In manufacturing pharmaceuticals, controlling contamination is vital in clean rooms and sterile areas. To do this, we rely heavily on HEPA filters as well as heating, ventilation and air conditioning (HVAC) systems to keep air quality high; however, surface contamination is still a threat to us. It is in this scenario where disinfectants become very important.
Nevertheless, using disinfectants will not guarantee they will work; therefore, the performance of all disinfectants must be demonstrated scientifically using actual conditions. Validation of the disinfectant demonstrates that the disinfectants chosen will reduce or completely eliminate microbial contamination in a repeatable manner. Regulatory authorities expect all manufacturers to use an organized validation program based on Good Manufacturing Practices. This organized validation program creates a key part of every company's overall contamination control program.
The validation process involves:
The following are some considerations:
1. Antimicrobial spectrum of activity
2. Compatibility with surfaces
3. Non-corrosive to surfaces
4. Safe for operators to use
5. Residue left after use
6. Required contact time
The following are some common disinfectants used in the pharmaceutical industry:
- Isopropyl alcohol (alcohol)
- Quaternary ammonium compounds
- Hydrogen peroxide
- Phenolic compounds
Additionally, it is common to implement rotation procedures on disinfectants to reduce the development of antimicrobial resistance.
- Microorganisms on surfaces
- Disinfectant is used
- Microbial reduction is measured
This method mimics the actual conditions found in a cleanroom.
This includes:
- The effective life of diluted solutions
- The effectiveness of the solution(s) as time passes
- Clarify each physical area (Example: If you are validating Grade A, B, C, D, etc.)
- Identify the specific types of disinfectants.
- Identify the specific area of validation.
- Include standard organism strains (bacteria and fungi)
- Include environmental isolates from your facility
These will be used to represent the worst-case contamination scenario.
- They should include stainless steel, glass, or epoxy.
- You should clean and sterilize any representative surfaces prior to testing.
- Let the test surface dry prior to adding the disinfectant and simulate the actual contamination conditions.
NOTE: You need to provide defined contact time for the disinfectant.
- You will need to neutralize the disinfectant after you have recovered the microorganisms.
- You will compare the number of surviving microorganisms to the original inoculum.
- You should compare the results against the acceptance criteria you established.
- Prepare a Validation Report.
Typical criterions are:
Example:
Quality Assurance responsibilities include:
- Reviewing protocols and reports
- Approving the quality standards to be met
- Validation to ensure proper compliance with Good Manufacturing Practices
- Overall assessment of effectiveness on an ongoing basis
In order to avoid contamination in pharmaceutical manufacturing facilities, disinfectants must be validated for their efficacy concerning micro-organisms found in the manufacturing environment and their ability to maintain cleanroom standards.
The phased validation process will ensure compliance with regulations, safety of final products and disinfectant selections that can effectively disinfect. As a heavily regulated industry, disinfectant validation is considered not only a regulatory requirement, but also an important safeguard to produce high-quality products for patients.
What is Disinfectant Validation?
Validation of disinfectants is a documented method that reveals how effective a disinfectant will work to reduce or eliminate a microorganism on surfaces in a specific pharmaceutical setting.The validation process involves:
- Choosing appropriate disinfectants
- Testing them against their intended microorganisms
- Testing them against the surfaces within the facility in question to ensure effectiveness and consistency
- Establishing appropriate usage procedures for the disinfectants.
Why Disinfectant Validation is Important
Pharmaceutical manufacturing environments, including but not limited to cleanrooms, are controlled and designed to be free of contamination at an appropriate level. While these environments are clean, they are not sterile unless designed for aseptic processes. Therefore, microorganisms can exist on surfaces in the environment and a potential source of contamination. Disinfectant validation provides assurance that:- Microbial control will be effective
- Products will not be contaminated
- Aseptic processing will be supported
- Regulatory criteria will be met
Selection of Disinfectants
The selection of a suitable disinfectant is the initial step in the validation process.The following are some considerations:
1. Antimicrobial spectrum of activity
2. Compatibility with surfaces
3. Non-corrosive to surfaces
4. Safe for operators to use
5. Residue left after use
6. Required contact time
The following are some common disinfectants used in the pharmaceutical industry:
- Isopropyl alcohol (alcohol)
- Quaternary ammonium compounds
- Hydrogen peroxide
- Phenolic compounds
Additionally, it is common to implement rotation procedures on disinfectants to reduce the development of antimicrobial resistance.
Types of Microorganisms Used for Validation
The microorganisms tested during validation must be representative of those that are present in the manufacturing area. These types of microorganisms generally tested include the following:- Gram-positive and Gram-negative bacteria
- Yeasts & molds
- Environmental isolates from the production facility
Methods of Disinfectant Validation
1. Suspension Examination
Tests liquid disinfectants' effectiveness. This method gives preliminary testing results but will not reflect conditions on surfaces.2. Surface (Carrier) Testing
This is the only real way to validate a disinfectant used within the pharmaceutical industry.- Microorganisms on surfaces
- Disinfectant is used
- Microbial reduction is measured
This method mimics the actual conditions found in a cleanroom.
3. In-Use Testing
Demonstrates the effectiveness of a disinfectant in performing duties under routine operations.This includes:
- The effective life of diluted solutions
- The effectiveness of the solution(s) as time passes
Disinfectant Validation Procedure
You will need to develop an organized and detailed procedure in order to complete the validation process.Step 1. Define Objectives and Scope of Validation
- What do you want to validate? (the physical area, type of disinfectant, test area, etc.)- Clarify each physical area (Example: If you are validating Grade A, B, C, D, etc.)
- Identify the specific types of disinfectants.
- Identify the specific area of validation.
Step 2. Selection of Microorganisms for Validation Testing
You will select the following types of microorganisms.- Include standard organism strains (bacteria and fungi)
- Include environmental isolates from your facility
These will be used to represent the worst-case contamination scenario.
Step 3. Preparation of Test Surfaces
You will need to select representative surfaces.- They should include stainless steel, glass, or epoxy.
- You should clean and sterilize any representative surfaces prior to testing.
Step 4. Inoculation of Microorganisms on Test Surfaces
- Use a standardized quantity of microorganisms to inoculate the test surface.- Let the test surface dry prior to adding the disinfectant and simulate the actual contamination conditions.
Step 5. Application of Disinfectant on Test Surfaces
Use a disinfectant according to your SOP using either the spray or wipe method.NOTE: You need to provide defined contact time for the disinfectant.
Step 6. Recovery of Microorganisms from Test Surface after Contact Time
- You will recover microorganisms from the test surface by using your recovery method after your defined contact time.- You will need to neutralize the disinfectant after you have recovered the microorganisms.
Step 7. Enumeration of Surviving Microorganisms
- You will count the number of surviving microorganisms.- You will compare the number of surviving microorganisms to the original inoculum.
Step 8. Data Analysis
- Calculate the log reduction based on your recovery count.- You should compare the results against the acceptance criteria you established.
Step 9. Documentation of Validation Process
- Document all observations made and all results obtained.- Prepare a Validation Report.
Key Parameters in Validation
1. Contact duration
The disinfectant should have enough time to work on a surface.2. Dilution ratio
Properly diluted disinfectants will not damage surfaces while providing adequate disinfecting ability.3. Surface type
The materials of the surfaces being disinfected may affect the disinfectant's performance.4. Environmental conditions
Temperature and humidity could affect how well the disinfectant works.Measure of Disinfectant Effectiveness
The effectiveness of a disinfectant is assessed using log reduction.Typical criterions are:
- 3-log reduction for general areas
- 5-log reduction for critical areas
Disinfectant Rotation Strategy
The purpose of disinfecting rotational strategy is to help reduce the development of resistance amongst microbes.Example:
- Use of general disinfectants daily
- Use of sporicidal agents weekly or monthly
Documentation Requirements
Documenting all activities correctly is critical in order to maintain compliance. The following documents should be maintained:- Validation protocol
- Test data/results
- Microbial recovery records
- Final validation report
Common Challenges in Validation
Common problems that an organization encounter are:- Inadequate recovery of the microorganisms
- Variability of test results
- Improper neutralization of disinfectants used
- Use of inappropriate microorganisms
Best Practices for Disinfectant Validation
The recommended methods are:- A risk-based approach should be used
- Environmental isolates should be included in the validation process
- Real-use conditions should be repeated in the validation process
- Wiping technique should be validated
- Personnel involved should receive comprehensive training
Importance of Quality Assurance in Disinfectant Validation
The purpose of Quality Assurance is to make sure that the validation has been done correctly.Quality Assurance responsibilities include:
- Reviewing protocols and reports
- Approving the quality standards to be met
- Validation to ensure proper compliance with Good Manufacturing Practices
- Overall assessment of effectiveness on an ongoing basis
When Revalidation is Necessary
Revalidation is required when:- A new disinfectant is introduced
- A formula is changed
- Environmental monitoring results indicate a change
- The cleaning procedure is modified
In order to avoid contamination in pharmaceutical manufacturing facilities, disinfectants must be validated for their efficacy concerning micro-organisms found in the manufacturing environment and their ability to maintain cleanroom standards.
The phased validation process will ensure compliance with regulations, safety of final products and disinfectant selections that can effectively disinfect. As a heavily regulated industry, disinfectant validation is considered not only a regulatory requirement, but also an important safeguard to produce high-quality products for patients.
Frequently Asked Questions on Disinfectant Validation
Q1. How do you validate a disinfectant for use?
Answer: Disinfectant validation means proving the disinfection capabilities of the product in regards to its ability to reduce microbiological contamination of in-use surfaces under normal conditions.Q2. What is meant by disinfectant validation?
Answer: Disinfectant validation is important in assuring the necessary controls of contamination and safety of products and to comply with Licensing guidelines of production in the pharmaceutical marketplace.Q3. What testing methodologies are used for validation?
Answer: Common methods used to validate disinfectants are suspension testing, surface (carrier) testing and in-use testing.Q4. What microorganisms do you use for validation purposes?
Answer: Validation uses standard strains to support validation of the disinfecting agent against environmental isolates of those microorganisms that may be introduced to the facility.Q5. What is log reduction?
Answer: The number of bacteria killed by a disinfectant will be referred to as a log reduction in disinfectant validation study. For example, a 3 log reduction would indicate that a disinfectant has reduced a population of 1000 microorganisms to 1 microorganism and a 5 log reduction would have reduced a population of 100,000 microorganisms to 1 microorganism.Q6. Why is disinfectant rotation necessary?
Answer: Disinfectant rotation is necessary to prevent the development of microbial resistance and to provide additional organism kill with the broader range of effective products.Q7. When is revalidation warranted?
Answer: Revalidation is warranted when there is a change in the disinfectant, environmental trend changes or change in the Procedures/Protocol.Q8. What do regulators expect?
Answer: Regulators expect disinfectants to be validated, that there is consistent documentation supporting the validation and that businesses are following Good Manufacturing, i.e. producing Quality and Consistent products for the marketplace.
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