MULTILAYER PLASTIC VIALS - OXYCAPT™: Contributing to Stability of Cell & Gene Therapy Products

INTRODUCTION

Mitsubishi Gas Chemical (MGC) is a leading company in the field of special polymers with oxygen-absorbing and barrier func­tions. In 2019, MGC launched new products named OXYCAPT™ Multilayer Plastic Vials, featuring a high oxygen, carbon dioxide, and ultraviolet barrier. Since then, a lot of biologics and cell and gene therapy companies have started their evaluations, and we have received positive results from them.

As cell and gene therapy products are usually stored under harsh conditions, such as deep-cold or cryogenic temperatures, the property of containers has been more focused recently. Glass vials have been used for injectable drugs for many years, but they have issues of breakage and container closure integrity (CCI) when stored at deep-cold or cryogenic temperatures. Alterna­tively, polymer vials are often used for cell and gene therapy products, but some issues, such as breakage at -180°C and CCIT during the thawing process, have been found. Under these situ­ations, we developed OXYCAPT Multilayer Plastic Vials that can overcome such drawbacks.

OVERVIEW OF OXYCAPT™

OXYCAPT is a multilayer plastic vial developed by MGC, of­fering several advantageous properties as a primary drug con­tainer, such as excellent oxygen, carbon dioxide, and ultraviolet (UV) light barrier, strong water vapor barrier, very low extracta­bles, high pH stability, low protein adsorption and aggregation, high transparency, high break resistance, easy disposability, and light weight, etc.

OXYCAPT consists of three layers: the drug contact layer and the outer layer are made of COP, and the oxygen barrier layer is made of MGC’s novel polyester.

As stated previously, OXYCAPT provides an excellent oxygen and carbon dioxide barrier. For example, the oxygen and carbon dioxide barrier of an OXYCAPT vial is about 20 times better than that of a COP monolayer vial. OXYCAPT also provides an excel­lent UV barrier. While about 70% of 300 nm UV light transmits through glass and COP, only 1.7% transmits through OXYCAPT. We have confirmed this feature contributes to the stability of bio­logics. The water vapor barrier of OXYCAPT is similar to those of COP, which has been used for injectable drugs for many years. This means OXYCAPT easily meets the re­quirements of a water vapor barrier pro­posed by the ICH guideline.

Studies have shown an extremely low level of extractables from OXYCAPT. One study was conducted to confirm the levels of volatile, semi-volatile, and non-volatile impurities from OXYCAPT. Water and four solutions (50% ethanol, NaCl, NaOH, and H3PO4) were selected, and impurities were measured by gas chromatography mass spectrometry (GC-MS) and liquid chromatography-UV spectroscopy-mass spectrometry (LC-UV-MS) after 70 days at 40°C. Compared with the control, impuri­ties were not detected in the OXYCAPT containers. The other study confirmed in­organic extractables levels from OXYCAPT were similar to those from COP, which is well known as an extremely pure polymer with a better extractables profile than Type 1 glass. Lower levels of inorganic extracta­bles are known to contribute to the stability of pH in drug products.

OXYCAPT vials are produced by co-injection blow-molding technology. We have also developed inspection methods to test the oxygen barrier layer. All of the containers are fully inspected by state-of-the-art inspection machinery. We can offer ready-to-use (RTU) vials in standard nest and tub or tray formats. These formats are mainly sterilized using gamma rays. There are 2-, 6-, 10-, and 20-mL variants for the vials.

Each polymer meets the requirements of United States Pharmacopeia (USP) 661, 87, and 88, as well as those of the Euro­pean Pharmacopeia, and has been filed in the US FDA’s drug master file (DMF). OXYCAPT vials are also compliant with each pharmacopoeia and have been filed in the DMF.

BREAK RESISTANCE AT CRYOGENIC TEMPERATURE

Break resistance is one of the impor­tant factors for vials for cell and gene ther­apy products stored at deep-cold or cryogenic temperature. Because cell and gene therapy products are very expensive and valuable for patients, break resistance is an essential property to prevent unex­pected losses. To confirm the efficacy of OXYCAPT, we conducted some dropping tests using OXYCAPT and COP vials. As glass is always broken after these tests, we didn’t add it to the sample list.

First, we prepared OXYCAPT 10R vials filled with 5 mL of water and stored them at -80°C for 1 week, 6 months, and 2 years. All the vials were dropped from 150-cm height after each storage period and inspected by naked eyes. No break­age and water leakage were observed in the vials after the dropping test.

Second, we prepared OXYCAPT and monolayer COP 10R vials filled with 10 mL of water and stored them in liquid ni­trogen gas phase (around -180°C) for 1 month. All the vials were dropped from 150-cm height and inspected by naked eyes. No breakage and water leakage were observed in OXYCAPT, but some of monolayer COP vials were broken after the dropping test. We assume there is a risk that medical workers, such as doctors and nurses, drop the expensive and pre­cious drugs by mistake, so the break re­sistance is an essential property for such high value products.

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CONTAINER CLOSURE INTEGRITY AT -80°C WITH DRY ICE

All pharmaceutical containers must maintain integrity against microbial con­tamination and have a gas barrier when a drug is sensitive to oxygen or carbon dioxide (CO2). Gene therapy drugs are usually stored at deep-cold temperature and transported with dry ices. During stor­age and transportation, packages, includ­ing vials, are exposed to temperatures of around -80°C in a deep freezer or dry ice, which is a potential risk to container clo­sure integrity (CCI) due to differences in the coefficient of thermal expansion (CTE) of the vial and rubber closure materials.

The CCI of Type I glass vials is partic­ularly at risk from very low temperatures compared with plastic vials because the CTE of typical Type I glass is a factor of 10 smaller than that of rubbers. On the other hand, standard plastic vials have a potential risk of CO2 trans­mission when stored with dry ice. To examine the benefits of OXY­CAPT, MGC conducted a CCI test with dry ice.

We prepared OXYCAPT vial and general rubber closures. The rubber closure is a typical bromo butyl rubber with -65°C Tg. We also prepared press-on-cap closures and OXYCAPT’s positive control with a fine hole of a 5-μm nominal diameter.

First, all the vials, closures, and aluminum seals were in­serted into a chamber where the air was replaced with nitrogen, then they were assembled and crimped by hand in the chamber. After preparing the samples, we measured the partial pressureof CO2 in the vials’ headspace (T0). The samples were then stored in a deep freezer at -80°C for 7 days. After storage in the freezer, the CO2 pressure in the headspace was measured (T1). Next, the remaining samples were immediately inserted into an insulation box with 30 kg of dry ice. After storage in the CO2-rich environ­ment for 7 days, CO2 pressure in the headspace was measured (T2). Lastly, the remaining vials were stored at room temperature for 4 days to sublimate the dry ice, and CO2 pressure in the headspace was measured (T3 & T4).

Headspace pressure of CO2 was measured with an FMS-Carbon Dioxide, manufactured by LIGHTHOUSE Instruments (VA, US). The instrument is based on frequency modulation spec­troscopy (FMS), which is a non-destructive method.

At temperatures lower than -65°C, bromo butyl rubber loses its elastic properties, which may lead to loss of airtightness at the interface between vial and rubber closure. Therefore, maintaining a temperature inside the insulation box under -65°C is crucial for measuring the leakage precisely in this test.

The test result shows the headspace CO2 pressure of OXY­CAPT with traditional rubber closure (Entry 1), OXYCAPT with press-on-cap (Entry 2), and OXYCAPT positive control sample (Entry 1’). Although much CO2 partial pressure was detected in Entry 1’, no CO2 partial pressure was observed in Entry 1 and 2. This study has demonstrated OXYCAPT has an excellent CCI even under a CO2-rich environment.

CARBON DIOXIDE BARRIER AT ROOM TEMPERATURE

CO2 molecules permeates through polymers and get into a vial’s headspace, affecting drug stability. As the rate of CO2 transmission is different among polymer materials, we performed related studies using OXYCAPT and COP vials.

OXYCAPT and commercially avail­able COP 10R vials were prepared with bromo butyl rubber (BBR) and aluminum seal closures. First, all the vials and BBR and aluminum seals were placed in a ni­trogen chamber for a couple of days. Sec­ond, the vials were sealed with the closures using a hand-crimper in a nitrogen cham­ber. Next, these vials, filled with nitrogen gas, were placed in a box filled with CO2 and stored at 23°C.

The result shows the headspace CO2 partial pressure of OXYCAPT and COP vials. Although the CO2 partial pressure of COP vials immediately rose, reaching around 700 torr in 60 days, the OXYCAPT vials were able to keep CO2 partial pres­sure to very low levels.

We also calculated the CO2 transmis­sion rate of OXYCAPT and COP vials by using the test results of CO2 partial pres­sure. While only 0.018 cm3 of carbon dioxide transmitted through OXYCAPT 10R vials per day at 23°C, 0.423 cm3 transmit­ted through 10R COP vials. This result demonstrates that the CO2 barrier of OXYCAPT is more than 20 times better than that of monolayer COP.

CONTAINER CLOSURE INTEGRITY WITH DRY ICE AFTER FREEZING & THAWING PROCESS

Some research shows CO2 doesn’t permeate into the COP vial’s head space that much at deep-cold temperature, al­though it permeates much more at room temperature. To verify this theory, we con­ducted some related studies after freezing and thawing processes.

Cell and gene therapy products are usually frozen during storage and trans­ported with dry ices. Before injection to pa­tients, the products are thawed in a hot water bath or at room temperature. There­fore, we kept OXYCAPT and COP vials at -75°C in CO2-rich environment for 18 days and then placed at room tempera­ture for 4 days.

As we had expected, both the COP and OXYCAPT vials could keep 0% of CO2 at -75°C under a CO2-rich environment for 18 days. However, the COP vials couldn’t keep 0% of CO2 after additional storage at room temperature for 4 days, although OXYCAPT could.

There are basically two phenomena of gas molecule permeation with plastic containers, dissolution and diffusion. The diffusion speed at -75°C is much slower than at room temperature, but the coeffi­cient of dissolution at -75°C is higher at room temperature. Therefore, a lot of CO2 is dissolved into the COP polymer at -75°C and permeated into the COP vial’s head­space during the thawing process at room temperature. On the other hand, as OXY­CAPT has a high gas-barrier property, it can prevent CO2 permeation into the headspace.

NEXT STUDY

To verify the excellent properties of OXYCAPT for cell and gene therapy products, we have begun additional studies, such as CCIT in liquid-nitrogen gas phase and pH shift with dry ice. As it is said that glass cannot be used for cell and gene therapy products stored at deep-cold or cryogenic temperature, we have also added type 1 glass vials to the samples to confirm if this is true or false. As a chemical company, we contribute to sharing more scientific data with the pharmaceutical industry.

CONCLUSION

In conclusion, these latest results have contributed to the on­going studies verifying OXYCAPT’s superior properties for cell and gene therapy products. In addition to the advantages of COP, such as a strong water vapor barrier, high break resistance, very low extractables, and low protein adsorption, OXYCAPT also pro­vides a strong oxygen, carbon dioxide, and UV light barrier. We believe OXYCAPT offers a multitude of benefits to the rapidly growing field of cell and gene therapy products.

Shota Arakawa is a Research Manager in the R&D Division of Mitsubishi Gas Chemical Company, Inc. (MGC). He earned a Diploma in Science in 2007 and a Master’s of Science in 2009 from Osaka University. Since April 2009, he has been working for MGC and is in charge of macromolecular science, specifically in synthesis of polymers and material development. Since 2012, he has joined the development team for multilayer plastic vial and syringe for biologics.

Tomohiro Suzuki graduated from Waseda University in 1997 and joined Mitsubishi Gas Chemical in 1998. He was a part of the Oxygen Absorbers Division until 2011, and was transferred to the Advanced Business Development Division in 2012 to be a member of the OXYCAPT development team. Since then, he has been in charge of project management of OXYCAPT Plastic Vials & Syringes. His current position is Associate General Manager.