Disinfection Qualification Testing
Considerations for Aseptic and Cleanroom Manufacturing Environments
Obtaining the highest confidence that aseptic, cleanroom and other critical manufacturing environments are properly cleaned, sanitized and disinfected is paramount in ensuring the production of safe and effective pharmaceutical products and/or medical devices.
The microbiological safety of these products is primarily determined by the quality of raw materials, the integrity of the manufacturing process, as well as the effectiveness of cleaning and disinfection procedures performed in the facility.
It is for this reason that the U.S. Food and Drug Administration (FDA) requires manufacturers of pharmaceutical and other critical products to qualify and validate the disinfection procedures used in these manufacturing environments.
What is Disinfection Qualification?
Disinfection and sanitization in the pharmaceutical and controlled manufacturing spaces refer to the killing, inactivation, removal or reduction of contaminating microorganisms to levels considered safe per industry standards and regulations.
The terms “cleanroom disinfection qualification,” “disinfection validation,” and “cleaning validation” are often used in the pharmaceutical and aseptic manufacturing industries interchangeably.
While these terms seem to define the same thing, they are actually rather different. In fact, validations build upon qualifications.
Disinfection qualifications formally evaluate the efficacy and suitability of antimicrobial products and procedures used to eliminate contaminant microorganisms on various surface types and components within an aseptic, sterile or otherwise controlled manufacturing environment.
Why are Disinfection Qualification Studies so Important?
Disinfection qualifications effectively mitigate the microbial contamination that may occur during the manufacture of a product. Mitigating such contamination ultimately helps to ensure a safe product for the end-user or patient.
Control of microbial contamination is required by the FDA’s current good manufacturing practice for finished pharmaceuticals as defined in 21 CFR §211.113, which states:
Control of Microbiological Contamination
(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.
These requirements are additionally clarified in FDA’s 2004 Guidance for Industry – “Drug Products Produced by Processing-Current Good Manufacturing Practice.”
The suitability, efficacy, and limitations of disinfecting agents and procedures should be assessed. The effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces.
While federal regulations and guidance documents mandate microbial control of sterile and non-sterile manufacturing environments, the interpretation and enforcement of these regulations can be seen through GMP inspections and the resulting FDA Form 483 warning letters.
The extent of the deficiencies listed in a 483 warning letter can mean the difference between being operational or being shut down.
It has been well documented that the observations citing “the failure to ensure disinfection” in 483 warning letters have been trending upward.
Why Does the FDA Require Disinfection Qualification Studies?
United States Pharmacopoeia (USP) <1072> “Disinfectants and Antiseptics” states that the disinfection qualification study is...
“considered necessary since critical process steps like disinfection of aseptic processing areas, as required by GMP regulation, need to be validated and the EPA registration requirements do not address how disinfectants are used in the pharmaceutical, biotechnological and medical device industries.”
To better understand this nuance, you must first understand the regulation of disinfectant and sanitizer products themselves.
When Should Disinfection Qualification Studies be Conducted?
The ideal time to conduct a disinfection qualification study is at the construction of the manufacturing facility, before operation, when disinfection processes and products are being considered.
At a minimum, a qualification should be performed before starting full-scale GMP manufacturing operations and prior to an FDA GMP audit.
Unfortunately, disinfection qualifications are often performed reactively instead of proactively, either in response to a product contamination, an environmental monitoring excursion or to the observations listed in the feared FDA Form 483 warning letter.
Waiting to perform a qualification study in these scenarios can lead to a cease in manufacturing operations and the commissioning of a disinfection qualification study much larger than necessary.
How Should Disinfection Qualification Studies be Performed?
As previously mentioned, the disinfection and sanitization of surfaces in the pharmaceutical and controlled environment manufacturing space refers to the killing, inactivation, removal and reduction of contaminating microorganisms to levels considered safe per industry standards and regulations.
But how are disinfection qualification studies to be performed?
Suspension-based Testing vs. Coupon-based
Testing In general, disinfectant efficacy evaluations are made using either suspension-based methods or coupon/surface-based methods. Suspension methods evaluate the reduction of a known organism population inoculated directly into a sample of the liquid disinfectant.
Following inoculation and the observation of a predetermined contact time, samples of the inoculated substance are removed, neutralized and evaluated for survivors as compared to an untreated control suspension.
Scope of Qualification Testing
Each manufacturing facility is different and therefore each qualification study is different. Considering the various combinations of surfaces, organisms, disinfectant products and disinfection procedures, these studies can become rather complex.
Design Overview of a Disinfection Qualification Study
Once the study parameters have been established, a testing protocol is developed. The overall testing process is generally executed as follows. Each surface coupon is individually inoculated with a test organism.
A sufficient number of coupons must be inoculated to evaluate each disinfectant, each test organism and each disinfection procedure for each coupon replicate.
Properly designed, appropriately qualified and consistently executed disinfection procedures are critical to the production of safe and effective biopharmaceuticals, medical devices and other sterile or non-sterile products.
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- United States Pharmacopeia (USP) 34, Chapter <1072> Disinfection and Antiseptics – General Information pp.579-580, May 1, 2011.
- American Society for Testing and Materials (ASTM). Test Method, Standard Guide for Evaluation of Cleanroom Disinfectants, E2614-08.
- U.S. Food and Drug Administration (FDA), Guidance for Industry Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice, 2004.
- Block, SS, Disinfection, Sterilization, and Preservation. Lippincott, Williams and Wilkins, Philadelphia, PA., 2001.
- Madsen, R.E and Moldenhauer, J. Contamination Control in Healthcare Product Manufacturing, Volume 1., DHI Publishing, River Grove, IL. (2013).
- 6nspections, Compliance, Enforcement, and Criminal Investigations, Retrieved http://www.fda.gov/ iceci/enforcementactions/WarningLetters/default.htm, 2013.
- Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 CFR Part 211.