Beginning Slide - TITLE OF PRESENTATION DISINFECTANT QUALIFICATION An Overview

Robert F. Guardino Director of Microbiology

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DATE OF PRESENTION October 30, 2006 OTHER INFORMATION

DISINFECTANT QUALIFICATION

Regulatory and Industry Guidance Disinfectant Efficacy Methods Disinfectant Rotation

REGULATORY GUIDANCE

CFR
21 CFR 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals - . 42 Design and construction features. (9) Control and laboratory operations (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions. - . 56 Sanitation. (b) written procedures for cleaning methods and materials used for cleaning. (c) written procedures for use of cleaning and sanitizing agents . . . Fungicides shall not be used unless registered and used in accordance with FIFRA.
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21 CFR part 211 Continued

- . 67 Equipment cleaning and maintenance. (a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals

- . 113 Control of microbiological contamination. (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 any sterilization process.
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International Regulations
ICH Guidance for Industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients August 2001 - 5.2 Equipment Maintenance and Cleaning. Reads much like 21 CFR 211.67 - 8.5 Contamination Control. 8.50 Such carryover should not result in the carryover of . . microbial contamination that may adversely alter the . . impurity profile. Precautions to avoid contamination should be taken when APIs are handled after purification.

ICH GMP Guide Continued - 12. Validation 12.1 Validation Policy Companys overall policy for validation, including the validation of cleaning procedures. Validation should extend to those operations determined to be critical to the quality and purity of the API. - 12.7 Cleaning Validation Cleaning procedures should normally be validated. Equipment cleaning / sanitization studies should address microbiological and endotoxin contamination . . .
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EU Guide to GMP
Final Version of Annex 15 Qualification and Validation. July 2001 CLEANING VALIDATION

36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure.

38. Normally only cleaning procedures for product contact surfaces of the equipment need be validated. Consideration should be given to non-contact parts.
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EU Guide to GMP Cont.

REVALIDATION 45. processes, including cleaning, should be periodically evaluated to confirm that they remain valid.

Medicines Control Agency (MCA)

Rules and Guidance for Pharmaceutical Manufacturers Sanitation - Disinfectants and detergents should be monitored for microbial contamination: dilutions should be kept in previously cleaned containers and should not be stored for long periods unless sterilised. Partly emptied containers should not be topped up. Production areas should be designed to permit disinfection between campaigns, using validated methods.

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MCA Continued

Disinfection - Waste Disposal - 32. Disinfection and / or wastes and effluents disposal . . . Careful consideration should be given to procedures and equipment aiming at avoiding environmental contamination as well as to their validation or qualification.

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Classification of Disinfectants
FDAs Guidance on 510(k) for Liquid Chemical Germicides Low Level Disinfectant: A germicide that kills most vegetative bacteria and lipid or medium sized viruses when used according to labeling. Intermediate Level Disinfectant: A germicide that kills all microbial pathogens (including Mycobacteria), except bacterial endospores, when used according to labeling.
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Classification of Disinfectants Cont.

High Level Disinfectant: A germicide that kills all microbial pathogens, except large numbers of bacterial endospores, when used according to labeling.

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GUIDANCE
FDA Guidance for Industry Sept 2004 - Sterile Drug Products Produced by Aseptic Processing: Section X Laboratory Controls states: 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.
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USP NF 2006 Supplement 2

<1072> DISINFECTANTS AND ANTISETICS, New Informational Chapter Official: Aug 1, 2006
Good overview of the topic with relevant test and interpretative information (will be discussed in more detail by Dr. Farrington in the Tuesday 8:30 10:30 session). Recommends 2-log reduction for bacterial spores and 3log reduction for vegetative bacteria. Diluted disinfectants must have an assigned expiration dating justified by effectiveness studies.

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DISINFECTANT QUALIFICATION METHODS

Acknowledgement: Amy Lovell Covance

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METHODS
Carrier Test Suspension (Direct Inoculation) Test Surface Test

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When To Do A Carrier Test

Performed by commercial disinfectant vendors to establish claims May be performed by end-users to compare relative efficacy of disinfectants against particular organisms on a standard surface.

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SUSPENSION (Direct Inoculation) TEST

What is the suspension test? When to do a suspension test? Problems associated with a suspension test.

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What Is A Suspension Test?

The Suspension test is a dilution and plating method. The organism is added directly to the use-dilution of the disinfectant. After the appropriate contact time serial dilutions are performed in a neutralizing broth and plated in duplicate so as to achieve counts within the statistically valid range.

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When To Do A Suspension Test

Used as a screening test to evaluate: Relative efficacy of a variety of disinfectants against test organisms without the surface variables. Different contact times (from the same test set-up). Removes the recovery issues during early evaluation of disinfectants. Once variables are defined proceed with surface testing.
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Suspension Test Problems

Problems with neutralization of certain disinfectants
Letheen will not work to neutralize all disinfectants. DE broth is a good substitute along with DE agar for plating. Catalase may be added to the broth for neutralizing Hydrogen Peroxide.

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SURFACE TEST
When to do a Surface Test What is a Surface Test Surfaces and Organisms Time points / Methods of application Validation / Inactivation

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When To Do A Surface Test

To simulate disinfectant use in your facility.

To evaluate disinfectant efficacy as a function of surface type.

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What Is A Surface Test?

Testing Disinfectants used in your facility on surfaces regularly disinfected. Vegetative organisms tested wet; sporeformres dried on surface prior to testing.

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Surfaces And Organisms

Surfaces that undergo regular disinfecting in critical areas (i.e.: clean rooms and manufacturing areas). Testing can be performed on ATCC strains, however, environmental isolates are expected. Many environmental species are more difficult to eradicate. Select environmental isolates based on frequency of recovery during environmental monitoring and to include as many morphologic types as possible.
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Time Points / Methods Of Application

Choose time points based on how the disinfectant is actually used. Select minimum contact time as the worst case. Longer contact times may be evaluated later if efficacy is not demonstrated initially. We typically apply disinfectants by spraying to eliminate application variables and to evaluate only the disinfectant efficacy. Alternatively, apply the disinfectant as it is applied in your facility, i.e., mopping, or wiping.

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Recovery Method
Contact Plates problems include: contact plate medium must inactivate the disinfectant and recoveries may be poor. Swabs recovery of organisms may be poor. Rinse preferred method with good microbial recovery. Submersion may be suitable if adequate recovery can be demonstrated.
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Validation / Inactivation

Neutralizer toxicity demonstrate recovery of organisms from the neutralizing medium / diluent in the absence of disinfectant. Neutralizer efficacy demonstrate recovery of organisms from neutralizer broth / diluent spiked with worst case (highest) disinfectant concentration. Surface recovery studies to evaluate the ability to recover the test organisms from test surfaces in the absence of disinfectants.
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Problems you may face with a surface test

Recovery of dried spore-formers from a surface. Neutralization problems Do I consider a mold a vegetative organism or a sporeformer? Desiccation and loss of viability with long contact times.
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Recovery Of Dried Spore-formers

70% recovery of a dried spore-former from a surface is difficult. Use different criteria for dried spore-formers, e.g., not more than 0.50 Log from the inoculum. If it does not meet this criteria a correction factor may be used. Alternatively set your recovery criteria to provide a minimum level to determine the acceptance criteria.

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Inactivation Problem with a Surface Test

MCTA (Microbial Content Test Agar) contact plates will not be a suitable neutralizer for all disinfectants. Use D/E agar contact plates for sporicidal agents. Beware, D/E may be toxic to some organisms. Use an alternate recovery method, e.g., rinse with a suitable neutralizing agent. That plus dilution may suffice.

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Disinfectant Rotation

The premise for rotation is that by using only one disinfectant you will eventually encounter organisms that are resistant to the disinfecting agent.

It is claimed that resistance is acquired and mediated by some of the same mechanisms that are responsible for antibiotic resistance, e.g., mutation or DNA transfer leading to an altered permeability to or direct inactivation of the disinfectant.

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Questions Regarding Rotation

Is disinfectant rotation necessary? Why or why not? What are the advantages? What are the disadvantages?
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Is Disinfectant Rotation Necessary?

Disinfectant rotation is a regulatory expectation. Not specifically listed in the FDA GMPs, but it is the industry norm. Annex 1 Manufacture of Sterile Medicinal Products. Revision of the Guide to GMP. Working Party on Control of Medicines and Inspections European Commission states in section 37 under Sanitation: Where disinfectants are used, more than one type should be employed.

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Is Disinfectant Rotation Necessary? Cont.

USP 29 Supplement 2, Aug 1, 2006 covers the issue of disinfectant rotation as follows:
Because it is theoretically possible that the selective pressure of the continuous use of a single disinfectant could result in the presence of disinfectant-resistant microorganisms . . . the rotation of disinfectants has been advocated. It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent.
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Why?
Choose disinfectants that have claims that will complement each other, i.e., to provide the broadest spectrum of activity. Sporicidal agents (sterilants) are too harsh to use routinely. Use on a periodic basis in place of a disinfectant. Rotate disinfectants if your environmental monitoring program indicates tolerant organisms. Disinfectants will need to be qualified with the new environmental isolates.
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Advantages / Rationale
It is a regulatory expectation. There is evidence in laboratory studies that resistance can occur and rotation controlled the development of resistant strains (Connor 1993, Kopis 1996). Environmental monitoring data shows an increase, especially newly encountered organisms. Rotate a disinfectant with a sterilant (sporicidal agent)
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Disadvantages / Arguments Against

The obvious work and cost of qualifying additional disinfectants. It has never been conclusively demonstrated that chemical resistance occurs in the pharmaceutical manufacturing settings (Prince, 1998). Incompatible disinfectants; residue of one interacting with, and inactivating another, e.g., Quats and Phenolics.

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Selected References on Rotation

Connor, D.E. and M.K. Eckman, Rotation of Phenolic Disinfectants, Pharmaceutical Technology, Sept. 1992, p 148. Connor, D.E. and M.K. Eckman, Rotation of Phenolic Disinfectants Enhances Efficacy Against Adherent Pseudomonas aeruginosa, Pharmaceutical Technology, Oct. 1993, p 94. Kopis, E.M. Rotation of Disinfectants to Combat Microbial Resistance, Cleanrooms, Oct. 1996, p 48.
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References Continued:
Prince, R. Disinfectant Rotation Practices Revolve Around Two Schools of Thought, Clean rooms, Jan. 1998. Kopis, E.M. Answers to the 10 Most Common Questions Regarding Microbial Control in Cleanrooms, Cleanrooms, Jan. 1997 Vellutaro, A. A Systematic Approach to Selecting Disinfecting Agents for Aseptic Pharmaceutical Manufacturing, Cleanrooms, April 1996.
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DISINFECTANT QUALIFICATION - An Overview

October 30, 2006 Robert F. Guardino

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