GMP Q&A/Disinfectant Rotation: How Many types of Disinfectants are needed?

Disinfectant rotation

For a long time, the use of more than one disinfectant has been recommended in Appendix 1 of the EU GMP. Appendix 1 provides further information on the strategy of rotating the use of disinfectants, but the current text in Appendix 1 May lead to a certain degree of interpretation of its meaning - "More than one disinfectant should be used to ensure that they have different mechanisms of action and that their combination is effective against all bacteria and fungi." Disinfection should include the regular use of sporicides."

A simple explanation is to rotate disinfectants for the microorganisms that need to be controlled. This should be based on which type of microorganisms pose a risk to the facilities, processes or products being manufactured. It should be made clear that the regulatory authorities do not require the rotation of two fungicides with the same fungicidal claim, but it is necessary to ensure that the rotation meets the relevant fungicidal requirements.

For most companies, rotation control will target bacteria, bacterial spores, molds and yeasts. Generally, viricides are not required, unless they are related to living cells. Broad-spectrum fungicides are effective against all organisms except the most resistant ones - bacterial endospores. Therefore, based on the risk, a good rotation strategy is to alternate between broad-spectrum fungicides (as mentioned above) and spicides.

Another benefit brought by simplifying the rotation method is the reduction in the amount of disinfectant used in a factory. This will make the management of correct disinfectant rotation easier, reduce the risk of errors, lower disinfection costs and minimize the impact on the environment. If factories also choose low-residue disinfectants as part of their rotation strategy, this will also have a positive impact on the management of disinfection residues.

Pollution control in material transfer

A key issue in cleanroom control is the transfer of items and materials from uncontrolled warehouses to cleanrooms and their entry into high-level areas. A well-regulated transfer disinfection procedure will address the possibility of contamination entering critical areas or equipment, such as isolators.

A good transfer disinfection procedure will include two elements. The transfer of daily items, such as consumables, protective clothing materials and environmental monitoring equipment. The second part of this process is to manage the incoming non-routine items. Appendix 1 recognizes the contamination risk caused by non-routine items and enhances disinfection to reduce the risk - "Any unapproved items that need to be transferred should be pre-approved as exceptions." Appropriate risk assessment and mitigation measures should be recorded in accordance with the manufacturer's CCS and should include specific disinfection and monitoring plans approved by the quality assurance department.

Any assessment of the risk of contamination during material transfer should take into account the following factors:

• Was the disinfection process in place? If so, can the selected disinfectant cover the expected visible microbial contamination range, including bacterial endophytic spores?

• Has the factory determined the compatibility of the materials to be disinfected with the disinfectant?

Has the disinfection method taken into account the common flexible surfaces, the contact time in high-airflow areas, as well as the required artificial flexibility and focus? If the answers to these questions are to utilize "spraying technology", then there might be some gaps in CCS.

Views on disinfectant rotation in different regulations and guidelines:

Regarding whether disinfectants need to be rotated, China, the United States, Europe and industry associations have different views on this. There has also been considerable controversy over the development of microbial tolerance to disinfectants over the years. In addition to the above-mentioned EU GMP Appendix 1, the views of other regulations and association guidelines on this are as follows:

Chapter 9 Disinfection in Appendix I of China GMP (2010 Edition)

Article 44 The clean area shall be cleaned and disinfected as necessary in accordance with the operating procedures. Under normal circumstances, the type of disinfectant used should be more than one. To promptly detect whether tolerant strains have emerged and their spread, regular environmental monitoring should be conducted. The sterilization effect of ultraviolet rays is limited and they cannot be used to replace chemical disinfectants.

FDA Industry Guidelines: Sterile Pharmaceuticals Produced by Aseptic Processing - Current Good Manufacturing Practice (cGMP)

The disinfectants used daily should effectively target the active and common microbial communities recovered from the factory facilities. Many common disinfectants are ineffective against spores. For instance, 70% isopropyl alcohol is ineffective against Bacillus spores. Therefore, a reasonable sterilization procedure also includes a sporicide, which is used in accordance with a written plan and when environmental data indicate the presence of spore-forming microorganisms.

USP <1072> Disinfectant and preservative

The formation of antibiotic tolerance in microorganisms is a well-described phenomenon. However, it is unlikely that microorganisms will develop tolerance to disinfectants, as disinfectants are reagents with stronger killing power than antibiotics, and high concentrations should be used to inhibit a small number of microorganisms that usually do not grow actively.

The principle of the cleaning and disinfection procedure for PDA TR 70 aseptic production facilities
There has been considerable controversy over the possibility that microorganisms may develop tolerance to cleaning agents, disinfectants and sporicides for many years. The concern that microorganisms may develop tolerance to these products is based on the theoretical relationship of their tolerance to antibiotics.

To date, there are no published conclusive experimental data to prove that microorganisms have developed tolerance to these products. Antibiotic tolerance is usually achieved by modifying a single gene (or obtaining a single gene), thereby blocking the specific action of the antibiotic. The antimicrobial reagents used in clean rooms remain effective continuously because they have multiple effects on a series of cellular physiological activities. This means that the small amount of microorganisms found in the clean room need to complete multiple mutations within a relatively short period of time (such as a 5-minute contact time) to overcome the adverse effects of antimicrobial reagents. Therefore, considering environmental factors and the relatively low number of microorganisms, it is highly unlikely that microorganisms will develop tolerance to the reagents used for disinfection.

Therefore, pharmaceutical and biotech companies no longer adhere to the practice of alternating between the two disinfectants. This early and widely accepted practice led to excessively high residue levels and ignored the actual disinfection effect. Nowadays, most companies adopt a system that alternates between one disinfectant and one sporicide to more effectively reduce microbial load. This rotation is superior to the rotation of multiple disinfectants. When necessary, only one sporicide that has been proven effective can be used without rotation. If used regularly, it can disrupt pollution levels and ensure that appropriate environmental requirements are met.

However, due to the inherent corrosiveness of sporicides, the use of sporicides alone is not encouraged.

All rotation systems should be reasonably evaluated based on regional classification, environmental monitoring data and/or risk assessment.

2010 Edition GMP Difficult Questions and Answers (CFDA Advanced Training Institute

Question: In the 2010 version of GMP, there was no mention of "disinfectant rotation". Does it mean that "disinfectants do not need to be rotated"?

Answer: Article 43 of the Appendix on Sterile Drugs stipulates the following: "Under normal circumstances, the types of disinfectants used should be more than one." Although microorganisms in cleanrooms do not develop tolerance to disinfectants, due to the different disinfection efficacy grades and action mechanisms of disinfectants, the practice of rotating the use of disinfectants is more effective in controlling microbial contamination in cleanrooms and has been widely applied in the practice of the pharmaceutical industry.

Question: In most domestic enterprises, the hand sanitizers used in production workshops are 75% ethanol, and there are no alternative disinfectants. May I ask if there will be the development of certain tolerant bacteria after long-term use, and how should we solve this problem?

Answer:

Using 75% ethanol for glove disinfection is a relatively good approach, as it is highly volatile and its residue level is widely recognized.

2. As the bactericidal effect of isopropyl alcohol is higher than that of ethanol, isopropyl alcohol is also used as a glove disinfectant abroad.

3. There is no need to alternate between ethanol and isopropyl alcohol as disinfectants. Just choose one.

4. No matter what kind of disinfectant is used in the clean room, from the perspective of the mechanism of action, no so-called drug-resistant bacteria will be produced. For instance, alcohols themselves cannot kill spore-forming microorganisms, which is determined by their mechanism of action. Therefore, in environments where only alcohol-based disinfectants are used, if spores are detected, factors such as facilities and personnel behavior should be considered. If necessary, more efficient disinfectants can be replaced.