Choosing a suitable disinfectant for a pharmaceutical operation can be a complex process. Christopher Fournier* and Dominique Leclercq** of Mar Cor Purification, outline the main considerations set down by the FDA and in the US pharmacopoeia
The choice of a disinfectant is critical for a pharmaceutical cleanroom not only because of potential losses due to contaminated product but also because of user safety as well as room turnaround. This selection process is not as simple as it seems, as there are multiple factors that have to be considered when choosing a product for use in a pharmaceutical cleanroom. Just as most processes and products used in a pharmaceutical production facility have to be validated, cleaning and disinfection products are subject to the same process according to FDA and USP standards.
The typical disinfection process used in most facilities follows the familiar procedure: HEPA vacuums are used to remove larger particles and debris; this is followed by using a detergent to clean the surface; finally followed by the use of a biocide, which is typically wiped, sprayed or fogged, all in an effort to eliminate microbial matter.
The final step in the process is the most critical and receives the greater amount of regulatory scrutiny. Biocides that are manufactured for use in the US must be registered with the EPA, which requires manufacturers to submit data that demonstrates the effectiveness of the product. In addition to these regulations, biocides used in cleanrooms are subject to FDA and USP guidelines, which classify them, describe their mechanism of action and efficiency, and request minimum efficacy levels and describe how to get the disinfection process validated.
USP standardsThe specific standard that the United States Pharmacopeia (USP) uses to regulate cleanroom disinfectants is USP 29 NF-24 <1072>. This standard classifies the biocide and gives clear definitions on decontamination techniques, the use of disinfectants, sanitising agents, sporicidal agents and sterilants. The most effective of these biocides, a sterilant, for instance, is defined by the USP as a chemical agent that destroys all forms of microbiological life. According to that definition, the use of a sterilant in an aseptic environment guarantees efficacy against fungi, viruses, mycobacteria and all forms of bacteria and their spores. The destruction of bacteria spores is a crucial point of differentiation, as few biocides are registered as effective sporicides at reasonable concentrations.
USP <1072> outlines the various factors affecting disinfectant choice and the process for appropriate disinfectant selection for the pharmaceutical manufacturing environment. Key factors mentioned in the document are:
- 1. Spectrum of activity of the disinfectant
2. EPA claims
3. Concentration of the disinfectant
4. Surface material to be disinfected
5. Organic matter and load on the surfaces
6. Need for residual bactericidal activity
7. Corrosivity with multiple applications
8. Operator safety
9. Compatibility of the disinfectant with other cleaners or disinfectants
10. Disinfectant rotational plan, and
11. Steps taken to ensure the disinfectant does not contaminate the pharmaceutical. Each of these factors needs to be thought through in the evaluation of a disinfectant.
According to a written guidance1, the FDA states that a sound disinfection programme should include the use of a sporicidal agent. The <1072> classification states that the only sporicidal agents that are appropriate for use in the sterilisation process are aldehydes, bleach, ozone, hydrogen peroxide, peracetic acid (PAA) and ethylene oxide. In reality, only a few of these chemicals can be used because they are either toxic, carcinogenic and/or mutagenic (aldehydes, bleach, ozone, ethylene oxide) or hazardous (hydrogen peroxide) because it requires a high concentration in order to be effective.
Peracetic acid is one of the few sporicidal technologies that can perform this job safely and effectively. The key reason for this is that peracetic acid is an effective sporicide at very low concentrations (less than 1%). Adding to the case of peracetic acid is that the chemical is also listed in <1072> classification as a validated cold sterilant. So it represents a doubly effective chemistry. Considering that the only other chemicals validated as both a sporicidal agent and a sterilant by the USP <1072> are hydrogen peroxide (H2O2), which is deployed in a vapour form and at high concentration (over 10%), and ethylene oxide, there is a clear need for a more user-friendly option.
Sporicidal action corresponds to periodic disinfections according to the USP and FDA requirements. Peracetic acid at 0.015% concentration in a liquid form can be used for daily low level bio-decontamination in aseptic rooms replacing bleach (toxic and corrosive), quaternary ammonium or other low level biocides. They require longer contact times and additional steps for removing the remaining residual material.
Peracetic Acid has additional benefits that increase its value as a cleanroom sporicidal agent. Some of these benefits are that the chemical is fully biodegradable (it breaks down into oxygen, water and acetic acid), and leaves no residual on the surfaces after it evaporates. The material can also be validated as a sterilant even at a very low concentration level. In addition, peracetic acid can be used in both liquid or vapour form, is fully compatible with modern cleanroom materials, and is available at a pharmaceutical grade chemical purity level.
Because there is now an official requirement from regulatory agencies mandating use of a sporicide in aseptic areas, the use of peracetic acid in bio-pharma cleanrooms is increasing.
As a US-based manufacturer of sterilants, Minntech/Mar Cor Purification has seen an increase in the demand for its ready-to-use peracetic acid formulation Actril Cold Sterilant. The formulation, which is available in both standard packaging and cleanroom packaging, is applied either by wiping or spraying surfaces in cleanrooms.
Independent testing has verified a 4 log reduction on living micro-organisms and over 3 log reduction on bacteria spores within less than 5min contact time. In contrast, USP <1072> requires a 3 log reduction on bacteria and virus and 2 log on bacteria spores. Short contact time means savings in downtime and also means that a smaller amount of chemical is needed to perform the same task, since there is less need for the liquid on the surfaces according to the 5min maximum validated contact time.
For the cleanroom desiring to validate, train and stock a minimum number of chemicals for efficient operations, peracetic acid can be used in a liquid form for manual disinfection procedures and in a vapour form as an airborne disinfection agent in cleanrooms and aseptic areas. Another product developed by Minntech/Mar Cor Purification, the Minncare Dry Fog System (Cleanroom Technology, March 2004) has been used by hundreds of bio-pharma facilities and offers the benefit of using a peracetic acid that provides cold sterilant and sporicide effectiveness in combination.
Dry fog procedures showed a reduction of over 6 log in normalised conditions (NF-T-72-281) well in excess of the USP <1072> guidelines, which recommend a minimum of 2 log reduction on bacteria spores. Dry fogging with peracetic acid offers the same benefits to a cleanroom as the manual wiping procedures: fast process time, easily validated, biodegradable product, no possibility of efficacy resistance.
Biocides being applied by a fogging system
Biological indicators
The role of biological indicators is critical to any disinfecting procedures; to verify the action of the procedure that allows the process to be validated and to achieve repeatable results for ongoing procedures. Since the biological indicators (BIs) are the mechanism to verify results, an overview with respect to peracetic acid disinfections is important.
The USP <1035> gives the definition of and details the different types of BIs. In addition, it suggests how to select the right one for a specific disinfection process. The BIs for bacteria spores are very often used in the validation of a disinfection or sterilisation process, however, every type of BI is specific to a certain sterilisation process and is made for that process.
For example, a BI made for controlling a dry heat sterilisation process has to be different from that for a process controlling an ethylene oxide or a peracetic acid airborne bio-decontamination procedure. According to USP <1035>, it is the manufacturer’s responsibility to produce and provide documentation of the BI specification and the user’s responsibility to select the appropriate BI corresponding to their specific sterilisation or bio-decontamination process.
In certain situations, the user of the product must evaluate the BIs’ performance and suitability when used to control that user’s specific process. The D value, the envelope’s permeability and the envelope’s performance at high relative humidity, are so specific to local factors that they have to be evaluated and documented by the user as part of the validation process before they can be used in an actual procedure.
In summary, the FDA and USP guidelines play a big part in developing pharmaceutical activities in facilities all over the world. Developing effective, compliant disinfection procedures for the facilities is where the users of disinfectants sometimes get into trouble. The best course of action for users to save time and money is to follow the recommendations set forth by the USP <1074>, getting the right efficacy, and simplifying the protocols. When considering the risk versus the benefits, peracetic acid is one of the better choices for cleanroom disinfection and is now being used by more bio-pharma companies.
Contacts
*Christopher Fournier, Vice-President Marketing
Mar Cor Purification,160 Stedman Street
Lowell, MA 01851, USA
T +1 978-453-9600
**Dominique Leclercq, Sales Manager Europe
Minntech - Mar Cor Purification, Sourethweg 11, 6422 PC Heerlen, The Netherlands,
T +32 473 472491
References
1. Guidance For Industry, Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice September 2004 Pharmaceutical CGMPs Section x. Laboratory Controls Part A. Environmental Monitoring Point 3. Disinfection Efficacy.
Biliography
1. José E. Martinez, “What is Disinfectant Validation?” Pharmaceutical Technology. Mar 2, 2006.
2. William Rutala, PhD, David Weber, MPH, et. Al. CDC Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. CDC Website. November 2008.
3.Residuals of Peroxide on Surfaces after Minncare and Actril Evaporate. Mar Cor Purification Technical Bulletin: 2008.
4.2 Actril Master Label
5. Clostridium difficile Endospores and PAA Germicides. Mar Cor Purification Technical Bulletin: 2008.
6. Virucidal Efficacy of a Disinfectant for Use on Inanimate Surfaces (Polio virus Type 2). Test Report: 1995.
7. Actril and Minncare Cold Sterilants: Effectiveness against MRSA & MSSA. Mar Cor Purification Technical Bulletin: 2007.
8. William Rutala, PhD, David Weber, MPH, et. Al. CDC Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. CDC Website. November 2008.
9. Actril Tech Notes and Data Research Report. Minntech Corporation: 1999.
10. Residuals of Peroxide on Surfaces after Minncare and Actril Evaporate. Mar Cor Purification Technical Bulletin: 2008