A Risk Based Approach to Cleaning and Disinfection - bcw.be file1/ A Risk Based Approach to Cleaning...

1/

A Risk Based Approach to Cleaning and Disinfection

El Azab Walid Technical Services [email protected]+32479790273

Copyright © 2018 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation

Regulatory requirements 1Design robust cleaning and disinfection procedure2Conclusion3

Content


Definitions used in the draft Annex 1 may not be in line with ISO and pharmacopeia

disinfection sanitization Cleaning DecontaminationSterilization

Sanitization DecontaminationCleaning

▪ Reducing on inanimate surfaces, the number of all forms of microbial life including fungi, and bacteria

▪ Reducing number, activity or potency of unwanted matter (or hazardous material) to an acceptable level by a suitable method using appropriate biological or chemical indicators

▪ Removal from facility and equipment surfaces of product, chemical or organic residues

Sterilization

▪ Process leading to a sterile status

Disinfection

▪ kill microorganism on inanimate surfaces, based on suspension and/ or coupon testing validation.


Japan (JP) Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing (2006)

a. “The program should contain procedures for screening and classifying bacterial isolates in eachmanufacturing environment.”

b. “Cleaning agents and disinfectants should be validated for their appropriateness and reliability inremoving contaminants prior to use. Cleaning and disinfection efficacy should be assessed andconfirmed based on type and count of microorganisms characterized by periodic environmentalmonitoring”

c. “If selected disinfectants might have inferior efficacy against microorganisms isolated from theenvironment, the efficacy should be reevaluated and the replacement with or alternate use ofdifferent disinfectants should be considered and implemented, as appropriate”

d. “If environmental monitoring data indicate or suggest the presence of spore-forming bacteria orfungi, suitable sporicides or fungicides should be selected for disinfection.”


United States Food and Drug Administration (US FDA) guidance on aseptic manufacturing (2004)

a. “…. Routinely used disinfectants should be effective against the normal microbialvegetative flora recovered from the facility.….”

b. “…Therefore, a sound disinfectant program also includes a sporicidal agent, usedaccording to a written schedule and when environmental data suggest the presence ofsporeforming organisms.”

c. “…. If indicated, microorganisms associated with adverse trends can be investigated asto their sensitivity to the disinfectants employed in the cleanroom in which theorganisms were isolated.”


Brazil National Health Surveillance Agency (ANVISA) resolution - RDC n.17 (2010)

a. “Article 315. The sanitation of clean areas is particularly important in themanufacture of sterile products.

§ 1 These areas should be cleaned and sanitized frequently, according to aspecific program approved by Quality Assurance.

§ 2 The areas should be monitored regularly to detect the emergence ofresistant microorganisms.”


European Medicines Agency (EMA) EudraLex Annex 1 (2008) and The Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation (PIC/S) – PE 009-13 Annexes (2017)

a. “61. The sanitation of clean areas is particularly important. They should be cleanedthoroughly in accordance with a written programme. Where disinfectants are used, more thanone type should be employed. Monitoring should be undertaken regularly in order to detectthe development of resistant strains. »


European Medicines Agency (EMA) EudraLex Annex 1 –Draft

One or two step cleaning and disinfection

Rotation program

Removal of disinfectant residue program

On-going verfication

1

2

3

4


The rotation definition should be adequately defined in the cleaning and disinfection procedures.

it one disinfectant alternated with the use of a second disinfectant?

is it one or more than one disinfectant with a sporicidal agent?


Rotation = one disinfectant along with a sporicidal agent

United States Pharmacopeia (USP) <1072>:

“The rotation of an effective disinfectant with a sporicide is encouraged. It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent.”

“Other disinfection rotation schemes may be supported on the basis of a review of the historical environmental monitoring data.”

“…the most frequently isolated microorganisms from an environmental monitoring program may be periodically subjected to use-dilution testing with the agents used in the disinfection program to confirm their susceptibility, as there are real differences among different species in resistance to the lethal effects of different sanitizers.”


Rotation = one disinfectant along with a sporicidal agent

Parenteral Drug Association (PDA) Technical Report (TR) 70:

“Today, most firms use a system whereby a disinfectant is rotated with a sporicide to more effectively reduce the bioburden levels.”

“All rotation systems should be evaluated via the use of area classification, environmental monitoring data, and/or risk assessment.”

12/Copyright © 2017 STERIS Corporations. All Rights Reserved.

Rotation: One or two Disinfectant or another Rotation Approach

Copyright © 2017 STERIS Corporations. All Rights Reserved.

BENCHMARK

Does your company Developed the cleaning & disinfection program based on the environmental monitoring data or

environmental risk based assessment?

Yes, 50%

No, it was decided

based on the regulatory

requirements, 50%

Does your company rotate more than one disinfectant along with a sporicide?

Yes, 67%

No, 33%


Regulatory requirements 1Design robust cleaning and disinfection procedure2Conclusion 3

Content


Cleaning and disinfection program – a lifecycle approach

3. Disinfectant

and sporicide selection

5. Procedure

design 4.

Disinfectant and sporicide

qualification

1. Manufacturing process understanding

6. on-going

verification

2.Microbial Risk Assessment


1. Process understanding

Strategy

03

01

02

Type of process: dry vs wet open vs close non sterile vs sterile

Soil or particles level

Locations

Un-classified area Classified area:

Grade D, C Grade B, A

High residue generation Low residue generation Very low residue generation


Cleaning and disinfection a one or a two-step?

Parameter/Risk classification

Interaction of the residue withthe disinfectant

Amount of residue on the surface of the cleanroom*

Composition of the disinfectant

Technique of application the disinfectant

Environment where the disinfectant is being applied**

3 2 1

YesAbsence of data to support a yes or no

interactionNo

Visually visiblePartially visually

visible Non-visually

visible

Disinfectant with no surfactant

N/ADisinfectant

formulated with a surfactant

No mechanical action:

spraying or vaporization

N/AMechanical

action: Mopping, wiping

Cold room: 2-8°C or less

N/AAmbient

temperature: 15°-25°C

Example

1


Cleaning and disinfection a one or a two-step? Example

1

…

A separate cleaning step is not essential prior to disinfection. Therefore, a one-step cleaning and disinfection procedure is

acceptable

a separate cleaning step is not required prior to disinfection. However, depending environment where the disinfectant is applied (e.g., cold

room) a cleaning step may be beneficial.*

RPN < 5

5 > RPN < 7

RPN >7

* If the disinfectant studies has not been performed with the same environment conditions.** independently the application technique used.

a separate cleaning step is needed prior to disinfection. **


Cleaning and disinfection a one or a two-step? Example

Residue may interact with the disinfectant efficacy?

Two step cleaning and disinfectionprocedure is needed

=Clean before disinfect

How much is the amount of residue on the cleanroom’s surfaces?

No

Yes

High amount of residue

Low to moderate amount of residue*

Does the disinfectant formulation contains surfactant?

Yes

No

Application technique of the disinfectant?

Technique without mechanical action

Technique using a mechanical action

Environment where the disinfectant is applied is at ambient temperature?

Disinfectant qualification has been performed at the temperature of use

(e.g., cold room)

A one step cleaning and disinfectant procedure is justified

Yes

No No

Yes**

1


2. Microbial risk assessment

Evaluation of the quality risk to the product based on the microbial contamination source.

Evaluation of the microbial contamination trend against the cleaning and disinfection program

Based on the residual risk level:

Verification or confirmation of the disinfectant efficacy

Improve the cleaning and disinfection procedure

Through on-going verification:

Confirm efficiency of the cleaning and disinfection program to control environmental bioburden

Confirm regulatory and industry best practices compliance

Identification and trending of microorganisms through the Environmental Monitoring program


Vegetative microorganism

Microorganism EM detected

Spore/fungi microorganism

Log reductionrequired

EU: > 4 logUS: > 3 log

EU: > 3 logUS: > 2 log

Contact time required

Environmental condition (e.g.

temperature, high level of soil)

Contact time could be > 10 min – 15 min

Use a cleanerPrior to disinfection

Contact time could be < 10 min – 15 min

Direct use possible

Material/residues compatibility

Normal rinse strategy

Direct rinse strategy

HSE REACH, BPD, CPL etc… compliant

Wearing appropriate safety gear

Disinfectant: AlcoholsPhenols QUATS

Hydrogen peroxideSodium hypochlorite

Sporicidal agent

3. Disinfectant and sporicide selection: what to take into considerations?


4. Disinfectant and sporicide qualification Non exhaustive list

Disinfectant standard

EU

International

US

EN 1040EN1275EN 1437

CEN216-1991EN

EN 1276EN1650

EN 13704

EN 13713EN13697

Phase 1: suspension testBactericidal and fungicidal and sporicidal test

Phase 2: quantitative testStep 1: suspension test:

BactericidalFungicidalsporicidal

Step 2: hard surface carrier test

Annex 1 & 15Eudralex

ASTMASTM 2614-08

ASTM E2197-11

Guide for disinfectant used in CleanroomSporicide qualification disk

PDA Technical Report 70Industry practice but not fully accept by EU

AOAC AOAC 991:47 Hard surface carrier test method

USP Ph USP 1072

PIC/S PI 006-07

FDA guide Aseptic processingSlide 21


Surface selectionGroup like surfaces and select representatives, e.g.: Based upon criticality to

the process/potential risk to product

Based upon greatest challenge to disinfection (porosity, surface roughness, electrostatic energy, etc.)

Based upon frequency

Isolate selection

Broad spectrumMost frequently occurring isolate Demonstrated decontamination difficulty at the facility Current regulatory focus upon Burkholderia cepaciacomplex, Bacillus cereus, and molds

Qualification study

Regulatory and non-governmental requirements

Disinfectant Expiry Testing Contact time Condition of the study Dilution choice

4. Disinfectant and sporicide qualification


5. Procedure design: the frequency of the cleaning and disinfection based on QRM principle

Step 1: Risk Factor determination

Step 2: Risk Factor determinationDuration

# Pe

ople

Proximity

Ris

k C

lass

Step 3: Design the cleaning and disinfection SOP


5. Procedure design - the frequency of the cleaning and disinfection based on QRM principle:

Grade C area or ISO 8 operation and ISO 7 at rest

Example


5. Procedure Design: Implement in the procedure (SOP) the cleaning and disinfection technique EXAMPLE


5. Procedure Design: Implement in the procedure (SOP) the cleaning and disinfection technique

Most critical areas to least critical areas

Apply disinfectant to wiper or spray on the surface (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)

Pull and lift

Overlapping strokes (by 20%)

Example


5. Procedure design – removal of disinfectant residue:

“ cleaning program should be effective in the removal of the disinfectant agent.” –Annex 1 draft EU GMP

Cleaning Program Rinse Program

Contact Product Non - Contact Product


The rinse program or removal of the disinfectant residueVisual inspection should be enough to assess the frequency of the removal of disinfectant residue:

3

Disinfectant frequency of use

Material construction and compatibility

Appearance of Residue build-up

Interaction with another disinfectant Residue

Factors influencing Disinfectant residue

build up are:

01

02

03

04


6. On-going verification

Effectiveness of a cleaning and disinfection program should be based on:

Microbial risk assessment results

Periodic historical EM data review

Periodic auditing of the practices

Disinfectants qualification and validation

Microbial specifications: clean rooms classification and product types


Inadequate cleaning and disinfection programs – MHRA observations (2015 -2016)

Source: MHRA GMP inspection deficiency data 2016MHRA GMP inspection deficiency data 2015


Inadequate cleaning and disinfection programs – US FDA observations (2017-2018)

Resources: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2018/ucm602078.htm

“Your firm failed to use adequate contact times for sporicidal agents used as part of your disinfection program for the aseptic processing area.”

“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.”

An area of the ceiling spanning across at least two HEPA filters (b)(4) the (b)(4) had dark stains on the ceiling frame and the HEPA filters. Your routine cleaning of the cleanroom does not cover cleaning of the ceiling and HEPA filters which are only replaced when there is damage

Your firm failed to establish and follow an adequate system for cleaning and disinfecting the room and equipment used to control the aseptic conditions

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2018/ucm602078.htm


Inadequate cleaning and disinfection programs – US FDA observations (2018)

Resources: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm622651.htm

“Specifically, municipal tap water, a component of the (b)(4) and (b)(4) cleaning and disinfecting solutions are used on surfaces in the Class 10,000 cleanrooms and Class 100 laminar flow hoods where syringes are aseptically filled with 0.9% Sodium Chloride/heparin solutions. The municipal tap water has been found to be a potential source of microbial contamination through FDA sampling..”

“We also acknowledge your firm’s commitment to validate and establish a revised cleaning program at XX Franklin through a comprehensive risk based review based on: (a) an expanded assessment of the microbiological flora typically found in manufacturing; (b) an evaluation of the disinfectant / (b)(4) to be used for inactivation including concentration effectiveness, and rotational frequencies; and (c) an assessment of procedures that govern when and where the cleaning agents are used, as well as how often these activities are reevaluated.”

“the adequate removal of residues of disinfecting and cleaning solutions in the Class 100 laminar flow hoods has not been validated.” – Product contact equipment

https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm622651.htm


Conclusion – Keep it simple but understand your process

Identify and confirm the parameters or variables

Assess the impact of each variables

Design a procedure taking into consideration the impact of the variables

Monitor the performance of the procedure in place

Review and confirm the effectiveness. Plan for action when needed

Keep it simple =

Understand the process


Thank You

For your listening

El Azab Walid Technical Service Manager – STERIS

[email protected]+32479790273


References • Sutton, S and L Jimenez., A Review of Reported Recalls Involving Microbiological Control 2004-2011 with Emphasis on

FDA Considerations of “Objectionable Organisms”, American Pharmaceutical Review, 15, 42-57, (2012). • Cundell, T. Mold Monitoring and Control in Pharmaceutical Manufacturing Areas. (2016) Am. Pharm. Rev., 19(5).• $18.2 million in settlement over mold at manufacturing facility, access on Jul 1, 2017 at:

http://www.modernhealthcare.com/article/20170112/NEWS/170119945• Smith, J. “Rotational Cleaning-Is It Necessary?” Cleanroom Technology (January 2014)• Martinez, JE “The Rotation of Disinfectant Principle True or False?” Pharmaceutical Technology (2009)• Sutton, S. “Disinfectant Rotation in a Cleaning= Disinfection Program for Clean Rooms and Controlled Environments”

CRC Press Taylor Francis (2007) edited by Gurusamy Manivannan• Sutton, S. “Disinfectant Rotation a Microbiologists View” Cleanrooms, 2005, access on May 25, 2017 at:

https://www.cemag.us/article/2005/07/disinfectant-rotation-microbiologists-view • PDA Technical Report Number 70: Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing

Facilities (2015)• European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1,

Manufacture of Sterile Medicinal Products • United States Pharmacopeia 38 (USP) <1072> – Disinfectants and Antiseptics. The United States Pharmacopeia

Convention/National Formulary, Rockville, MD.• Sartain K.E., Disinfectants rotation, access on Jul 1, 2017 at: https://www.cemag.us/article/2005/03/disinfectant-

rotation• FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-

based drug products, access on May 25, 2017 at: https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

• United States Department of Health and Human Services Food and Drug Administration, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, 2004.

• Regulatory Science of Pharmaceuticals and Medical Devices from Ministry of Health, Labour and Welfare of Japan, Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing, 2006.

• Rogers M. and Polarine J., Rinsing Strategy, access on August 25, 2017 at: http://www.ivtnetwork.com/article/jim-polarine-and-marc-rogers-rinsing-strategy

• Sandle T., a guide to cleaning and disinfecting cleanrooms, 3rd edition, the CDC Handbook, 2012, p.173-180.

Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.


Surface Disinfectants, Cleaners & Alcohols

• Sporicides (Sterilants)– Spor-Klenz® Ready-To-Use

• Phenolic disinfectants– Environ™ LpH– Environ Vesphene™

• Quaternary ammonium disinfectants– Vesta-Syde® SQ

• Alcohols & Cleaners– Septihol® Sterile– Septihol WFI– Septihol Ethyl WFI and others


The goal of cleaning and disinfection program should bebeyond elementary regulatory compliance.

1. The regulatory guidelines are not aligned regarding the number of disinfectants required in conjunction with a sporicidal agent (disinfectant rotation).

2. The USA FDA, JP and ANVISA guidelines expect the manufacturer to justify the number of disinfectants and the rotation based on EM data review.

3. The draft Annex 1 propose that when “More than one type of disinfecting agent should be employed, and should include the periodic use of a sporicidal agent.”

The cleaning and disinfection program should be considered as part of the EM program lifecycle approach.

The number of disinfectants used along with a sporicidal agent should be justified by a formal MRA, periodic EM data review and periodic auditing of the cleaning and disinfection procedures rather than being arbitrarily imposed.

Vs

A Risk Based Approach to Cleaning and Disinfection - bcw.be file1/ A Risk Based Approach to Cleaning...

Documents

Transcript of A Risk Based Approach to Cleaning and Disinfection - bcw.be file1/ A Risk Based Approach to Cleaning...