Evaluating Oxygen and Moisture Scavenging Films

A medical device technology company determines whether active scavenging films are viable alternatives to traditional gas-flushing and -purging methods.

By Thomas Harper, Fred Halperin, Bridget Lang, and Michael DiCicco; Johnson & Johnson (Raritan, NJ)
and William Abrams, Brian Fitzpatrick, Deepti Gupta, and Peter Sagona; CSP Technologies Inc. (Auburn, AL)

Medical devices and pharmaceuticals can be compromised by the presence of oxygen (O2) or moisture during the sterilization and shelf life of a product. Manufacturers have implemented a variety of in-line procedures to reduce O2 and moisture levels to improve product integrity.

To date, in-line options for removing O2 and moisture in combination with a desiccant within packages are limited to vacuum packaging and nitrogen or argon purging and flushing. These procedures can be costly and inefficient for the manufacturing cycle and can often be unreliable and difficult to monitor from a quality assurance perspective. Moreover, these procedures may not facilitate the complete removal of O2

Active packaging systems are increasingly employed in medical devices, pharmaceuticals and foods.2, 3 These active packaging systems scavenge target gases within the package and improve product shelf life and safety.4, 5, 6 O2 absorbers that are part of active packaging systems provide an alternative to vacuuming and gas-flushing technologies.⁷

Johnson & Johnson (J&J) Sterile Process Technology (SPT) continuously investigates methods to improve the shelf life and stability of sterilized medical devices. SPT collaborated with CSP Technologies to determine whether its active scavenging films could be a viable alternative to traditional gas-flushing and -purging methods and to confirm CSP product claims that the scavenging films consistently remove O2 within a confined space to levels <<1%.

Two scavenging films of particular interest are CSP-1940 and CSP-1941. CSP-1940 scavenging film removes O2 and moisture, whereas CSP-1941 absorbs only O2. The mode of activation for O2 scavenging for both CSP scavenging films is ultraviolet (UV) radiation, and the activation equipment and process are easy to implement and validate.⁸ These films have been incorporated into new drug applications in the United States and the European Union.

SPT evaluated whether using CSP-1940 and CSP-1941 scavenging films for terminally sterilized pouches could provide performance and operational benefits relative to current gas purging systems. Reported herein are the outcomes of three investigations that were conducted to evaluate the feasibility of the CSP scavenging films for use in sterile packaging applications, as outlined below:

1. Evaluate effectiveness of CSP-1940 and CSP-1941 scavenging films to reduce O2 levels <<1% post-UV-radiation activation relative to the performance claim.
2. Evaluate feasibility of using a traditional terminal sterilization process such as gamma irradiation to activate the CSP-1940 and CSP-1941 scavenging films and compare the films’ performance to that using UV-radiation activation.
3. Ensure effectiveness of CSP-1941 scavenging film in terms of UV-radiation activation after the scavenging film is exposed to an ethylene oxide (EtO) sterilization cycle.

TECHNOLOGY
CSP’s core technology focuses on a patented three-phase polymeric system that generates a microarchitecture of one polymer within another. By combining two immiscible polymers with a particulate, CSP creates a network of interconnected channels that facilitate the controlled transport of small molecules throughout the blend. 2, 8, 9 Uniformly dispersed, the pathways permit the diffusion of volatile substances into, out of, or through the material, enabling it to be custom formulated to absorb moisture, gases, odors/aldehydes; to release nutrients, biocides, flavors, or fragrances; or to modify the transport properties of particular plastics.1, 2, 3, 6, 8, 9, 10 Many commercially available products use this patented three-phase polymeric system in protecting and enhancing the products’ useful life.⁶

The CSP scavenging films’ polymer system is a blend of several components, the first of which is an oxidizable base polymer, poly(ethylene methylacrylate cyclohexenyl methylacrylate) (EMCM; refer to Figure 1A).⁸ The second component is a masterbatch consisting of a transition metal catalyst and a nonmigratory photoinitiator, in addition to a channeling agent and a base polymer.⁸ The nonmigratory photoinitiator permits the packager to initiate the O2 scavenging mechanism just prior to filling, which maximizes the capacity of the active scavenging component.¹¹

Upon UV-radiation activation, the polymer system of the CSP scavenging films absorbs residual O2 (via irreversible bonding) in the package headspace and additional O2 that may permeate through the primary packaging barrier.¹¹  The mechanism in which the polymer system absorbs O2 is as follows:

1. Activation energy is required in order for EMCM to react with O2.
2. Energy for the reaction is provided by UV-radiation, which initially excites the photoinitiator.
3. A transitional metal catalyst helps initiate a chain reaction with EMCM, making it more reactive to react with O2.

Figure 1A: EMCM employed in the CSP scavenging films.

Figure 1B: Inactivated scavenging film (top) and activated scavenging film that has turned brown upon O2 absorption (bottom).

The CSP scavenging films transition to brown over time as EMCM reacts with O2 (refer to Figure 1B). This change of color provides a visual cue that the CSP scavenging films are functioning properly. More importantly, EMCM is unique in the fact in that no degradation products are generated as a result of the O2-scavenging process.¹¹ Figure 1A also illustrates EMCM pendant groups in the polymer backbone network in CSP scavenging films.

MATERIALS AND METHODS
CSP scavenging films’ performances have not been characterized when employing gamma radiation activation or when employing UV-radiation activation post-EtO sterilization. The length of the investigation is based on the ability to achieve and record very low O2 levels within the pouches. Below is a list of the materials and equipment used:

•    CSP-1940 O2/H2O scavenging films.
•     CSP-1941 O2 scavenging films.
•     Aluminum foil-lined pouches (7 × 7 in.).
•     DuPont Tyvek pouches (7 × 7 in.).
•     Tekni-Plex clear barrier films.
•     GE Silicone II household glue.
•     Rubber O-ring fixtures/spacer frames.
•     Heat sealer.
•     UV-radiation activation chamber (capable of activating CSP scavenging films up to 4000 mJ/cm²).
•     Hamilton 10-ml Gas-Tight syringe.
•     Mocon Pac Check 450 oxygen meter (and associated accessories).
•     MDS Nordion Gammacell 220 Research Irradiators (2).
•     SPT research EtO sterilization chamber.

Pouch preparation and procedure. Each of the three investigations utilized the same type of sampling pouch: a hermetically-sealed aluminum foil-lined laminated polyblend film for reduced O2 permeation. An O-ring is placed inside each pouch to create adequate headspace for repeated sampling from the same pouch. Each pouch is affixed with a silicone septum on the exterior surface from which single or multiple headspace samples are taken. Figures 2A and 2B depict the construction of the pouch with the silicone septum used for sampling, respectively. Below is an outline of the pouch preparation and procedures for the three investigations:

1. UV-radiation activation of CSP-1940 and CSP-1941 scavenging films:

• Properly sized CSP scavenging films are activated using a calibrated UV activation chamber.
• CSP scavenging film and an O-ring are inserted into the pouch.

Figure 2A:  CSP scavenging film and O-ring placed within a pouch.
Figure 2B:  Sealed pouch with applied silicone septum.

• Pouch is then heat sealed.
• Silicone septum is applied onto the pouch.
• Replicates pouches (min. n = 2) for each sampling point are prepared.
• Pouches are shipped to SPT for sampling O2 levels on a weekly basis using the oxygen meter.
• Additional silicone is reapplied to the septum to ensure proper seal during sampling.

2. Gamma radiation activation of CSP-1940 and CSP-1941 scavenging films:

• Properly sized CSP scavenging films and an O-ring are inserted into the pouch.
• Pouch is then heat sealed.
• Silicone septum is applied onto the pouch.
• Replicate pouches (min. n = 2) for each sampling point are prepared. 
• Established dosage for the investigation is 25, 35, and 45 kilogray (kGy):
    o Pouches are exposed to various doses of gamma radiation by timed placement inside gamma cells (decay factors and dose rates during time of exposure are 0.220/4.4 kGy/h and 0.516/10.2 kGy/h for the gamma cells); controls (0 kGy exposure) for replicate pouches are also included.
    o Decay factors and dose rates during time of exposure are 0.2202/4.382 kGy/4 and 0.5160/10.20 kGy/h for the gamma cells.
• Pouches are sampled for O2 levels triweekly using the oxygen meter.
• Additional silicone is reapplied to the septum to ensure proper seal during sampling.

(Please note that CSP instructs its customers to employ UV-radiation to activate their scavenging films. SPT used a gamma radiation source to activate the CSP scavenging films during terminal sterilization.)

3. Evaluate the effects that EtO sterilization has on the performance of the CSP-1941 scavenging film:

• Properly sized CSP scavenging film is inserted into a Tyvek pouch having a clear barrier film on one side (refer to Figures 3A and 3B).
• Replicate pouches (min. n = 2) for each sampling point are prepared.
• Tyvek pouches are subjected to an EtO sterilization cycle:

Figure 3A:  Tyvek pouch with O-ring.
Figure 3B:  CSP scavenging film and O-ring sealed within Tyvek pouch.


    o EtO sterilization cycle is an SPT nominal, vacuum-dry, production cycle in a research EtO sterilization chamber; controls (no UV-radiation activation) for the replicate pouches are also included.
    o Total EtO sterilization cycle exposure is ~25 hours.
• Tyvek pouches are subsequently express shipped to CSP.
• Tyvek pouches are opened to remove the CSP scavenging film.
• CSP scavenging film is immediately placed into the UV activation chamber.
• A piece of clear barrier film is placed over the CSP scavenging film to cover it during UV-radiation
activation:
   o This activity would simulate exposing the CSP scavenging film in a specially designed pouch used for EtO sterilization. It also simultaneously allows for an optimal transmission of UV-radiation.
• CSP scavenging film and an O-ring are subsequently inserted into the pouch.
• Pouch is then heat sealed.
• Silicone septum is applied onto the pouch.
• Pouches are express shipped back to SPT for sampling O2 levels on a bi-weekly basis using the oxygen meter.
• Additional silicone is reapplied to the septum to ensure proper seal during sampling.

(Please note that CSP-1940 scavenging film is not evaluated in this investigation owing to the molecular sieve adsorbing moisture during the EtO sterilization cycle. The EtO sterilization cycle’s high humidity would diminish the capacity of the molecular sieve to adsorb moisture and in turn reduce the ability of the CSP-1940 scavenging film to protect the package over time.)

RESULTS AND DISCUSSION
UV-radiation activation. The mean O2 levels are plotted versus the sampling day for the CSP-1940 and CSP–1941 scavenging films (refer to Figure 4). Both CSP scavenging films are able to decrease O2 levels to <<1% within the pouches. These data demonstrate the reproducibility of results for both CSP scavenging films, as an effective O2 scavenger. Overall, when either CSP scavenging film is properly sized to the container, O2 levels are consistently depleted to <<1%. The investigations indicate that both CSP scavenging films uphold their performance claim.

Figure 4. UV-radiation activation results of CSP-1940 and CSP-1941 scavenging films.

Gamma radiation activation. The mean O2 levels are plotted versus the sampling day as a function of gamma radiation dose for the CSP-1940 and CSP–1941 scavenging films (refer to Figures 5 and 6, respectively). As early as Day 21, 0% O2 is attained and maintained throughout the investigation out to Day 84, regardless of the gamma radiation dose received. Moreover, for both CSP scavenging films, the results also indicate that the amount of initial remaining O2 post-gamma irradiation (Day 0.5) is directly related to the dose received at onset. Specifically, the data for both CSP scavenging films reveal a rate dependency; an approximate twofold decrease in initial O2 levels is attained from an approximate twofold increase in gamma radiation dose (25, 45 kGy; Day 0.5). This is eclipsed by an even more rapid depletion in O2 levels experienced between Days 0 and 0.5 for both CSP scavenging films.
However, additional O2 levels are not recorded intermittently (between Days 0.5 and 21). The investigations are designed to evaluate the long-term behavior and performance of both CSP scavenging films as well as not to prematurely exhaust the pouch headspace for such purposes. Consequentially, it is uncertain on which [earlier] day O2 levels actually reach 0% for both CSP scavenging films.

Figure 5. Gamma radiation activation results of CSP-1940 scavenging film.

It can be projected, however, as evidenced by the rapid O2 depletion rate, that 0% O2 levels may be reached and maintained in as early as one week. Future investigations using gamma radiation activation should confirm this. There is no evidence that the O2 scavenging is reversible. Improved results in repeatability are found within these investigations. They are attributed to the resealing of the silicone septum immediately after sampling, as indicated by the low standard deviation values that are obtained (data not included for brevity). Finally, the results obtained from this investigation demonstrate that both CSP scavenging films can be effectively activated by gamma radiation. Thus, they can scavenge O2, maintaining low O2 levels over extended time periods in sealed pouches.
There are significant performance advantages and unique sterilization options that are created during a gamma irradiation sterilization process that activates the CSP scavenging films within a sealed medical device or pharmaceutical package. Two advantages in particular include an accelerated O2 depletion rate in comparison with the UV-radiation activation investigation (refer to Figures 4–6) and a dual-step approach that encompasses activating the CSP scavenging films at lower-than-set sterilization doses. In this dual-step approach, first would be to use a low dose of gamma radiation to activate the CSP scavenging films, thereby reducing bioburden levels. Once O2 is scavenged, a second sterilization dose can be applied to achieve sterility. This dual-step approach may enable a lower maximum dose of gamma radiation to be employed in achieving sterility, which could benefit products that may be compromised by high dose levels.

Figure 6. Gamma radiation activation results of CSP-1941 scavenging film.

Use with EtO sterilization cycle. The mean O2 level is plotted versus the sampling day for the CSP-1941 scavenging film (refer to Figure 7). CSP-1941 scavenging film is able to decrease O2 levels to <<1% for all pouches. Notably, during data collection, the early readings (Days 0–35) displayed a slight decrease in repeatability. A possible explanation for this could be that the CSP-1941 scavenging film is subjected to EtO sterilization and is then UV-radiation activated through a clear polyethylene terephthalate (PET) barrier, which absorbs some of the UV-radiation required for sufficient activation.

Using a packaging barrier material that is less UV-absorbing, such as a nonconjugated, nonphenyl ring-containing polymer, may improve the UV-radiation transmittance through the barrier and increase the activation energy received by the CSP-1941 scavenging film. Nevertheless, the results indicate the ability of CSP-1941 scavenging film to survive an EtO sterilization cycle. The data also suggest that the CSP-1941 scavenging film can be UV-radiation activated through a clear PET barrier of an EtO sterilization package such as a Tyvek pouch, depleting O2 levels to virtually 0%.
The O2 depleting capacity of the CSP-1941 scavenging film is not affected by the relatively higher humidity levels within the pouch resulting from the EtO sterilization cycle exposure. This is evidenced by comparing the results of the manufacturer’s suggested UV-radiation activation method with the UV activation method post-EtO sterilization cycle (refer to the overlay in Figure 7). The rate of O2 depletion between these two investigations does not appear to be affected by the EtO sterilization cycle. That cycle includes a high-humidity segment, which is often a critical segment of such EtO cycles.

Figure 7. UV-radiation activation results of CSP-1941 scavenging film post-EtO sterilization.

APPLICATIONS
The technology offered by the CSP scavenging films may be used where O2 or moisture is a problem in a closed environment. The removal of O2 and moisture can create an improved package environment during terminal sterilization or may simply extend shelf life of nonsterilized products. Although these investigations have focused on the efficiency of O2 depletion, the ability of the CSP scavenging films to deplete moisture simultaneously is also a very interesting aspect. The CSP scavenging films could be used where traditional desiccants are used or where purging is used to control oxidative effects of O2 or moisture. Possible uses of the CSP scavenging films include packaging for bioresorbable materials, biologics, and pharmaceuticals.

AUTOMATION
The versatility in commercial applications for CSP scavenging films includes the following:
•     Sized to accommodate the application.
•     Provided in precut pieces to accommodate pick-and-place automation.
•     Provided in continuous reels.
•     Heat-staked (laminated) to foil-lined pouches.
•     Provided with an adhesive backing.
•     Kinetics and total absorption capacity can be customized for size and performance to the final package.
•     Automation assistance can be provided by PMI Cartoning (Arlington Heights, IL), Harro Hoefliger (Allmersbach, Germany), and Siebler Romaco (Karlsruhe, Germany).

Figures 8A and 8B illustrate the delivery platforms of the CSP scavenging films; Figure 8C depicts a method of automated film or label placement.

Figure 8A: CSP scavenging film on reel.
Figure 8B: Scavenging films as die-cut/adhesive-backed labels.
Figure 8C: Automation of scavenging film.

CONCLUSIONS
SPT successfully evaluated two CSP scavenging films and concluded that both films exhibited the ability to reduce O2 levels consistently to <<1% within the pouches for each of the investigations within this study, thereby exceeding the CSP performance claim. Moreover, the CSP-1941 scavenging film could be UV-radiation activated through a clear barrier material and exceed the CSP performance claim after exposure to a commercial EtO sterilization cycle.

Lastly, the investigation also provided clear evidence that both CSP scavenging films could be effectively activated by gamma radiation and afterward the films uphold their performance.

The medical device and pharmaceutical development process presents a formidable challenge to successful product launches. In this light, SPT undertook this investigation to better understand and characterize the benefits that the two CSP scavenging films can offer. These benefits include:

Providing a more-effective means to remove O2. Traditional O2 purging or flushing systems yield a broad range of residual O2 levels. The variability in residual O2 levels is mainly because of equipment and processes. As a result, these processes can be difficult to validate and control over time. CSP scavenging films consistently reduce O2 levels to <<1% and are very well characterized with respect to kinetics and total absorption capacity. Also, activation of the CSP scavenging films in-line using UV-radiation can be continuously monitored.
Streamlining manufacturing. Purging a package with an inert gas takes time and can extend the EtO sterilization cycle time of manufacturing and packaging. The CSP scavenging films can be readily added into a package. They can also be heat-staked or adhered to the interior of foil pouches.⁴ ⁸ Multiple automation vendors have provided CSP scavenging film application modules onto traditional packaging lines. Current production lines can be modified to accommodate the insertion of the CSP scavenging films.

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