PDA Dis Infectant Qualification P4 Guardino Robert

8/3/2019 PDA Dis Infectant Qualification P4 Guardino Robert

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Beginning Slide - TITLE OF PRESENTATIONDATE OF PRESENTION

OTHER INFORMATION

DISINFECTANT QUALIFICATION An OverviewOctober 30, 2006

Robert F. Guardino

Director of Microbiology

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Regulatory and Industry Guidance

Disinfectant Efficacy Methods

Disinfectant Rotation

DISINFECTANT QUALIFICATION


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REGULATORY GUIDANCE

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21 CFR 211 - Current Good Manufacturing Practicefor Finished Pharmaceuticals

- . 42 Design and construction features. (9) Controland laboratory operations (v) A system for cleaningand disinfecting the room and equipment to produceaseptic conditions.

- . 56 Sanitation. (b) written procedures for cleaningmethods and materials used for cleaning. (c) writtenprocedures for use of cleaning and sanitizing agents .. . Fungicides shall not be used unless registered andused in accordance with FIFRA.

CFR


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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 preventmicrobiological contamination of drug productspurporting to be sterile, shall be established and

followed. Such procedures shall include validation of anysterilization process.

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International Regulations

ICH Guidance for Industry Q7A Good Manufacturing PracticeGuidance for Active Pharmaceutical Ingredients August 2001

- 5.2 Equipment Maintenance and Cleaning. Readsmuch like 21 CFR 211.67

- 8.5 Contamination Control. 8.50 Such carryovershould not result in the carryover of . . microbialcontamination that may adversely alter the . . impurity

profile. Precautions to avoid contamination should betaken when APIs are handled after purification.


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ICH GMP Guide Continued -

- 12. Validation 12.1 Validation Policy -

Companys overall policy for validation, includingthe validation of cleaning procedures. Validationshould extend to those operations determined tobe critical to the quality and purity of the API.

- 12.7 Cleaning Validation

Cleaning procedures should normally bevalidated. Equipment cleaning / sanitization

studies should address microbiological andendotoxin contamination . . .

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EU Guide to GMP

Final Version of Annex 15 Qualification andValidation. July 2001

CLEANING VALIDATION

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

38. Normally only cleaning procedures for productcontact 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 beperiodically evaluated to confirm that they remainvalid.

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Medicines Control Agency (MCA)

Rules and Guidance for Pharmaceutical Manufacturers

Sanitation - Disinfectants and detergents should bemonitored for microbial contamination: dilutions shouldbe kept in previously cleaned containers and should notbe stored for long periods unless sterilised. Partlyemptied containers should not be topped up.

Production areas should be designed to permit

disinfection between campaigns, using validatedmethods.


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MCA Continued

Disinfection - Waste Disposal

- 32. Disinfection and / or wastes and effluentsdisposal . . . Careful consideration should be givento procedures and equipment aiming at avoidingenvironmental contamination as well as to theirvalidation or qualification.

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Classification of Disinfectants

FDAs Guidance on 510(k) for Liquid ChemicalGermicides

Low Level Disinfectant: A germicide that kills mostvegetative bacteria and lipid or medium sized viruseswhen used according to labeling.

Intermediate Level Disinfectant: A germicide thatkills all microbial pathogens (including Mycobacteria),except bacterial endospores, when used according tolabeling.


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Classification of Disinfectants Cont.

High Level Disinfectant: A germicide that kills allmicrobial pathogens, except large numbers of bacterialendospores, when used according to labeling.

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GUIDANCE

FDA Guidance for Industry Sept 2004 - Sterile DrugProducts Produced by Aseptic Processing: Section XLaboratory 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 abilityto ensure that potential contaminants are

adequately removed from surfaces.


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USP NF 2006 Supplement 2

DISINFECTANTS AND ANTISETICS, NewInformational Chapter Official: Aug 1, 2006

Good overview of the topic with relevant test andinterpretative information (will be discussed in more detailby Dr. Farrington in the Tuesday 8:30 10:30 session).

Recommends 2-log reduction for bacterial spores and 3-log reduction for vegetative bacteria.

Diluted disinfectants must have an assigned expirationdating justified by effectiveness studies.

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DISINFECTANT QUALIFICATION

METHODS

Acknowledgement:

Amy LovellCovance


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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 toestablish claims

May be performed by end-users to compare relativeefficacy of disinfectants against particular organisms ona 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 thedisinfectant.

After the appropriate contact time serial dilutions areperformed in a neutralizing broth and plated in duplicate

so as to achieve counts within the statistically validrange.


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When To Do A Suspension Test

Used as a screening test to evaluate:

Relative efficacy of a variety of disinfectants againsttest organisms without the surface variables.

Different contact times (from the same test set-up).

Removes the recovery issues during early evaluation ofdisinfectants.

Once variables are defined proceed with surface testing.

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Suspension Test Problems

Problems with neutralization of certaindisinfectants

Letheen will not work to neutralize all disinfectants.

DE broth is a good substitute along with DE agar forplating.

Catalase may be added to the broth for neutralizingHydrogen 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 surfacetype.


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What Is A Surface Test?

Testing Disinfectantsused in your facility onsurfaces regularlydisinfected.

Vegetative organismstested wet; sporeformresdried on surface prior to

testing.

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Surfaces And Organisms

Surfaces that undergo regular disinfecting in criticalareas (i.e.: clean rooms and manufacturing areas).

Testing can be performed on ATCC strains, however,environmental isolates are expected. Manyenvironmental species are more difficult to eradicate.

Select environmental isolates based on frequency ofrecovery during environmental monitoring and to includeas many morphologic types as possible.


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Time Points / Methods Of Application

Choose time points based on how the disinfectant isactually used. Select minimum contact time as the worstcase. Longer contact times may be evaluated later ifefficacy is not demonstrated initially.

We typically apply disinfectants by spraying to eliminateapplication variables and to evaluate only thedisinfectant efficacy. Alternatively, apply the disinfectantas it is applied in your facility, i.e., mopping, or wiping.

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Recovery Method

Contact Plates problems include: contact plate mediummust inactivate the disinfectant and recoveries may bepoor.

Swabs recovery of organisms may be poor.

Rinse preferred method with good microbial recovery.

Submersion may be suitable if adequate recovery canbe demonstrated.


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Validation / Inactivation

Neutralizer toxicity demonstrate recovery of organismsfrom the neutralizing medium / diluent in the absence ofdisinfectant.

Neutralizer efficacy demonstrate recovery oforganisms from neutralizer broth / diluent spiked withworst case (highest) disinfectant concentration.

Surface recovery studies to evaluate the ability torecover the test organisms from test surfaces in theabsence of disinfectants.

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Problems you may face with a surface test

Recovery of dried spore-formersfrom a surface.

Neutralization problems

Do I consider a mold avegetative organism or a spore-former?

Desiccation and loss of viabilitywith long contact times.


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Recovery Of Dried Spore-formers

70% recovery of a dried spore-former from a surfaceis difficult.

Use different criteria for dried spore-formers, e.g.,not more than 0.50 Log from the inoculum. If it doesnot meet this criteria a correction factor may beused.

Alternatively set your recovery criteria to provide aminimum level to determine the acceptance criteria.

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Inactivation Problem with a Surface Test

MCTA (Microbial Content Test Agar) contact plates willnot 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 asuitable neutralizing agent. That plus dilution maysuffice.


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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.

Disinfectant Rotation

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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 theindustry norm.

Annex 1 Manufacture of Sterile Medicinal Products.Revision of the Guide to GMP. Working Party onControl of Medicines and Inspections EuropeanCommission 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 ofdisinfectant rotation as follows:

Because it is theoretically possible that the selectivepressure of the continuous use of a single disinfectantcould result in the presence of disinfectant-resistantmicroorganisms . . . the rotation of disinfectants has beenadvocated.

It is prudent to augment the daily use of a bactericidaldisinfectant with weekly (or monthly) use of a sporicidalagent.


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Why?

Choose disinfectants that have claims that willcomplement each other, i.e., to provide thebroadest spectrum of activity.

Sporicidal agents (sterilants) are too harsh to useroutinely. Use on a periodic basis in place of adisinfectant.

Rotate disinfectants if your environmentalmonitoring 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 thatresistance can occur and rotation controlled thedevelopment of resistant strains (Connor 1993,Kopis 1996).

Environmental monitoring data shows an increase,

especially newly encountered organisms.

Rotate a disinfectant with a sterilant (sporicidalagent)


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Disadvantages / Arguments Against

The obvious work and cost of qualifying additionaldisinfectants.

It has never been conclusively demonstrated thatchemical resistance occurs in the pharmaceuticalmanufacturing settings (Prince, 1998).

Incompatible disinfectants; residue of one interactingwith, 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 PhenolicDisinfectants, Pharmaceutical Technology, Sept.1992, p 148.

Connor, D.E. and M.K. Eckman, Rotation of PhenolicDisinfectants Enhances Efficacy Against AdherentPseudomonas aeruginosa, PharmaceuticalTechnology, Oct. 1993, p 94.

Kopis, E.M. Rotation of Disinfectants to CombatMicrobial Resistance, Cleanrooms, Oct. 1996, p 48.


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Prince, R. Disinfectant Rotation Practices RevolveAround Two Schools of Thought, Clean rooms, Jan.1998.

Kopis, E.M. Answers to the 10 Most CommonQuestions Regarding Microbial Control inCleanrooms, Cleanrooms, Jan. 1997

Vellutaro, A. A Systematic Approach to SelectingDisinfecting Agents for Aseptic Pharmaceutical

Manufacturing, Cleanrooms, April 1996.

References Continued:

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DISINFECTANT QUALIFICATION - An OverviewOctober 30, 2006

Robert F. Guardino

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