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Phase-Appropriate Application of Analytical Methods to Monitor Subvisible Particles Across the Biotherapeutic Drug Product Life Cycle

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Abstract

The phase-appropriate application of analytical methods to characterize, monitor, and control particles is an important aspect of the development of safe and efficacious biotherapeutics. The AAPS Product Attribute and Biological Consequences (PABC) focus group (which has since transformed into an AAPS community) conducted a survey where participating labs rated their method of choice to analyze protein aggregation/particle formation during the different stages of the product life cycle. The survey confirmed that pharmacopeial methods and SEC are the primary methods currently applied in earlier phases of the development to ensure that a product entering clinical trials is safe and efficacious. In later phases, additional techniques are added including those for non-GMP extended characterization for product and process characterization. Finally, only robust, globally-accepted, and stability-indicating methods are used for GMP quality control purposes. This was also consistent with the feedback during a webinar hosted by the group to discuss the survey results. In this white paper, the team shares the results of the survey and provides guidance on selecting phase-appropriate analytical methods and developing a robust particle control strategy.

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Abbreviations

AAPS:

American Association of Pharmaceutical Scientists

AC-SINS:

Affinity-capture self-interaction nanoparticle spectroscopy

AF4:

Asymmetric flow field flow fractionation

AUC:

Analytical ultracentrifugation

CD:

Circular dichroism

cIEF:

Capillary isoelectric focusing

CQA:

Critical quality attribute

DLS:

Dynamic light scattering

FDA:

Food and Drug Administration

FIH:

First in Human

FTIR:

Fourier-transform-infrared spectroscopy

GMP:

Good manufacturing practice

ICH:

International Conference of Harmonization

JP:

Japanese Pharmacopeia

LO:

Light obscuration

MALS:

Multi angle light scattering

μDSC:

Micro differential scanning calorimetry

nDSF:

Nano differential scanning fluorimetry

NTA:

Nanotracking analysis

OOS:

Out of specification

PABC:

Product Attribute and Biological Consequences

Ph. Eur.:

European Pharmacopeia

QC:

Quality control

RMM:

Resonant mass measurement

RP-HPLC:

Reversed-phase high-pressure liquid chromatography

SbVP:

Subvisible particles

SEC:

Size exclusion chromatography

SEM-EDX:

Scanning electron microscopy–energy dispersive X-ray

SLS:

Static light scattering

TDA:

Thermal denaturation assay

TEM:

Transmission electron microscopy

TOF-SIMS:

Time-of-flight secondary ion mass spectroscopy

USP:

United States Pharmacopeia

VP:

Visible particles

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Authors and Affiliations

  1. Lonza Drug Product Services, 4057, Basel, Switzerland

    Roman Mathaes & Anja Matter

  2. Amgen, Inc, One Amgen Center Dr, Thousand Oaks, California, 91320, USA

    Linda Narhi

  3. Coriolis Pharma, Fraunhoferstr. 18b, 82512, Martinsried, Germany

    Andrea Hawe

  4. Novartis, 4056, Basel, Switzerland

    Karoline Bechtold-Peters

  5. Wyatt Technology Corporation, 6330 Hollister Ave., Santa Barbara, California, 93117, USA

    Sophia Kenrick

  6. Molecular and Analytical Development, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, New Jersey, 08534, USA

    Sambit Kar

  7. West Pharmaceutical Services, Inc., 530 Herman O. West Drive, Exton, Pennsylvania, 19341, USA

    Olga Laskina

  8. University of Colorado, Denver, Colorado, USA

    John Carpenter

  9. National Institute of Standards and Technology, Gaithersburg, Maryland, 20899, USA

    Richard Cavicchi & Dean Ripple

  10. Commercial Product Support, Innovation and Investments, Pharmaceutical Development & Supplies, PTD Biologics Europe. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Ellen Koepf

  11. Mettler-Toledo, Autochem, Inc., Redmond, Washington, USA

    E. Neil Lewis

  12. U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Rukman De Silva

Authors
  1. Roman Mathaes
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  2. Linda Narhi
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  3. Andrea Hawe
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  4. Anja Matter
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  6. Sophia Kenrick
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  7. Sambit Kar
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  8. Olga Laskina
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  9. John Carpenter
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  10. Richard Cavicchi
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  11. Ellen Koepf
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  12. E. Neil Lewis
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  13. Rukman De Silva
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  14. Dean Ripple
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Corresponding author

Correspondence to Roman Mathaes.

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Mathaes, R., Narhi, L., Hawe, A. et al. Phase-Appropriate Application of Analytical Methods to Monitor Subvisible Particles Across the Biotherapeutic Drug Product Life Cycle. AAPS J 22, 1 (2020). https://doi.org/10.1208/s12248-019-0384-0

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  • DOI: https://doi.org/10.1208/s12248-019-0384-0

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