Download document - European Biopharmaceutical Enterprises

EBE Visual Inspection Committee – July 2016
A Biopharmaceutical Industry Perspective on the Control of Visible
Particles in Biotechnology-Derived Injectable Drug Products
For the past two years, representatives from eight different pharmaceutical companies which
manufacture biotechnological products have been discussing visible particles. 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. There is not a clear definition of the size
at which a particle becomes visible, due to the probabilistic nature of detecting particles.
Regulatory monographs in Europe and the United States require drug products for parenteral
administration to be “practically free” or “essentially free” of visible particles. In the case of
biotechnological products, the problem is complicated by the fact that all protein solutions
contain particles and these may or may not be visible. The EP monograph 2031, Monoclonal
Antibodies for Human Use, as revised in 2011 requires monoclonal antibody drug products
be ”without visible particles, unless otherwise justified and authorised”. The term "without
visible particles" can be highly misleading in the context of what is practically achievable and
may lead to differences in understanding between industry and agencies. Is the term “free from
visible particles” 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” and a low, justified level of proteinaceous particles after
production? This position paper reviews best practices in the industry in terms of visual
inspection processes and associated operator training, QC 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 perspectives on patient safety. The current
industry position is to consider “practically free from visible particles unless otherwise justified
and authorised” as a standard requirement for QC release of biotechnology derived drug products
including monoclonal antibodies subject to compliance with the European Pharmacopoeia. The
paper provides guidance on how the presence of proteinaceous particles, when a quality attribute
of the molecule, may be justified.
Visible Particle Paper authoring, review, publishing and socializing in conferences
April 3, 2014:
1st EBE Visual Inspection committee meeting F2F in Basel, Switzerland
May 5-7, 2014:
Layout/key guiding principles of the paper and case studies socialized
during EU CMC Strategy Forum, Sorrento, Italy
Sept 30, 2014:
2nd EBE Visual Inspection committee meeting F2F in Basel,
Switzerland
Early 2015 to July 2015: EBE/EFPIA member companies legal/management reviews
September 10-11, 2015: PDA Europe Conference - Particles in Injectables Berlin, Germany,
Impact of Particles on Quality of Biotherapeutics and Current
Approaches for Control, Tapan Das, BMS
October 26-27, 2015
PDA Visual Inspection Forum, Berlin, Germany
A Biopharmaceutical Industry Perspective on the Control of Visible
Particles in biotechnology derived injectable drug products, Maryam
Mazaheri, Medimmune
Oct 27, 2015:
Submission of the paper to PDA Journal of Pharmaceutical Science &
Technology
May 16, 2016:
AAPS NBC Boston, Rountable session Is It Practical to Achieve Zero
Visible Particles in Drug Product? Tapan Das, BMS (Moderator)
Hanns Christian Mahler Lonza (Speaker)
July 2016:
Paper Published in July/August 2016 issue of PDA J
Visible Particle Paper reference
http://journal.pda.org/content/70/4/392.abstract?etoc
SERGE MATHONET1,*, HANNS-CHRISTIAN MAHLER2, STEFAN T. ESSWEIN3, MARYAM
MAZAHERI4, PATRICIA W. CASH4, KLAUS WUCHNER5, GEORG KALLMEYER6, TAPAN K. DAS7,
CHRISTOF FINKLER8, and ANDREW LENNARD9
1Global Regulatory Affairs—Biologics CMC, Sanofi R&D, 91385 Chilly-Mazarin, France; 2Drug Product
Services,Lonza AG, 4002 Basel, Switzerland; 3NBE Analytical R&D, Abbvie Deutschland GmbH & Co. KG,
67061Ludwigshafen, Germany; 4Analytical Biotechnology, MedImmune, Gaithersburg, MD; 5PDMS
Analytical Development, Janssen R&D, 8205 Schaffhausen, Switzerland; 6Quality Combination Products,
Roche, 68305 Mannheim, Germany; 7Biologics Development, Bristol Myers Squibb, Hopewell, NJ; 8Analytical
Development & Quality Control, Pharma Technical Development Biologics EU, Roche, 4002 Basel,
Switzerland; and 9Regional Regulatory Affairs CMC, Amgen Ltd, Uxbridge, UK ©PDA, Inc. 2016
EBE Visual Inspection Committee – Linkedin
https://www.linkedin.com/groups/8513953