A Risk Based Cleaning

and Disinfection Program

 Topics Covered 2

❖ Regulatory Requirements

❖ Cleanroom Bioburden Control

❖ Cleaning and Disinfecting Technologies

❖ Cleaning and Disinfection Techniques

❖ Rotation and Residues

2
 3

Regulations and Guidance Documents

 Recent FDA 483 4

“C) On 06/08/2020, I observed visible black and brown stains on the ISO 5
Cleanroom ceiling tile stationed directly adjacent to the right of Table 2,
direct compounding area (DCA), within Cleanroom”
6/15/2020

https://www.fda.gov/media/140568/download

4
 Recent FDA 483 5

“Cleaning agents used to disinfect, clean, sanitize equipment, and or

production areas of non-sterile product are not suitable for use. I
observed your firm using expired sterile disinfectants to clean and
sanitize.”
FDA 483 2/26/2020

https://www.fda.gov/media/136443/download

5
 6

Cleanroom Bioburden Control

A Risk Based Contamination Control Strategy 7

Facility

Equipment Materials

Utilities Personnel

Process
 Review - Microflora in Cleanrooms 8

• 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
Review - Microflora in Cleanrooms (U.K.) 9
Aspergillus Spores 10
 Cleanroom Fungi 11

Courtesy Dan Klein

Aspergillus Spores 12

Courtesy Bruce Ritts

 13

Technologies
Cleaning and Disinfection: Product Selection 14

• EPA Classifications
– Sanitizer
– Disinfectant
– Sterilizer (Sporicide)
 Cleaning and Disinfection: Product Selection 15

• Sanitizer
– Proper use results in bacteria reduction of >99.9%
– 3-Log reduction Non-Food Contact Surfaces
– 5-Log reduction Food Contact Surfaces
EPA Classifications
– Used on precleaned surfaces unless tested with serum load
Cleaning and Disinfection: Product Selection 16

• Disinfectant
– Proper use results in 100% kill of vegetative bacteria,
target viruses and target fungi
– https://www.epa.gov/test-guidelines-pesticides-and-
toxic-substances/series-810-product-performance-
test-guidelines
– 4 Log reduction bacteria
– 3 Log reduction viruses
– May or may not require pre-cleaning
• Serum efficacy - 5% BSA and EN methods differ example:
“clean” and “dirty” as a soil load
Cleaning and Disinfection: Product Selection 17

• Sterilant
– Proper use results in 100% kill of all microorganisms, including
bacterial endospores (B. subtilis, C. sporogenes)
– 6 Log reduction
– Always requires pre-cleaning
• Water quality is important
18
Disinfectant Components 19

Component Function in Disinfectant

Water Solvent
Antimicrobial Kill, reduce microbes
Oxidants Oxidize, kill microbes
Tie up calcium, iron, stabilize oxidants, potentiates antimicrobial
Chelants action (ex. EDTA, Citric Acid)

Solvents Solubilization and stabilization of formula

Bases Alkalinity source, hydrolysis (KOH)
Acids Acidity source, hydrolysis (H3PO4)
Surfactants Emulsification, Wetting
Effect of Surfactants 20

• Influence of Surfactants on Wetting

– Ability to displace particles

– Penetrate soil and surface irregularities
– Better contact

No Surfactant A Surfactant B
Surfactants
Wetting Surface Tension and Penetration 21

Disinfectant with no surfactant

Disinfectant with surfactant

Microorganism or Soil

Good coverage
with
Surfactant

Substrate
Chemical types 22

• 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®
Sporicidal Efficacy 23
 Pass Thru Decon 24

• Challenges
− Efficacy
− Wet Contact Time
− Full Contiguous Coverage
− Delegated Task
− Complex Surfaces
− Technique Dependent
− Sporicidal Wipes
 25

Technology Selection
Disinfectants are a Balance 26

Safety Rinsability

Compatibility
Stability

Efficacy
Sporicidal Application Frequency 27

Should be
Sporicidal
written in
agent
SOP’s

Fungal and
Extraordinary
Rationale Bacterial Spore
Cleaning
Outbreaks

Weekly Monthly Quarterly

Grade D (ISO 8 at rest) 28
 29
Grade C (ISO 7 at rest, ISO 8 in operation)
Grade A (ISO 4.8) or B (ISO 5 at rest, ISO 7 in operation 30
Cleaning SOP Development 31
 32

Cleaning and Disinfection Application Methods

Application Techniques 33

• 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-CC018.5
• Grid (Blueprint of the Room)
• Pull and lift
• Overlapping strokes (by 20% or 2 inches)
• Figure 8 (String Mop) or Unidirectional overlapping
mopping strokes
• Modified Figure 8 with Flat Head Mops for Walls
* 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.
Application Techniques 34

•http://www.pppmag.com/article/714/June_2010/Cleaning_Practices_for_Cleanroom_Contamination_Control/
Two Bucket System & Three Bucket System 35

• Two Bucket
– Mop is placed in Bucket 2 (Rinse Bucket)
– Wring it Out
– Mop is placed in Bucket 1 (Clean or Primary Bucket)
– Wring it Out
– Apply to the floor
• Triple Bucket
• Mop in Bucket 2 (Rinse Bucket)
• Next Bucket 3 Ring Out Bucket
• Next Bucket 1 (Clean Bucket)
• Next Bucket 3 Ring Out Bucket
• Mop the Floor
• (Mop Rides in Bucket 2)
– 8-16 feet covered in mopping passes 1 and 2
 36
Mopping Technologies

• 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.
Cell & Gene Therapy: Hoods, Cabinets and Benches 37

• 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 Note: Cleaning frequency depends on the
70% IPA and dry wipe to remove process. Normally only disinfection is
residues needed.

37
 Tools 38

• 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

38
 39

Disinfectant Rotation & Rinsing Programs

Cleaning and Disinfection: Rotation 40

• Alternation of antimicrobial actives

– Two disinfectants in sequence, regular rotation, with sporicidal agent
as needed
– One disinfectant daily, with sporicidal weekly or monthly
 Japanese Pharmacopoeia 41

“A disinfectant program for when a microorganisms

that are resistant to a using disinfectant are
discovered. In which a disinfectant with different
efficacy is used until those microorganisms are no
longer detected or disinfectants with different
mechanisms of action are alternately used for
certain periods of time in turn. The effectiveness of
this method should be evaluated before its
implemented”
Disinfectant Rotation: Chinese Pharmacopoeia 42
 Draft Annex 1 v12 (2020) 43

520 4.36 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected 521
thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to
522 remove surface contamination should be performed. More than one type of disinfecting agent should
523 be employed to ensure that where they have different modes of action and their combined usage is
524 effective against all bacteria and fungi. Disinfection should include the periodic use of a sporicidal
525 agent. Monitoring should be undertaken regularly in order to assess the effectiveness of the
526 disinfection program and to detect changes in types of microbial flora (e.g. organisms resistant to the
527 disinfection regime currently in use). Cleaning programs should effectively remove disinfectant
528 residues.

Prior Cleaning Rotation Residue

Rotation
KEY ISSUES Is Sporicide a Is it only from
Is it necessary? Disinfecting Agent? disinfectants?

Copyright © 2020 STERIS. All Rights Reserved.

43
Cleaning and Disinfection: Rotation 44

• 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.”
Recent Rotation Article 45

“Regardless of the terminology, there is a regulatory expectation to establish an

adequate system for cleaning and disinfection in order to keep microbial
contamination under control. The use of an effective disinfectant with a periodic
shock to the environment with a sporicide is considered superior and is
encouraged over the rotation of multiple disinfectants. In my opinion, until the
industry coins a better term than “rotation” for the current standard industry
practice, the confusion over disinfectant rotation may continue. So, when
regulators ask if you rotate your disinfectants, skip the “yes-or-no” debate. Clearly
explain your cleaning and disinfection program, and then demonstrate through
data how your program is effective in microbial contamination control.”
Pharmaceutical Online, Crystal Booth, 9/14/18.
https://www.pharmaceuticalonline.com/doc/should-you-rotate-disinfectants-
industry-experts-weigh-in-0001
PDA Expert Panel October (2019) 46

• Conclusions
– Resistance does not occur in cleanrooms
– A sporicide must be part of the rotation
– One or two disinfectants are acceptable
Sources of Residue 47
PDA Technical Report #70 48

7.1.1 Types of Clean Room Disinfecting Agents

“Disinfectants…characteristically leave residues… [that] should be removed
via IPA wipe-down.”
9.2 Application Methods “The use of a mopping system for either walls or floors
removes residues…Wiping, as with mopping, cleans the surface of
residues…”
9.0 Cleaning and Disinfection “Cleaning is a critical step… because of the
buildup of antimicrobial chemical agent residues, product residues,
particulates, and other contaminants can inhibit an antimicrobial chemical
agent’s efficacy.” Visually Clean Residue
Physical Removal
Rotation
48

KEY ISSUES Is periodic Do mopping and Is it only from

rinsing wiping prevent disinfectants?
necessary? residue buildup?
Our Recommendation 49

Process changes, if required, should be risk based and data driven based
on current best practices
• Pre-cleaning – None, unless there is excessive soil
• Disinfectant – Should be able to handle some soil and have broad
spectrum efficacy
• Sporicide – Based on Environmental Monitoring data
– Different chemistry which provides your basis for rotation

• Rinsing – Goal is Visually Clean

– WFI or Alcohol on a routine basis, based on experience or risk assessment
– Cleaners can be used for buildup or after shutdowns
Industry References 50

• USP 43 <1072> Disinfectants and Antiseptics

• Draft Annex 1 v. 12 (Draft 2020) and MHRA Orange Guide (2017)
• FDA Aseptic Processing Guide (2004)
• FDA, MHRA, HPRA, CFDA, ANSM, ANVISA, FDAHA, ANMAT, Swissmedic, & EMA Expectations
• Industry Articles (Ex. Dr. Scott Sutton, Jose Martinez, Dr. Tim Sandle, Richard Prince, Rebecca Smith,
Jeanne Moldenhauer, Crystal Booth)
• PDA Cleaning and Disinfection TR No. 70 (October, 2015)
• PDA TR No. 69 on Biofilms (2015)
• The CDC Handbook - A Guide to Cleaning & Disinfecting Cleanrooms (Dr. Tim Sandle 2016)
• A Guide to Disinfectants and their use in the Pharmaceutical Industry (Pharmig 2017)
• USP 43 <1116> Microbiological Control and Monitoring of Aseptic Processing Environments
• USP 43 <1115> Bioburden Control of Non-Sterile Drug Substances and Products
• PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments
(2014)
• WHO Annex 6
• PIC/S
• Japanese and Chinese Pharmacopoeias
• PHSS Technical Monograph #20 “Bio-contamination characterization, control, monitoring and
deviation management in controlled/GMP classified areas
• IEST-RP-CC018.5 Cleanroom Housekeeping: Operating & Monitoring Procedures (2020)
Summary Slide 51

✓Regulatory Requirements

✓Cleanroom Bioburden Control

✓Cleaning and Disinfecting Technologies

✓Cleaning and Disinfection Techniques

✓Rotation and Residues

Speaker Contact Information 52

Jim Polarine
• Senior Technical Service Manager
• STERIS Corporation | Life Sciences
• Mobile: 314-616-9931
• E-Mail: Jim_Polarine@steris.com
• Web: www.sterislifesciences.com

STERIS Technical Services