Juha Mattila, Steris Finn-Aqua, takes a look at safe material transfer of device components, and terminal sterilisation of packaged products by using vapourised hydrogen peroxide.
Vapourised hydrogen peroxide (VHP) brings new possibilities for improvement by adding to the level of automatisation and overall simplification of aseptic assembly and packaging process for sensitive drugs in pre-filled syringe delivery devices, implants and other medical devices by VHP terminal surface sterilisation. Material transfer of components to aseptic assembly and packaging can also be improved by using atmospheric VHP bio-decontamination chambers for example instead of wiping surfaces of transfer bags and material airlock or hatch.
The need for low temperature bio-decontamination
Some key drivers for the growing interest towards VHP terminal surface sterilisation technology are the following:
- Increase in temperature- and radiation-sensitive injectable drug products
- Complex medical devices
- Growing costs of aseptic assembly and packaging of such products
- Sterilant residue concerns along with sensitive materials compatibility
Over the past decade the number of in-house installations in aseptic packaging areas of pharmaceutical manufacturing facilities has grown steadily, and is projected to continue per continuously increasing amount of emerging sensitive injectable drug products and implants in the market (1).
Hydrogen peroxide in vapour state, has been widely used in room, surface decontamination and device reprocessing applications for 30 years. In that time, Steris has been developing products and applications that have proven to be efficient for microbial inactivation. VHP applications include isolator workspaces, material transfer chambers and cleanroom bio-decontamination and terminal sterilisation of packaged products and medical devices.
Several scientific research papers over the past three decades prove vapourised hydrogen peroxide (VHP) to be very efficient for microbial inactivation (2). The sterilisation or bio-decontamination process is also relatively easy to adapt to manufacturing facilities. Implementation is facilitated by manufacturing capacity-sized, in-house units (from 500 liters to over 10,000 liters in chamber volumes), as well as the safe environmental properties of hydrogen peroxide, which yields the nontoxic byproducts of water and oxygen. Low temperature sterilisation in this article refers to the Steris VHP terminal sterilisation temperature range of +28…40 °C for sensitive drug products and materials. Material transfer processing by utilising VHP for surfaces bio-decontamination, also occurs at local room temperature conditions, but can vary more than terminal sterilisation temperature range, as sensitive drug is not yet present. Depending on type of equipment and application, VHP is generated from 35% or 59% pharmaceutical grade liquid hydrogen peroxide solution.
Material compatibility of VHP is one significant advantage, as the range covers most plastic materials used in devices and secondary packaging, as well as glass, electronics, stainless steel and aluminium used in processing equipment. Material discolouration or strong oxidation effects are not typical for plastic components and VHP does not penetrate through material walls. However, VHP is not compliant with cellulose-based materials such as paper or cardboard. Therefore, final cardboard packaging of finished products cannot be applied prior to VHP sterilisation of incoming production materials, but after.
6-log reduction of bioburden is a typical efficacy requirement for material transfer loads using VHP atmospheric bio-decontamination, and SAL 10-6 for product is targeted for packaged product when utilising the VHP terminal sterilisation process. Aseptic filling of the drug is required for the drug in primary container for a pre-filled syringe / delivery device application.
VHP atmospheric bio-decontamination
VHP bio-decontamination is used in material transfer of pre-sterilised components to production, such as vial stopper bags, wrapped components and syringes. The cycle outcome is achieved in atmospheric conditions and ambient temperature. The three process phases in the cycle are pre-conditioning, VHP bio-decontamination exposure and post-conditioning. Pre-conditioning prepares the load for exposure to hydrogen peroxide vapour that destroys bioburden during the VHP decontamination phase. Post-conditioning phase is required to aerate the load and remove peroxide residuals from the load and chamber prior to unloading materials to production side. Cycle duration depends on load and configuration, but Steris’ experiences in industry applications indicate that it typically remains well below one hour in total cycle time.
VHP deep vacuum low temperature surface terminal sterilisation
VHP low temperature surface terminal sterilisation process requires a controlled environment, meaning control over pressure, temperature, water and hydrogen peroxide humidity control, and cycle time. The sterilisation cycle is performed in deep vacuum conditions to achieve the controlled environment, and to ensure that complex device surfaces and possible diffusion-restricted pathways such as needles, receive exposure to VHP within the secondary packaging that utilises Tyvek or equivalent layer, allowing penetration of VHP and water vapour in and out of the package. During VHP exposure dry and non-condensing vapour is generated by controlling the environment in maintaining peroxide vapour continuously slightly below saturation point.
A low temperature VHP terminal sterilisation cycle consists of the following main phases: Pre-conditioning of the load and chamber (humidity removal and deep vacuum air removal), VHP exposure in deep vacuum conditions, and post-conditioning to remove peroxide residuals, and equalization to atmosphere prior to unloading. Typical cycle times vary between two and four hours depending on load configuration and on the amount and type of plastic materials used in the package. VHP sterilisation cycle is energy efficient, and therefore cost efficient. A typical cycle cost, depending on equipment and load size, varies between $18-38 (estimated by various size Steris VHP LTS-V processing units and cycles and their actual utility consumption measurement data).
Typical products are single-packaged delivery devices with parenteral drugs such as biologicals, biosimilars or other sensitive products, eg with specific proteins that are sensitive to heat and radiation. Another typical application is a single-packaged sensitive implant device that requires uncompromised sterility and low residual levels. Limitations for such devices when using other sterilisation methods may be in radiation sensitivity of material, or temperature sensitivity of material or electronics.
Think about the design of your manufacturing process in good time before locking down the device, syringe or secondary packaging design.
The drug and device product development process is lengthy and has many phases and factors that need to be considered for achieving the optimal outcome. There is potential to save time and cost when low temperature terminal sterilisation is considered before the device design is completed and production line planning is started.
Such devices are often assembled and packaged in aseptic cleanroom conditions and may only use low level or no automation in assembly, as it may require an isolator line or laminar cabinet, one by one. A terminal steriliser at the end of the aseptic packaging line can give more freedom for the automation of device assembly and packaging after aseptic filling step, and enable work to be done in lower cleanroom classification levels such as grade C or D, instead of grade A or B. This is a cost saving potential for manufacturing facilities and a bottleneck preventer for production quantities. For high value and smaller batch products, the in-house terminal sterilisation solution also saves time-to-market as the product does not need to be transported to a third party for further processing.
Feasibility testing is used to ensure device integrity and material compatibility for exposure to hydrogen peroxide as well as deep vacuum levels. The testing is carried out with a representative cycle that can kill challenge micro-organism in the hardest to reach locations of the device and package, as well as verify sufficient presence of VHP by using chemical indicators.
Cycle development is the next phase but it occurs with the built unit for the application and usually is carried out with full load of the product in question. These are important steps, as they provide an excellent basis for the validation of production cycles, and therefore benefit the approval process. Chemical and biological indicators are used for product feasibility testing, cycle development, validation and batch control purposes.
Equipment and process validation
These equipment and applications are subject to cGMP and GAMP requirements for process components and control systems. Process validation often demands electronic data security with 21 CFR part 11 compliance. Process validation is performed individually for the terminal sterilizer per ISO 14937. Although no specific validation standard for VHP sterilisation exists, the ISO 14937 standard does provide all required tools for defining the process validation to fulfill the requirements of the specific sterilisation application from both regulatory and optimised process perspectives.
