Contamination control in non sterile production
systems
Why do we clean, sanitize and disinfect?
Cleaning Sanitization & Disinfection
 Preventative and Reactive control strategy
 Required by regulations and consumer Quality
 Multiple options and applications
 Integration with manufacturing process
 Safety, Sustainability, Cost and Operational
implications
Regulations
 Similar requirements documented in other countries
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, FDA MHRA, EMHRA, Anvisa etc
Non sterile products - general principles
No specifics
Companies /Sites defined programs
Proven effectiveness
Example Regulations
Example Regulations
 CFR 211.43
 v) A system for cleaning and disinfecting the room and
equipment to produce aseptic conditions;
 (vi) A system for maintaining any equipment used to control
the aseptic conditions.
 CFR 211.56
 Any building used in the manufacture, processing, packing,
or holding of a drug product shall be maintained in a clean
and sanitary condition
Questions that have been asked
Show me where it says I have to clean and
sanitize ?
 How do I validate the C&S of the drains ?
 Can we keep extending the C&S interval?
 Can we sanitize the system without
cleaning it?
 Are you serious ?, visibly clean is
impossible!
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Definitions
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Cleaning - is the removal of product , materials and
other residues from a surface by chemical or mechanical
action
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Sanitize to treat product contact surfaces by a process
that is effective substantially reducing numbers of
undesirable microorganisms, but without adversely
affecting the product or its safety for the consumer
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Sterilization -the statistical destruction and removal
of all living organisms.
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Disinfection clean with a chemical in order to destroy
bacteria .
Scope and Scale of the Program
 Manufacturing Equipment
 Ancillary equipment - hoses, storage
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containers etc.
Tools and utensils
Facilities - walls, floors ,ceilings etc
Utilities - water, compressed air HVAC
Personnel
Scope and Scale of the Program
 Manufacturing Equipment
 Ancillary equipment - hoses, storage containers
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etc.
Tools and utensils
Facilities - walls, floors ,ceilings etc
Water Utilities - Compressed air, HVAC
Personnel
Scope and Scale of the Program
 Cleaning programs will vary by product and
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equipment
Major and minor cleaning programs
Washouts and changeovers
Degree of cleaning may vary due to method of
sanitization
Sanitization process will be relatively constant
Impact of Design
 Equipment has to be designed to be cleaned and
sanitized
 Basic Design principles
 1) Inert Materials
 2) Smooth Surfaces
 3) Prevent product/material accumulation
 4) Drainable
 5) Clean in Place
 6) Easy to dismantle
 7) Simple
Case studies of Poor design
Case studies of Poor design
Case studies of Poor design
Case studies of Poor design
Case studies of Poor design
Examples of Poor design
Clean/Sanitize out of place
 Common for ancillary equipment, tools and utensils
 Manual operation - higher risk
 Facility design implications
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Segregated area
Work Flow
Controlled environment
Transport procedures
Validation
 Impact on Hold times
 Storage areas
How do you know the Cleaning and
Sanitization is effective
What needs to be validated and what
does not?
 Definition of cleaning success criteria
 Impact of clean and dirty hold times
on validation
 Validation of C&S Frequency
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What will you validate?
• Product contact manufacturing
equipment
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Cleaning procedures
Sanitization procedures
Recovery Studies
Hold times
Utility systems – Water ,
• Operating procedures
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What will you not Validate
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Environmental monitoring programs
• Area and facility cleaning and disinfection
• Personal cleaning and disinfection
• Intermittent cleaning procedures
If you can’t validate
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Risk assessment of process and impact
Ongoing verification of performance
Performance documentation and
records
Proven Training and Qualification
Compendia or standard methods
Disinfection
Part of regular cleaning program
 Preventative measures designed to reduce
contamination risk
 No validation
 Utilize published data to support
effectiveness
 Procedure and records for application
 Training, qualification of monitoring people
 Need for cultural understanding of risks
 Change control
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Disinfection
Can be a key control step for environmental
control.
 Frequency of application based on risk
assessment.
 Data from OOS investigations and EM
programs.
 Rotation of agents.
 Residual/persistent effects
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Cleaning Validation
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Cleaning ValidationMistakenly left to the microbiologists
Cleaning is chemistry
Visually clean – basic
Three key requirements
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Regulatory and safety limits
Aesthetic and performance limits
Impact on equipment and sanitization limits
Risk based assessment –supported by data
• Time, cost and sustainability may be supplementary
factors in choice of cleaning methods
• Criteria do not change
Sanitization validation
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Linked to effectiveness of cleaning validation
Scientific basis for process
Limitations of assessment methods
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Representative sites versus system assessment
Recovery studies
Damaged organisms
Growth Method
Re-sanitization after validation
• Criteria measured at end of defined process – no
scope for optimization
Validation or verification
 Most validation is measurement of final conditions
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achieved
Usually do not do broth runs
Zeros tell you nothing
Have to have a scientific basis for why we expect kill
Majority of systems we are simply verifying
Equipment in a suitable sanitary condition
Alternative approach to validation
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Lab based data showing kill rates
Establish D&Z values for common organisms
Defined conditions
Monitor and document conditions predict log
kill
Optimize process for operations
Routine and recovery sanitization
How can you validate the
frequency of sanitization ?
Frequency of Sanitization
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Can this be validated ?
Sanitization is pro-active
Large number of variables impact on frequency
Not all controllable
Periodic testing of limited value
Proven Effectiveness over time may be better
Validation or extension of frequency ??
Hold times
 Dirty Hold time - time between end of process and
start of cleaning
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Product/material dependent
 Clean Hold time - time between completion of
cleaning process and start of sanitization
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Storage conditions
Final equipment condition – wet/dry
 Sanitized hold times – time between completion of
sanitization and the start of use of the equipment
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Environmental conditions
Clock start
Hold times
 Impact on Operations
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Requirements for facility design
Validation criteria
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Dirty hold time - chemistry
Clean hold time - environment
Sanitized hold time - maintenance of sanitized standard
 Technical rationale for validation basis
 Often missed as part of MDM control
Integration of CSD strategies
 Opportunity to develop technical rationales for
optimizing cleaning, sanitization disinfection.
 Procedures & Frequencies
 Major and minor cleaning
 Risk based approach linked to
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Design of equipment
Design of facility
Environmental control - HVAC etc ,
Validation data
Product categories
MDM data
New Projects
 CSD strategies often considered at end of projects
 Loose opportunities for integration
 Equipment and facility choices could give addition
flexibility to operations
 Increase capacity
 Potential to reduce costs
Summary
 Cleaning Sanitization and Disinfection are
 Sole preventative systems for micro control
 Often ignored as an improvement opportunity
 Not integrated into operational design or control
 Validation can provide key data to define strategy
 Facility disinfection programs are under utilized as a
control methodology
 Training and awareness is key
Questions