Advanced R&D isolator for decontamination and oxidation studies

H2O2 “Ultra-Low concentration” investigations on sterile pharmaceutical products

Vapour Phase Hydrogen Peroxide (VPHP) is largely exploited as sterilization agent due to its biocidal activity, ranging from scientific and medical machinery to industrial applications1,2.

For the sterilization of research and pharmaceutical isolators, VPHP cycles are generally designed in order to maintain stable hydrogen peroxide concentrations – measured in part-per-million (ppm) – in time over its microbicide, fungicide and sporicidal activity level, considered between 300 ppm up to 1200 ppm.

Advanced R&D isolator for H2O2 “Ultra-Low” investigations on sterile pharmaceutical products

Once the decontamination phase of the VPHP cycle is over, an aeration phase starts with the aim to rapidly decrease the vapour of hydrogen peroxide up to the concentration of 1 ppm. In fact, 1 ppm has been officially defined by the National Institute of Occupational Safety and Health (NIOSH) as the daily safety value for the operators and for the exposure of the production materials3.

Recently, several studies focused on the hydrogen peroxide residues upon the decontamination cycle and critical effects on the pharmaceutical products are now emerging. The oxidation of pharmaceutical molecules, the dissolution into liquid products and the adsorption within medical materials are just few consequences of the effect of sub-ppm VPHP concentrations4–6.

For instance, concerning the biotech pharmaceutical compounds that contain many aminoacidic residues sensitive to oxidative potentials, it does not represent a negligible topic. In fact, several groups are trying to mathematically model the effects of sub-ppm concentrations of hydrogen peroxide on their pharmaceutical products7–9.

In order to make available a tool allowing to experimentally investigate the various effects of sub-ppm VPHP concentrations, Comecer engineered a standard VPHP-sterility tester isolator with H2O2 “Ultra-Low” capabilities.

The modified isolator can firmly control VPHP concentrations ranging from 5 part-per-billion (ppb) to few ppm through a system referred to as Ultra-Low VPHP (UL-VPHP).

The core of the UL-VPHP system is represented by the hydrogen peroxide Picarro probe (Picarro PI2114 spectrometric gas concentration analyser, hereafter referred to as Picarro) that allows an online continuous measurement of VPHP concentration inside the isolator.

Based on the output signals of the Picarro, the system automatically adjusts the VPHP levels by increasing (inducing a “hot” response) and decreasing (inducing a “cold” response) the total amount of hydrogen peroxide inside the isolator in order to keep it stable within a ± 5 ppb range with respect to the desired value.

The “hot” response is involved in increasing the VPHP concentration; it takes advantage of specific designed system able to release minimal amount of H2O2 aerosol. VPHP-loaded air is then directly injected within the isolator’s chamber, thus increasing the VPHP level. On the other side, the lowering of VPHP levels is based on the “cold” feedback, consisting UV-C lamps; the 240 nm in wavelength electromagnetic emission catalyses the H2O2 radiolysis, inducing its breakage into H2O and O2.

The system can work in two different ways: in the first one, called static modality, the set VPHP concentration can be stably maintained in time for hours and days. Moreover. the elastic balance between the “hot” and “cold” responses also allows the dynamic moving across different H2O2 concentrations.

Indeed, through the second one, defined as dynamic mode, it is possible to set the time duration for a sequence of VPHP concentrations; the UL-VPHP system can automatically move toward the next pre-set concentration at the end of each phase and keep that level stable for the desired time.

Figure a

The figure a shows the dynamic mode of the UL-VPHP system in action. The table on the right of the graph resumes the recipe loaded on the software.

Advanced R&D isolator for H2O2 “Ultra-Low” investigations on sterile pharmaceutical products

Figure b

The figure b shows a magnification of the 10 ppb target performed during the recipe in the figure a.

As result, it has been achieved a unique machine able generate an extremely stable H2O2 ultra-low concertation inside an aseptic isolated chamber.
This solution is ideal to execute static and dynamic product oxidation test, H2O2 residue studies after decontamination and cycle optimization to minimize the decontamination time even with critical oxidant-sensitive medicinal products or API.
Comecer is using this technology also for material compatibility studies, disposable penetration test and to give to our customer a deep and complete control of the decontamination processes.

 

Authors: Giacomo Guidi, Riccardo Volta; R&D Department

 

Bibliography

  1. US EPA, O. of P. P. Hydrogen peroxide – Chemical Details | Chemical Search | Pesticides | US EPA.
  2. Klapes, N. A. & Vesley, D. Vapor-phase hydrogen peroxide as a surface decontaminant and sterilant. Appl. Environ. Microbiol. 56, 503–6 (1990).
  3. CDC – Immediately Dangerous to Life or Health Concentrations (IDLH): Hydrogen peroxide – NIOSH Publications and Products. https://www.cdc.gov/niosh/idlh/772841.html.
  4. Eisner, D. R., Hui, A., Eppler, K., Tegoulia, V. & Maa, Y.-F. Stability Evaluation of Hydrogen Peroxide Uptake Samples from Monoclonal Antibody Drug Product Aseptically Filled in Vapor Phase Hydrogen Peroxide-Sanitized Barrier Systems: A Case Study. PDA J. Pharm. Sci. Technol. 73, 285–291 (2019).
  5. Ikarashi, Y., Tsuchiya, T. & Nakamura, A. Cytotoxicity of medical materials sterilized with vapour-phase hydrogen peroxide. Biomaterials 16, 177–183 (1995).
  6. Hubbard, A. et al. Vapor Phase Hydrogen Peroxide Decontamination or Sanitization of an Isolator for Aseptic Filling of Monoclonal Antibody Drug Product—Hydrogen Peroxide Uptake and Impact on Protein Quality. PDA J. Pharm. Sci. Technol. 72, 348–366 (2018).
  7. Hui, A., Lam, X. M., Kuehl, C., Grauschopf, U. & Wang, Y. J. Kinetic Modeling of Methionine Oxidation in Monoclonal Antibodies from Hydrogen Peroxide Spiking Studies. PDA J. Pharm. Sci. Technol. 69, 511–25.
  8. Downey, D., McGarvey, B., Walsh, M. & Engle, J. A Model of Prefilled Syringes Exposure to Vapor Phase Hydrogen Peroxide (VPHP). PDA J. Pharm. Sci. Technol. pdajpst.2018.009431 (2019) doi:10.5731/pdajpst.2018.009431.
  9. Vuylsteke, B., Luyckx, I. & de Lannoy, G. The Diffusion of Hydrogen Peroxide Into the Liquid Product During Filling Operations Inside Vaporous Hydrogen Peroxide–Sterilized Isolators Can Be Predicted by a Mechanistic Model. J. Pharm. Sci. 108, 2527–2533 (2019).

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