CONTAINER CLOSURE SYSTEMS - Application & Effectiveness of Daikyo Crystal Zenith® Container Closure Systems for Radiopharmaceuticals

INTRODUCTION

The use of radiolabeled compounds in medicine has had a long history dating back at least to the 1940s. Today, protein- and peptide-based radiopharmaceuticals are increasingly employed diagnostically as well as for the treatment of disease, most notably in certain types of cancer. However, the synthesis and purification of these radioactive agents can be a difficult and costly process. Often, peptides used in the synthesis of radiopharmaceuticals can adsorb to the walls of container closure systems such that drug product cannot be fully recovered after the synthetic reaction has been terminated. In instances where the labeled peptide or protein must be stored prior to use, additional losses of valuable product can occur that could also affect potency. Consequently, the choice of the proper container closure system is critical for the recovery, transport, and storage of drug product. The use of a material such as Daikyo Crystal Zenith® cyclic olefin polymer may reduce losses due to adsorption while mitigating other problems associated with glass, including delamination and the potential risk of contamination to healthcare providers because of breakage when handling radioactive materials.

Nuclear medicine uses nuclear tracer and radiopharmaceuticals to diagnose and treat diseases. Radionuclides are typically combined with existing pharmaceutical compounds to produce radiopharmaceuticals,  which once administered to a patient, will become localized to a specific organ or cellular receptor. The radiation emitted by the radiopharmaceutical can be detected and used diagnostically to provide information about the extent of a disease process. Monoclonal antibodies (mAbs) along with tyrosine kinase inhibitors are currently the most rapidly expanding classes of anti-cancer drugs.1 A small number of mAbs have been labeled with toxic payloads like the radionuclides yttrium-90 or iodine-131. Ideally, these will bind selectively to receptors on malignant cells and destroy them by short-range ionizing radiation. However, a far broader application has been to label mAbs with a positron emitter for use in understanding the in vivo behavior and efficacy of these targeted drugs in individual patients and for more efficient drug development.

SELECTING CONTAINER CLOSURE MATERIALS FOR RADIOPHARMACEUTICALS

The process of selecting container closure materials compatible with a radiopharmaceutical product and its intended use is an important aspect of delivering safe medicines to patients. The materials used in container closure systems can have physical and chemical properties with the potential to compromise the drug product. Glass has traditionally been used as a primary container for pharmaceuticals since it has characteristics that enable generally safe and effective drug delivery, including good chemical resistance, impermeability to gases, and the fact that it is easily cleaned and sterilized. However, issues such as breakage, delamination, leachables, and physical and chemical compatibility can affect the safety and efficacy of the drug product. Glass delamination can result in the formation of visible glass flakes (lamellae) in parenteral drug products. Delamination originates from an unstable layer on the inner surface of a glass vial and has been attributed to the chemistry or composition of the glass, processing of the glass vial after manufacture, or the use of certain solvents and buffers used to formulate the drug product, including those with high pH or ionic strength or containing citrate or phosphate. In the case of radiopharmaceuticals, such issues may not only harm the patient, but the use of glass could also put the healthcare provider at risk should breakage or other contamination occur. Newer containment alternatives, including cyclic olefin polymers, are now being widely investigated for use with sensitive drug products, particularly biologics (therapeutic proteins). 

Low molecular weight compounds as well as peptides intended for use as radiopharmaceuticals or as tracers are frequently lipophilic and will avidly absorb to the walls of a glass container closure system. Adsorption will prevent recovery of costly precursor materials and the resultant synthesized labeled product. In addition, high molecular weight ligands used in nuclear medicine, such as radiolabeled antibodies also tend to adsorb to the primary containment system.

GLASS VS. PLASTIC CONTAINER CLOSURE SYSTEMS: A STUDY

Positron Emission Tomography (PET) imaging makes use of radionuclides including 68Ga, 18F, 86Y and 64Cu. Due to the short half-lives of these positron emitters, the radiolabeled product is typically used shortly after synthesis and purification.

A recent investigation conducted by Massachusetts General Hospital (MGH) compared the adsorption of a radiopharmaceutical for use in PET imaging to glass and Daikyo Crystal Zenith vials and evaluated which material allows for greater recovery of radiopharmaceutical product. The goal of the Study, “A container closure system that allows for greater recovery of radiolabeled peptide compared to the standard borosilicate glass system,” was to quantify how much 1) labeled drug product and 2) total reaction activity adhered to the container closure system.

As noted previously, many peptides are lipophilic and have a tendency to become adsorbed onto the walls of a container closure system. Several methods that have been shown to mitigate surface adsorption include the addition of a surfactant, such as bovine serum albumin (BSA) or Tween 20, coating the system with polyethylene glycol (PEG) or siliconizing agents, and the addition of organic modifiers to improve the solubility of peptides.2-4 Surfactants and modifiers, such as ethanol and acetic acid, are solvents that have been used to reduce the amount of adsorption to a container closure system; however, the addition of these agents is often undesirable for the synthesis of radiopharmaceuticals. All of the previously discussed methods may require additional purification steps to isolate the labeled product but still fail to remove impurities that have the potential to render the radiopharmaceutical unfit for human use.

Alternatively, a container closure system with inherently reduced surface adsorption, such as one made from a cyclic olefin polymer, could improve the product recovery without the need for modifying the container closure system surface properties or by adding other chemicals to the reaction mix.

Edeotreotide, also known as DOTAC, is a peptide-based molecule which, when bound to various radionuclides, is used in the diagnosis and treatment of certain types of cancer. The peptide contains the chelating group DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), which is capable of complexing with various lanthanide ions, such as 68Gallium.

Researchers at MGH selected a USP Type 1 borosilicate glass container closure system and a resin-based Daikyo Crystal Zenith containment system to compare the synthesis and recovery of 68Ga-chloride and 68Ga-DOTATOC (68Gallium-DOTA-D-Phe1-Tyr3-octreotide) from each type of reaction vial after radiolabeling the peptide. In all experiments using a sodium acetate buffering system and various amount of DOTATOC, the Crystal Zenith container closure system retained less of the total activity than the glass containment system. Over a range of different peptide amounts in a HEPES buffering system, less radioactivity remained in the Crystal Zenith system than the glass with respect to both the percentage of total activity and the percentage of 68Ga-DOTATOC labeled peptide.

Overall, the MGH study concluded that an advantage of the Crystal Zenith container closure system is that one can achieve higher recoveries without the addition of other surfactants that may require extra purification steps as well as have negative effects on the reaction chemistry. Approximately 10% more drug product was recovered from the Crystal Zenith containment system when compared to glass, and approximately 2.5% more of the total reaction activity was recovered from Crystal Zenith compared to glass vials. While the improvement in recovery in this study was relatively modest, such recovery can be critical to the cost of radiopharmaceuticals. Radionuclides and peptides are expensive, so that greater recovery of labeled product will result in a cost savings for the pharmaceutical manufacturer and more drug product available to treat patients.

THE CASE FOR CYCLIC OLEFIN POLYMERS

Several other factors associated with the unique properties of a cyclic olefin polymer support the suitability of Crystal Zenith vials for use with radiopharmaceuticals. In order to accurately measure and adjust the right radiolabel to the right dose, the product must be synthesized, placed in a container, and the amount of ionizing radiation measured using a dose calibrator or similar instrument. The thickness of a vial has an impact on the accuracy and precision of the dose being measured. While glass has variable thickness, cyclic olefins are injection molded, so overall consistency of the vial walls ensure a more precise measurement.

Crystal Zenith’s exceptional transparency and high resistance to most organic solvents, as well as its history of commercial use for contrast media and magnetic resonance imaging fluids, suggest that it may also be an attractive option for radiopharmaceutical containment. Like all plastics, Crystal Zenith is highly resistant to breakage and possesses excellent temperature characteristics. Solutions can be frozen at -20°C to -80°C in containers made of CZ for storage and transport without breakage. Cyclic olefins are compatible with a wide pH range, and in contrast to glass offer greater design flexibility for device integration. However, unlike many other plastics, Crystal Zenith exhibits low levels of leachable molecules and metal ions.

Selection of a container closure system for any drug product should be based on conditions required to maintain stability and ensure recovery of the protein or peptide used in the final drug product. For many radiopharmaceuticals, concentration of the drug product can be an issue. High concentration products, such as mAbs may not require special packaging because the loss of a small amount of product due to adsorption will be negligible. However, many radiopharmaceuticals are formulated at very low concentration. Consequently, the loss of 10 micrograms may be most of the radioactive material, so adsorption can become a major concern. A head-to-head comparison can often provide the most immediate answer to the best container closure system for the peptide or protein drug product, and pharmaceutical manufacturers should not rule out cyclic olefin materials, such as Daikyo Crystal Zenith, without first testing the material as an alternative to glass. In addition to providing a potential solution to losses due to adsorption, the use of Crystal Zenith can mitigate risks associated with breakage and delamination of glass while helping to ensure that the drug product is delivered to patients safely and effectively and at the correct dose.

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REFERENCES

1. van Dongen GAMS, Poot AJ, Vugts AJ. PET imaging with radiolabeled antibodies and tyrosine kinase inhibitors: immuno-PET and TKI-PET. Tumor Biol. 2012;33:617-615.
2. Midwoud PMV, Rieux L, Bischoff R, Verpoorte E, Niederlander HAG. Improvement of recovery and repeatability in liquid chromatography – mass spectrometry analysis of peptides. J Proteome Res. 2006;6:781-791.
3. Qadry SS, Roshdy TH, Char H, Terzo SD, Tarantino R, Moschera J. Evaluation of CZ-resin vials for packaging protein-based parenteral formulations. Int J Pharm. 2003;252:207-212.
4. Goebel-Stengel M, Stengel A, TachéY, Reeve JR, Jr. The importance of using the optimal plasticware and glassware in studies involving peptides. Anal Biochem. 2011;414:38-46.

Dr. Lloyd Waxman joined West in 2008 as a Principal Scientist. He has spent the past 6 years supporting the use of the Daikyo Crystal Zenith® polymer in primary containers used to store and deliver biologics. Dr. Waxman earned his BA and MA in Physics from Temple University and his PhD in Biophysics from Harvard University. He spent 6 years as a Research Scientist at Harvard Medical School in Boston, holds three patents, and has contributed to more than 60 publications.

Dr. Vinod Vilivalam is a Senior Director for Global Technical Marketing of Daikyo Crystal Zenith® and elastomers products at West Pharmaceutical Services, Inc. He provides scientific and technical support and leads various research alliances with academic and commercial institutions to characterize and develop solutions for unmet needs, and has published various peer-reviewed papers. Dr. Vilivalam earned his MS and PhD in Pharmaceutics in 1993 and 1996 from Duquesne University, Pittsburgh, and successfully completed a 2-year business management program in 1999 at The Wharton School, University of Pennsylvania.