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Abbreviations

%RSD:

Percentage of relative standard deviation

[imp]solids :

Impurity concentration in the SDD

[imp]solvent :

Impurity concentration in the primary spray solvent

API:

Active pharmaceutical ingredient

EP:

European pharmacopoeia

F&T:

Fate and tolerance

FID:

Flame ionization detector

GC:

Gas chromatography

HPMCAS:

Hydroxypropylmethyl cellulose (hypromellose) acetate succinate

ICH:

International conference on harmonisation

IPC:

In process control

JP:

Japan pharmacopoeia

LOQ:

Limit of quantification

NF:

National formulary

ppm:

Parts per million

RER:

Relative evaporation rate

RH:

Relative humidity

RSout :

Relative saturation of solvent at the spray-dryer outlet

SDD:

Spray-dried dispersion

Tcondenser :

Condenser temperature

Tg :

Glass-transition temperature

Tin :

Spray-dryer inlet temperature

Tout :

Spray-dryer outlet temperature

β:

Diffusion parameter

ΔHvap :

Heat of vaporization

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors are greatly thankful for the analytical input from Kristin Ketner (Bend Research); engineering support from Johnny Baumann (Bend Research); and project coordination from Jessica Yankovich (Bend Research).

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Authors and Affiliations

  1. Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA

    Hongfei Yue, Joel D. Young & John A. Castoro

  2. Drug Product Science & Technology, Bristol-Myers Squibb Company, Reeds Lane, Moreton, Merseyside, CH46 1QW, UK

    Sarah J. Nicholson

  3. Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA

    Daniel Hsieh

  4. Bend Research, 64550 Research Road, Bend, Oregon, 97701, USA

    Rodney J. Ketner, Robert G. Hall & Jeremy Sackett

  5. Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, Reeds Lane, Moreton, Merseyside, CH46 1QW, UK

    Elizabeth C. Banks

  6. Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA

    Michael E. Randazzo

Authors
  1. Hongfei Yue
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  2. Sarah J. Nicholson
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  3. Joel D. Young
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  4. Daniel Hsieh
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  5. Rodney J. Ketner
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  6. Robert G. Hall
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  7. Jeremy Sackett
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  8. Elizabeth C. Banks
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  9. John A. Castoro
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  10. Michael E. Randazzo
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Corresponding author

Correspondence to Hongfei Yue.

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Yue, H., Nicholson, S.J., Young, J.D. et al. Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray-Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach. Pharm Res 32, 2636–2648 (2015). https://doi.org/10.1007/s11095-015-1649-7

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  • DOI: https://doi.org/10.1007/s11095-015-1649-7

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