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Article CommentaryCommentary

A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology-Derived Injectable Drug Products

Serge Mathonet, Hanns-Christian Mahler, Stefan T. Esswein, Maryam Mazaheri, Patricia W. Cash, Klaus Wuchner, Georg Kallmeyer, Tapan K. Das, Christof Finkler and Andrew Lennard
PDA Journal of Pharmaceutical Science and Technology July 2016, 70 (4) 392-408; DOI: https://doi.org/10.5731/pdajpst.2015.006189
Serge Mathonet
1Global Regulatory Affairs—Biologics CMC, Sanofi R&D, 91385 Chilly-Mazarin, France;
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  • For correspondence: Serge.Mathonet@sanofi.com
Hanns-Christian Mahler
2Drug Product Services, Lonza AG, 4002 Basel, Switzerland;
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Stefan T. Esswein
3NBE Analytical R&D, Abbvie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, Germany;
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Maryam Mazaheri
4Analytical Biotechnology, MedImmune, Gaithersburg, MD;
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Patricia W. Cash
4Analytical Biotechnology, MedImmune, Gaithersburg, MD;
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Klaus Wuchner
5PDMS Analytical Development, Janssen R&D, 8205 Schaffhausen, Switzerland;
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Georg Kallmeyer
6Quality Combination Products, Roche, 68305 Mannheim, Germany;
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Tapan K. Das
7Biologics Development, Bristol Myers Squibb, Hopewell, NJ;
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Christof Finkler
8Analytical Development & Quality Control, Pharma Technical Development Biologics EU, Roche, 4002 Basel, Switzerland; and
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Andrew Lennard
9Regional Regulatory Affairs CMC, Amgen Ltd, Uxbridge, UK
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Abstract

Regulatory monographs in Europe and the United States require drug products for parenteral administration to be “practically free” or “essentially free” of visible particles, respectively. Both terms have been used interchangeably and acknowledge the probabilistic nature of visual particle inspection. The probability of seeing a particle in a drug product container varies according to the size and nature of the particles as well as container and inspection conditions. Therefore, the term “without visible particles” can be highly misleading in the context of what is practically achievable. This may lead to differences in understanding between industry practitioners and regulatory agencies. Is this term intended to mean “zero particles”, or is there any intention to distinguish between particle type such as “zero extraneous visible particles” or “zero proteinaceous particles”? Furthermore, how can “zero” particles as a criterion for release testing be reconciled with “practically free from particles” as stated in the definition and a low, justified level of proteinaceous particles after production?

The purpose of this position paper is to review best practices in the industry in terms of visual inspection process and associated operator training, quality control sampling, testing, and setting acceptance criteria corresponding to “practically free of visible particles” and providing considerations when visible proteinaceous particles are deemed unavoidable. It also provides a brief overview of visible particle characterization and gives perspectives on patient safety. This position paper applies to biotechnology-derived drug products including monoclonal antibodies in late-phase development to licensed products.

LAY ABSTRACT: In the 2011 monoclonal antibody monograph revision, European Pharmacopoeia experts acknowledged that protein products may also contain proteinaceous particles at release or that protein particles may form during storage. Indeed, industry experience has demonstrated that therapeutic proteins such as monoclonal antibodies can exhibit a propensity for self-association leading to the formation of aggregates that range in size from nanometres (oligomers) to microns (subvisible and visible particles). As a result, the requirement for drug product appearance for monoclonal antibodies was changed from “without visible particles” to “without visible particles unless otherwise authorised or justified”. In our view, “practically free from particles” should be considered a suitable acceptance criterion for injectable biotechnology and small-molecule products, as long as appropriately defined. Furthermore, we argue that visual inspection is a suitable quality control release test and that “practically free from particles” is a suitable specification when adequately described.

  • 100% inspection
  • Lyophilized
  • Quality control sampling
  • QC sampling
  • Particle identification
  • proteinaceous particles
  • visible particles
  • © PDA, Inc. 2016
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PDA Journal of Pharmaceutical Science and Technology: 70 (4)
PDA Journal of Pharmaceutical Science and Technology
Vol. 70, Issue 4
July/August 2016
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A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology-Derived Injectable Drug Products
Serge Mathonet, Hanns-Christian Mahler, Stefan T. Esswein, Maryam Mazaheri, Patricia W. Cash, Klaus Wuchner, Georg Kallmeyer, Tapan K. Das, Christof Finkler, Andrew Lennard
PDA Journal of Pharmaceutical Science and Technology Jul 2016, 70 (4) 392-408; DOI: 10.5731/pdajpst.2015.006189

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A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology-Derived Injectable Drug Products
Serge Mathonet, Hanns-Christian Mahler, Stefan T. Esswein, Maryam Mazaheri, Patricia W. Cash, Klaus Wuchner, Georg Kallmeyer, Tapan K. Das, Christof Finkler, Andrew Lennard
PDA Journal of Pharmaceutical Science and Technology Jul 2016, 70 (4) 392-408; DOI: 10.5731/pdajpst.2015.006189
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  • Article
    • Abstract
    • 1. Problem Statement
    • 2. Visual Inspection at End of Drug Product Manufacturing—100% Inspection Followed by Sampling Inspection
    • 3. QC Sample Testing
    • 4. Control of Visible Particles in Lyophilized Products
    • 5. Particle Identification and Characterization
    • 6. Patient Safety
    • 7. Conclusions
    • Conflict of Interest Declaration
    • Acknowledgments
    • Appendix 1: Inspector Certification
    • Appendix 2: Risk Assessment of Visible Particles
    • References
  • Figures & Data
  • References
  • Info & Metrics
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Cited By...

  • Definition of Particle Visibility Threshold in Parenteral Drug Products--Towards Standardization of Visual Inspection Operator Qualification
  • Comparing visual inspection methods for parenteral products in hospital pharmacy: between reliability, cost, and operator formation considerations
  • Identification and Root Cause Analysis of the Visible Particles Commonly Encountered in the Biopharmaceutical Industry
  • Characterization of a Novel Particle in a Pharmaceutical Drug Product
  • Development and Qualification of Visible Particle Load Analysis Methods for Injectable Drug Product Primary Packaging Components
  • Micro-Flow Imaging: Estimation of the Contribution of Key Factors to the Variability of Subvisible Particle Count Measurement by a Nested Statistical Analysis
  • Development of Protein-Like Reference Material for Semiquantitatively Monitoring Visible Proteinaceous Particles in Biopharmaceuticals
  • Achieving "Zero" Defects for Visible Particles in Injectables
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Keywords

  • 100% inspection
  • Lyophilized
  • Quality control sampling
  • QC sampling
  • Particle identification
  • proteinaceous particles
  • Visible particles

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