A Risk Based Cleaning and Disinfection Program

Jim Polarine Jr. MA.

Senior Technical Service
Manager
May 22, 2019

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 Understand the
basis of
Chemical
selection, use
and application

Describe the
Importance of LEARNING Detail the
proper order of
Cleaning and
Disinfection OBJECTIVES cleaning

List appropriate
application
methods

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Topics Covered

➢ Regulatory Requirements

➢ Cleaning and Disinfecting Technologies

➢ Cleaning and Disinfection Techniques

➢ Rotation and Residues

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Regulatory Requirement
USP 41 <1072> Disinfectants and Antiseptics:

“A sound cleaning and sanitization program is needed for controlled environments

used in the manufacture of Pharmacopeial articles to prevent the microbial
contamination of these articles. Sterile drug products may be contaminated via
their pharmaceutical ingredients, process water, packaging components,
manufacturing environment, processing equipment, and manufacturing
operators”

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Industry Guidance

PDA TECHICAL REPORT #70 “Cleaning and Disinfection Programs from Aseptic Manufacturing
Facilities”:

“The purpose of the cleaning and disinfection program is not only to control microbial
contamination but also to serve as a corrective action for the loss of control for viable
excursions contamination. While the destruction of viable cells are an integral part of the
cleaning and disinfection program, the use of disinfection as a singular focus without
efforts to control contamination from entering the area is without technical merit.
Environmental monitoring (EM) evaluates the efficacy of controls on the manufacturing
environment. It is through control of bioburden levels entering the area, along with
cleaning and disinfection, that acceptable viable control of the manufacturing or
appropriate testing environment is achieved. “

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Draft of Annex I: Disinfection
Disinfection
568
569 5.31 The disinfection of clean areas is particularly important. They should be cleaned and
570 disinfected thoroughly in accordance with a written programme (for disinfection to be
571 effective, cleaning to remove surface contamination must be performed first)., More than one
572 type of disinfecting agent should be employed, and should include the periodic use of a
573 sporicidal agent. Disinfectants should be shown to be effective for the duration of their in use
574 shelf-life taking into consideration appropriate contact time and the manner in and surfaces
575 on which they are utilized. Monitoring should be undertaken regularly in order to show the
576 effectiveness of the disinfection program and to detect the development of resistant and/or
577 spore forming strains. Cleaning programs should be effective in the removal of disinfectant
578 residues.
579
580 5.32 Disinfectants and detergents should be monitored for microbial contamination;
581 dilutions should be kept in previously cleaned containers and should only be stored for
582 defined periods. Disinfectants and detergents used in grade A and B areas should be sterile
583 prior to use.
584
585 5.33 Disinfectants should be shown to be effective when used on the specific facilities,
586 equipment and processes that they are used in.
587
588 5.34 Fumigation or vapour disinfection of clean areas such as Vapour Hydrogen Peroxide
589 (VHP) may be useful for reducing microbiological contamination in inaccessible places.

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 Recent FDA WL

“Your firm used a broad-spectrum hard surface

disinfectant that was not labeled as sporicidal or
sterile as the sole sanitizing agent for sanitizing
the ISO 5 classified area.”
FDA WL 2/11/19.
[Link]
arningLetters/2019/[Link]

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Recent FDA WL: Cleaning and Disinfection

“A. (b)(4) and (b)(4) cleaning and disinfecting solutions used in the critical
processing zones and direct support zones are made with non-sterile tap
water and held in non-sterile bottles that are used at (b)(4) per the
cleaning procedure (FRAN-SOP002).
B. your firm’s preparation and use of a (b)(4) solution during (b)(4)
cleaning and disinfecting of the Class 10,000 cleanrooms and Class 100
laminar flow hoods where sterile saline/heparin filled syringes are
manufactured has not been validated.
C. the adequate removal of residues of disinfecting and cleaning solutions
in the Class 100 laminar flow hoods has not been validated.”
FDA WL 9/14/18
[Link]
[Link]

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Recent WL on Cleaning and Disinfection

“1. Your firm failed to use adequate contact times for sporicidal
agents used as part of your disinfection program for the aseptic processing
area.
1. Your firm failed to establish an adequate system for cleaning and
disinfecting the room and equipment to produce aseptic
conditions. 21 CFR 211.42(c)(10)(v)
1. Your response did not include any supporting documentation
related to the review and revision of your cleaning procedure to address the
inadequate contact time you use for sporicidal agents.”
FDA WL March 1, 2018
[Link]
[Link]

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Cleanroom Contamination Control

“Your firm used non-pharmaceutical grade drinking water, obtained from a

bottled water dispenser located in the break room of your facility, in the
production of non-sterile stock solutions and non-sterile drug
products. Our investigators determined that the water was used in the
production of dozens of drug products. During the inspection, our
investigators collected a sample of the water obtained from the
dispenser. FDA analysis of the (b)(4) identified the presence
of Burkholderia cepacia, which is considered an objectionable
microorganism.”
FDA WL May 9, 2018
[Link]
[Link]

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 Cleanroom Behavior

“Investigators observed an operator sitting with her upper body

leaning into the ISO-5 classified area with the sleeves of her
non-sterile gown resting directly on the work surface of the
ISO-5 classified area, thereby providing a potential source of
contamination”
FDA WL July 10, 2018
[Link]
/2018/[Link]

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 Recent WL

“no use of sporicidal disinfectant on

surfaces inside aseptic filling
room (b)(4), although your
environmental monitoring detected
spore-forming organisms there; and”
FDA WL 1/19/17.

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 Cleaning and Disinfection:
Product Selection
• EPA Classifications
– Sanitizer
– Disinfectant
– Sterilizer (Sporicide)

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 Cleaning and Disinfection:
Product Selection
• Sanitizer
– Proper use results in bacteria reduction of >99.9%
– 3-Log reduction
– Used on precleaned surfaces unless tested with serum load
EPA Classifications

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 Cleaning and Disinfection:
Product Selection

• Disinfectant
– Proper use results in 100% kill of vegetative bacteria,
target viruses and target fungi
– [Link]
toxic-substances/series-810-product-performance-
test-guidelines
– May or may not require pre-cleaning
• Serum efficacy - 5% BSA and EN methods differ example:
skimmed milk as a soil load

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 Cleaning and Disinfection:
Product Selection
• Sterilant
– Proper use results in 100% kill of all microorganisms, including
bacterial endospores (B. subtilis, C. sporogenes)
– Always requires pre-cleaning
• Water quality is important

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 Classifications

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 Review - Microflora in Cleanrooms
(U.K.)
• Tim Sandle
• PDA J Pharm Sci and Tech 2011, 65:392-403
• A Review of Cleanroom Microflora: Types, Trends, and
Patterns

• Examined isolates from 2000-2009 in U.K.

• Grade A/B and C/D

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 Review - Microflora in Cleanrooms (U.K.)

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 Review - Microflora in Cleanrooms (U.K.)
A/B C/D
Genus (6729) (2500)
Micrococci (and related) 38% 40%
Staphylococci 21% 11%
Bacillus (and related) 13% 10%
Pseudomonas (and related) <1% 8%
Corynebacterium (and related) 3% 5%
Rhodococci <1% N/A
Fungi N/A 3%

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 Staphylococcus haemolyticus

Courtesy Grace Thornhill

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 Aspergillus Spores

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 Cleanroom Fungi

Courtesy Dan Klein

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 Fungal Spores
Aspergillus Spores

Courtesy Bruce Ritts

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 SEM: Pseudomonas 5,000X
magnification

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 Bacillus Subtilis

Courtesy Bruce Ritts

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 Biofilms

Courtesy Dan Klein

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 Chemistries & Frequency

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Purpose of Cleaning and Disinfection
Control microbial contamination
• Destruction of viable cells
Corrective action for loss of control
• Viable and non-viable excursions
Disinfection used in conjunction with contamination control program
• Prevent contamination from entering the room

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Cleaning and Disinfection

Hospital Grade Disinfectants are formulated with surfactants,

dispersants, and chelants to provide a moderate level of
cleaning and microbial kill in cleanrooms.

Post construction and after worst case events either a triple

cleaning or a double cleaning with a neutral or acidic cleaner
would be recommended.

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 Disinfectant Components

Component Function in Disinfectant

Water Solvent
Antimicrobial Kill, reduce microbes
Oxidants Oxidize, kill microbes
Tie up calcium, iron, stabilize oxidants, potentiates antimicrobial
Chelants action

Solvents Solubilization and stabilization of formula

Bases Alkalinity source, hydrolysis (KOH)
Acids Acidity source, hydrolysis (H3PO4)
Surfactants Emulsification, Wetting

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 Effect of Surfactants
• Influence of Surfactants on Wetting

– Ability to displace particles

– Penetrate soil and surface irregularities
– Better contact

No Surfactants Surfactant A Surfactant B

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 Wetting Surface Tension and Penetration

Disinfectant with no surfactant

Disinfectant with surfactant

Microorganism or Soil

Good coverage with

Surfactant

Substrate

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Contamination Control
Control what enters your environment
• Viable and non-viable
Begin with items transferred into facility
• Components, carts, personnel, tanks, tools, etc.
• Defined entrance procedures
Good control leads to less
• Excursions
• Investigations
• Down time

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Materials
All items cleaned, sterilized or disinfected
Highest level of decon possible

Automatic
Manual
Sterilization OR Disinfection OR
Disinfection
(VHP)

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 Chemical types

• Disinfectants and sanitizers • Sterilants and sporicides

– Phenolics (potentially)
– Quats – Sodium hypochlorite
– Alcohols – Chlorine dioxide
– Hydrogen Peroxide 3% – Hydrogen peroxide 6%
– Peracetic acid
– Peracetic acid/hydrogen
peroxide blends
– Glutaraldehyde/formalde
hyde
– Ozone
– Nitrogen Dioxide
– Vaporized Peracetic Acid
and VHP®

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 Factors influencing performance
• pH
• Temperature
• Contact time
• Concentration
• Surface
• Presence of organic matter
• Water Quality (hardness)

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Tanks, Carts and Equipment
Tank/Vessel
• If interior sterile, only address exterior
Special attention to wheels
• Increased contact time
• Manual wiping

Note: Captive carts (or commodity transfer in pass through) is HIGHLY preferred

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Cleaning Supplies
Chemicals
• Sterilizing filtration (.2 u)
• Gamma Radiation
• Autoclaving
• Pre-purchased sterile
Mop heads/Sponges –
Sterilized
Other equipment
• Mops, buckets, squeegees,
carts
• Sterilized (disinfected at a
minimum)

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Manufacturing Components and Supplies
Sterile components used in process
• Packaged in container that can be sanitized

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Disinfectant Application

Spraying
• More wetting, no cleaning

Mopping
• Mechanical action cleaning, less wetting

Wiping
• For smaller surfaces, less wetting

Fogging/Gassing
• Excellent efficacy, high residues, no cleaning

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 Application Techniques
• Most critical areas to least critical areas
• Apply disinfectant to wiper or spray on the surface
(garden variety sprayer)
• Changing out the use dilutions* (2-3 Bucket routines)
• 600 sq. ft (56 sq. meters) in ISO-5,6 (A & B)
• 1,000 sq. ft (93 sq. meters) in ISO- 7,8 (C & D)
• IEST-RP-CC018.4
• Grid (Blueprint of the Room)
• Pull and lift
• Overlapping strokes (by 20%)
• Figure 8 (also called figure S) or Unidirectional
overlapping mopping strokes

* Anne Marie Dixon, Ch. 11, Cleaning of Non-Product Contact Surfaces, p 226, in Cleaning and Cleaning Validation for the Pharmaceutical and
Medical Device Industries, Vol. 1 Basics, Expectations, and Principles. Paul L. Pluta, Ed., PDA, Bethesda, MD, and DHI Publishing, LLC, River Grove, IL.
2009.

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 Two Bucket System

➢Sterilant (Disinfectant) in front bucket, optional to put some

sterilant (Disinfectant) in waste bucket (bucket beneath the
ringer)
➢Dip mop head into front bucket, let excess liquid drain off,
apply to the surface.
➢When mop head appears to be dragging on the surface, dip
into waste bucket, then wring out. Go back to front bucket
and dip mop head, let excess liquid drain off and apply to the
surface.
➢Repeat above steps

➢Other Mopping Systems: Single Bucket, Triple Bucket,

MicronSwep System by Vileda and the Mop King System.

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 Application Techniques

[Link]
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 Bucket Systems

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 Newer Mopping Systems
• Mop King Jr.
• [Link]

•Stainless steel
•Battery operated and electronically monitored
•Holds 15 Rayon or Microfiber flat mops
•Holds 1.5 gal solution
•Dispensed with the precise amount of solution
•Fits on housekeeping cart
•Flat mops guided along rail to a wetting tray
•Pump activates, dispenses solution to mop head

AmKing Technologies, Bedford, NH

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 Newer Mopping Systems
MicronSwep system by Vileda Professional and Micronclean
([Link])

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CE Duo
Features and Benefits
Courtesy of Vileda Professional
• Combines microfiber and foam
technologies
You get disinfection and removal in the same
tool. 99.99% reduction in surface bacteria
without disinfectant.
• Two sided cleaning tool
Doubles the floor space cleaned with each
bucket dip.
• Only mop system that will clean floors,
walls and ceilings
Eliminates the cost and inefficiency of
maintaining multiple systems.
• Lightest and most ergonomic tool on the
market
Reduces fatigue and potential for muscle
strains.

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 Two & Three Bucket Systems

Courtesy of Perfex Corp.

Courtesy of Micronova Mfg.

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 Commonly Used Equipment
Courtesy Micronova Mfg.

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 Latest Equipment

Isolator Tool

Courtesy of Micronova Mfg.

Lyo Tool

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 Cleaning and Disinfection:
Techniques

• Pharma Pump up sprayer

– Compatible with Sporicides and
Disinfectants
– Specifically designed to be compatible
– 1.5 Gallon
– Up to 120°F and 45 psi
– cGMP ready:
• Materials of Construction
• Certificate of Conformity (Serial Number)
• Assembled using SOP
• Quality Control performance checks

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 Product Selection Criteria
• How to choose???
– Performance – may need multiple products
– Substrate compatibility
– Cleaning ability
– Change Control
– Globally Available
– Supply Chain
– Disaster Response Plan
– Ease of application
– Validatability
• SDS, COA available
• Stability Studies (Opened Container, Closed Container, Use Dilution)
• Toxicity Studies, Analytical Methods
– Application and contact time requirements
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 Cleaning and Disinfection Best Practices

• How often to clean???

– Environmental cleaning frequency determined by:
• ISO Classification of area
• The level of risk
• Activity level in area or use
• Environmental monitoring feedback
• Type of process being performed & equipment used

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 Sporicide: Application Frequency

• Sporicidal agent
– Rationale
• Weekly
• Monthly
• Quarterly
• Should be written in SOP’s
– Extraordinary Cleaning
– Used Based on Risk
– Fungal and Bacterial Spore Outbreaks

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 CNC (Controlled Not Classified) Area Cleaning
Frequency
• Hallways and Floors ---Mop daily ---Rinse as needed

• Walls and Ceilings---Mop monthly—Rinse as needed

• Equipment (carts, racks, trash receptacles, etc.)---Wipe

weekly---Rinse as needed

• Rinsing is based on visual observation and safety

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 Grade D (ISO 8 at rest)

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 Grade C (ISO 7 at rest, ISO 8 in operation)

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 Grade A (ISO 4.8) or B (ISO 5 at rest, ISO 7 in
operation)

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 Recommended Frequency
Daily Weekly Monthly Yearly
Controlled Area
Floors X X
Ceilings X
Walls X
Fixtures/Equipment X
Class 100,000 (ISO 8)
Floors X
Ceilings X
Walls X
Fixtures/Equipment X X
Class 10,000 (ISO 7)
Floors X
Ceilings X X
Walls X
Fixtures/Equipment X
Class 100 (ISO 5)
Floors X
Ceilings X
Walls X
Fixtures/Equipment X
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 Cleaning SOP development

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 Hoods, Cabinets and Benches

Clean and Disinfect prior to and after use

Spray with cleaner, then wipe: top to bottom

and back to front, include all sides and
work surface

Take care not to wet filter media

Following cleaning, disinfect with a sporicidal

agent

Spray work surface and sides and keep wet for

validated contact time

Following sporicide, wipe down with 70% IPA

and dry wipe to remove residues Note: Cleaning frequency depends on the
process. Normally only disinfection is needed.

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Non-Product Contact Surfaces
Precautions:
If in close proximity to product contact surfaces

− Eliminate residues
carefully
− Inadvertent transfer to
product contact
surface
− Residues are possible
source of
contamination
Note: Disinfectants that leave no residual should be employed OR use a rinse step with IPA/WFI
after disinfectant application for critical, near product contact parts.
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Non-Structural Cleanroom Surfaces
Routine:
• Tanks, Carts, Racks, Bins, Stairs, Tubing/Pipes (Exterior), Monitors, Samplers, Tools
Hard to Clean:
• Tops of doors, Tracks, Conveyors, Phones, Underside of tanks/carts, Wheels
Frequency: Dependent upon classification and process

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Tools
Procedure dependent upon where tool is used

− Consider whether materials

can withstand disinfection or
sterilization
− Electronics, materials, or
gaskets
− Sterilize if you can
− Otherwise, clean, disinfect,
wipe with alcohol

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 Drains
Do not place drains in Grade A or B
areas
• Limit to Grade C and D
Cap drains if possible
Routine interior disinfection
difficult
• Cannot assure wetting of all
surfaces
• Biofilm prevents penetration, and
returns quickly
Disinfect exterior with sporicide
(bleach, hydrogen
peroxide/peracetic acid)

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 PDA TR # 70: Drain Cleaning

“Drains will most probably incorporate a biofilm on

the inside of the drain that would prevent
penetration of the disinfecting agent through the
biofilm and from contacting the drain surface.
Disinfecting the exterior of the drain’s visible surface
with sodium hypochlorite or peracetic acid and
hydrogen peroxide may reduce bioburden, but such
bioburden is expected to return within a short time
period.”
- PDA TR #70.

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 Disinfectant Rotation & Rinsing

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 Cleaning and Disinfection:
Rotation
• Alternation of antimicrobial actives
– Two disinfectants in sequence, regular rotation, with sporicidal agent
as needed
– One disinfectant daily, with sporicidal weekly or monthly

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 Cleaning and Disinfection: Rotation

• USP 41 <1072> Disinfectants and

Antiseptics
– “The development of microbial resistance to
antibiotics is a well-described phenomenon. The
development of microbial resistance to
disinfectants is less likely to occur at
significant levels, as disinfectants are more
powerful biocidal agents than antibiotics.”

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 Disinfectant Rotation: ANVISA

Article 315
Item1: ”these areas should be cleaned and
sanitized frequently in accordance with a
specific program approves by Quality
Assurance.”
Item 2 says “the areas should be monitored
regularly to detect the emergence of
resistance microorganisms”.

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 Cleaning and Disinfection:
Disinfectant Rotation

“Where disinfectants are used, more than one type should be

employed. Monitoring should be undertaken regularly in order to
detect the development of resistant strains.”

MHRA - Rules and Guidance for Pharmaceutical Manufacturers

and Distributors. (2018 Draft Doc.)

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 Cleaning and Disinfection: Rotation

• Martinez, JE. The rotation of disinfectants

principle: true or false? Pharmaceutical
Technology (2009), p 69
– “Rotation of a common disinfectant and a
sporicidal helps ensure that bacterial spores do
not take hold in manufacturing and aseptic areas.
But the rotation of common disinfectants such
as those based on phenol- derivatives, aldehydes,
and oxidizing agents has no scientific basis.”

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Cleaning and Disinfection: Resistance & Rotation

• PDA TR No. 70 2015

“The antimicrobial agents typically employed in
cleanrooms continue to be effective because they
have numerous effects on a number of aspects of
cellular physiology. That means multiple mutations
would be required in a short period of time (ex. 5
minutes) with exposure to low numbers of cells
typically found in a cleanroom to overcome their
detrimental effects. As such, resistance of a cell to
agents used in a disinfection process would be highly
unlikely given the environmental conditions and low
cell number.”

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 Cleaning and Disinfection: Rotation

PDA TR No. 70
“Given this knowledge, the pharmaceutical and
biotechnology industries have moved away from
the rotation of two disinfecting agents. This
formerly common practice led to high residue
levels and subordinate efficacy performance.
Today most firms use a system whereby a
disinfectant is rotated with a sporicide to more
effectively reduce the bioburden levels. The
rotation of a disinfectant with a sporicide is
superior to the use of rotations of multiple
disinfectants.”

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 Cleaning and Disinfection: Rotation
• USP 41 <1072> Disinfectants and Antiseptics
• Annex 1 (Draft 2018) and MHRA Orange Guide (2016)
• FDA Aseptic Processing Guide (2004)
• FDA, MHRA, HPRA, CFDA, ANSM, ANVISA, CFDA, FDAHA, Swissmedic, & EMA
Expectations
• Industry Articles (Ex. Scott Sutton, Jose Martinez, Richard Prince, Rebecca Smith)
• PDA Cleaning and Disinfection TR #70 (2015)
• PDA TR #69 on Biofilms (2015)
• The CDC Handbook - A Guide to Cleaning & Disinfecting Cleanrooms (Tim Sandle 2018)
• A Guide to Disinfectants and their use in the Pharmaceutical Industry (Pharmig 2017)
• USP 41 <1116> Microbiological Control and Monitoring of Aseptic Processing Environments
• PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare
Establishments (2014)
• WHO Annex 6
• PHSS Technical Monograph #20 “Bio-contamination characterization, control, monitoring and
deviation management in controlled/GMP classified areas

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 Cleaning and Disinfection: Rinsing
Do I need to rinse?
483 observations
(2013)
– Your firm does not always keep
laminar flow hoods visually clean of
residue on HEPA filter surfaces and
covering grates……I observed
white and yellow residue on the
HEPA filters…..and in areas up to
approx. eight inches square on the
filter…..
– I observed white particles on the
floor of the clean
room…approximately two to three
millimeters square.
– Recent WL reference:
[Link]
entactions/warningletters/2017/ucm
[Link]
– Dr. Sharon Thoma’s view on
residues
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 Cleaning and Disinfection: Rinsing
• Rinse as needed to control residue
– Appearance
– Functionality – sticky or opaque surfaces
– Product risk
– Interaction/interference with other chemical agents
being used
– Safety issue (stickiness, tackiness, slippery)
• Rinse agents
– Alcohols or Water
– Cleaners: Acidic, Basic or Neutral (low
concentrations)
– Periodic rinsing based on aesthetics and safety
• Annex I Draft: Cleaning programs should be
effective in the removal of disinfectant residues.

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 This is a
problem?
Why? We
clean the
door all the
time…

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 Surface Types and Topography

-Sticky mats
-Drains
-Edges and corners

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 Surface Conditions Effect Performance

Courtesy Bruce Ritts

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 PDA TR # 70: Conducting Investigations related
to Cleaning and Disinfection

Common Causes:
– Application issues
– Dilution issues
– Insufficient contact times
– Expired product
– Incorrect biocide for cleanroom bioburden
– Lack of adherence to protocols
– Equipment issues (rusting and pitting)
– Using inadequate cleanroom tools

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 Questions?

jim_polarine@[Link]
Cell: (314) 616-9931
Office: (314) 290-4793

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