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Biologics Containment Delivery

Biopharmaceuticals (e.g., monoclonal antibodies, proteins) require special container/delivery systems in order to help ensure safety and efficacy. Key features of these systems include ability to prevent drug product alteration and suitability for cold storage. This section presents papers addressing these and other topics.

Evaluation of CZ-resin vials for packaging protein-based parenteral formulations.
S.S. Quadry, et al.  International Journal of Pharmaceutics, 252 (1-2), 207-212 (2003)


This article demonstrates that compared to glass, vials comprising Daikyo Crystal Zenith® cyclic olefin polymer provide for significantly less protein binding – and therefore are a viable alternative to glass for biologic drug product packaging/delivery.

Link: http://www.sciencedirect.com/science/article/pii/S0378517302006415

The Shape of Drugs to Come – New Modalities Featured. 


This excellent article by Amgen scientists overviews the structures and functions of different drug products, namely:  small molecules, therapeutic proteins, monoclonal antibodies, fusion proteins, bispecific T-cell engager antibody constructs, bispecific antibodies, peptides, peptibodies, oncolytic immunotherapy viruses, antibody drug conjugates, car-T cells, RNA interference, and listeria-based immunotherapy.

Link: https://www.amgenscience.com/the-shape-of-drugs-to-come/

A container closure system that allows for greater recovery of radiolabeled peptide compared to the standard borosilicate glass system. 


A. Leece, et al.  Applied Radiation and Isotopes, 80, 99-102 (2013)


Employing radiolabeled protein molecules, it was demonstrated that there is less adhesion to a vial comprising the Daikyo Crystal Zenith® cyclic olefin polymer (COP), then to a vial comprising glass.  COP enables better recovery of protein, a clear advantage.

Link: https://www.journals.elsevier.com/applied-radiation-and-isotopes

CONTAINER CLOSURE SYSTEMS - Application & Effectiveness of Daikyo Crystal Zenith® Container Closure Systems for Radiopharmaceuticals.
L. Waxman and V. Vilavalam.  Drug Development and Delivery (May 2014)



This article describes the use cyclic olefin polymer in closure systems for radiopharmaceuticals - the key benefit being maintaining activity by minimizing loss through adsorption to container surfaces.

Link: http://www.drug-dev.com/Main/Back-Issues/CONTAINER-CLOSURE-SYSTEMS-Application-Effectivenes-690.aspx

A Novel Container Closure System for Radiopharmaceuticals. 
A. Leece, et al. (Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School).  The Journal of Nuclear Medicine, 53 (supplement 1), 1479 (May 2012)


The work described in this article indicates that for limited or expensive peptides, containers comprising cyclic olefin polymer provide for substantially higher recovery and unvarying product yield, as compared to containers comprising glass.

Link: http://jnm.snmjournals.org/content/53/supplement_1/1479.abstract

The Truth Behind Protein Aggregation in Prefilled Syringes. 
A. Siew.  BioPharm International, 29 (11), 50-52 (2016)


For biologic drug products in prefilled syringes, this article considers sources of protein aggregation (e.g., interaction with silicone oil) and methods for mitigation (e.g., use of polymer-based components)

Link: http://www.biopharminternational.com/truth-behind-protein-aggregation-prefilled-syringes?pageID=2

Classification and Characterization of Therapeutic Antibody Aggregates.
M. Joubert, et al.  Journal of Biological Chemistry, 286 (28), 25118–25133 (July 15, 2011)


This article considers how different types of stress (mechanical and thermal) result in the formation of different numbers and types of aggregates.

Link: http://www.jbc.org/content/286/28/25118.full.pdf

Chemical Modifications in Therapeutic Proteins Generated under Different Stress Conditions. 
Q. Luo, et al.  Journal of Biological Chemistry, 286 (28), 25134–25144 (July 15, 2011)


This article addresses the chemical modifications to proteins that result from chemical, thermal, and mechanical stress, and how these  modifications affect aggregation.

Link: http://www.jbc.org/content/286/28/25134.full.pdf

Review:  Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals.
J. Bee, et al.  Journal of Pharmaceutical Sciences, 100 (10), 4148-4170 (October 2011)


This article discusses how interactions with surfaces and leachables can result in aggregate formation, as well as  strategies to mitigate this issue.

Link: http://dx.doi.org/10.1002/jps.22597

Available for purchase – free to members of American Pharmacists Association (APhA)

Protein Aggregation and Particle Formation in Prefilled Glass Syringes. 
A. Gerhardt, et al.  Journal of Pharmaceutical Sciences, 103 (6), 1601–1612 (June 2014)


This article considers the effects on protein aggregation resultant from agitation-related exposure to silicone-oil/water interfaces and oil/water interfaces.

Link: http://dx.doi.org/10.1002/jps.23973

Available for purchase – free to members of American Pharmacists Association (APhA)

Overlooking Subvisible Particles in Therapeutic Protein Products:  Gaps That May Compromise Product Quality. 
J. Carpenter et al.  Journal of Pharmaceutical Sciences, 98 (4) 1201-1205 (April 2009)


This article considers the ill effects that particles can have on protein drug product efficacy, including inducement of immune response.

Link: http://dx.doi.org/10.1002/jps.21530

Available for purchase – free to members of American Pharmacists Association (APhA)

An Industry Perspective on the Monitoring of Subvisible Particles as a Quality Attribute for Protein Therapeutics. 
S. Singh, et al.  Journal of Pharmaceutical Sciences, 99 (8) 3302-3321, (August 2010)


This article discusses the opinions of industry leaders regarding the importance of measuring sub-visible particles (< 10="" microns)="" and="" understanding="" if="" there="" is="" a="" relation="" between="" protein="" aggregation="" and="">

Link: http://dx.doi.org/10.1002/jps.22097

Available for purchase – free to members of American Pharmacists Association (APhA)

Protein Aggregation:  Pathways, Induction Factors and Analysis. 
H.C. Mahler, et al.  Journal of Pharmaceutical Sciences, 98 (9), 2909-2934 (September 2009)


This article reviews potential pathways for protein aggregation, and analytical methods to detect, characterize, and quantify said aggregates. It is also emphasized that no single method can be employed for the entire range and types of aggregates.

Link: http://wolfson.huji.ac.il/purification/Course92632_2014/Aggregation/MAHLER2009.pdf

Shaken, Not Stirred:  Mechanical Stress Testing of An IgG1 Antibody.
S. Kiese, et al., Journal of Pharmaceutical Sciences, 97 (10), 4347-4366 (October 2008)


This article considers the effect of agitation on protein aggregation.  Stirring and shaking result in different types of aggregates and in different quantity. Stirring was determined to generate the greater level of stress.

Link: http://dx.doi.org/10.1002/jps.21328

Available for purchase – free to members of American Pharmacists Association (APhA)

Review:  Forced Degradation of Therapeutic Proteins. 
A. Hawe et al.  Journal of Pharmaceutical Sciences, 101 (3), 895-913 (March 2012)


This article discusses the methods to perform, and evaluate results of, stress testing of proteins.  Typical methods include elevated temperatures, freeze/thaw cycles, mechanical stress and exposure to radiation.

Link: https://www.researchgate.net/publication/51798661_Forced_Degradation_of_Therapeutic_Proteins

Silicone Oil- and Agitation-Induced Aggregation of a Monoclonal Antibody in Aqueous Solution. 
R. Thirumangalathu, et al.  Journal of Pharmaceutical Sciences, 98 (9) 3267-3181 (September 2009)


This article examines the effects on aggregation of proteins resulting from silicone oil exposure, in conjunction with agitation, temperature, pH or ionic strength.

Link: http://jpharmsci.org/article/S0022-3549(16)33087-8/pdf

Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd.