DOCUMENTATION

CLEANING VALIDATION SEMINAR

Surabaya , 20 August 2015

Sayekti Sayekti Sulisdiarto

ISPE Indonesia Affiliate

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 OUTLINE

Documentation

SOP’s
-Cleaning Protocol Report
Process Cleaning Cleaning
- Cleaning Validation Validation
Validation

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 Cleaning Process
Standard Operation Procedure
Cleaning Process SOP consists of :
• Materials List with part numbers and descriptions ( tools , cleaning
agents )
• Responsibilities List on the step of :
– Preparation
– Cleaning
– Inspection
• Procedures
– Specific for each or categories of equipment
– Step-wise and sequenced
– Concise, clearly written in simple language, yet detailed
– Include T.A.C.T. (Time, Action, Concentration/Chemistry, Temperature)
– Reference distinct measures or metrics to determine achievement of
T.A.C.T. parameters
– Include documentation requirements
– Include diagrams for clarity

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 Cleaning Process
SOP’s should include
• Preparation • Preparation of area, tools & cleaning agent
• Documentation • Status Tags, Checklists , Cleaning & Use Log
• Disassembly • Exploded diagrams or digital photos
• Cleaning • Step-Wise, Tools, TACT, Measures
• Completion • Cleaning of Tools, Baskets, Carts
• Inspection • Methods & Tools, Locations for Inspection
• Drying • Environment / Controls
• Wrapping / • Materials, Handling, Location
Covering /
Storage
• Post-Cleaning • Re-Tagging, Cleaning & Use Log
Documentation
• Equipment • Dating Requirements, Re-Cleaning Requirements
Expiration
• Pre-Use • Verification of Expiration, Integrity of Wraps / Covers
Inspection
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 Cleaning Process
SOP Contents Peculiar to Cleaning
Validation
• Time after use before cleaning
• Maximum interruption within a cleaning process
(such as hold times after a pre-rinse or time before a final rinse)
• Time after cleaning before use
• Cleaning Frequency
(if tied to levels of cleaning such as major clean and minor clean)
• Elements Affecting Cleaning That Would Be Included
in Batch Records or Master Cleaning Policy
• Maximum number of batches and/or days in a
campaign

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 Cleaning Process
Records for cleaning
• Batch Record-Like Format is preferred
• Enables formal review of cleaning procedures
• Enforces consistency between operators
• Enforces sequence of activities
• Captures accomplishment of T.A.C.T. through documented
completion of key steps, including:
– Preparation of cleaning agent
– Disassembly checklist
– Pre-rinse, Wash, Final Rinse
– Drying
– Inspection
– Covering and Storage
– Cleaning and Storage of Tools
• Captures start / stop times and critical process parameter
achievement

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 Cleaning Process
Special Considerations for Sanitization
Procedures
• Cleaning steps must be completed prior to the application of the
sanitant
– Contact time with chemical sanitant is critical
– Method of application may need to be demonstrated to reliably
leave sufficient “liquid” on the surface to effect the sanitization
– Expiration dates for formulated sanitizers are particularly
important
• Aseptic techniques should be taught and practiced
• Other validation considerations:
– Sanitant efficacy must be demonstrated in the presence of
known residues from processing or cleaning at the levels that
are typically present after an effective cleaning procedure;
ensure the cleaning agent residues don’t inactivate the
sanitant
– Re-use of a sanitizing solution must be validated as they often 7
 Cleaning Process
Challenges in Creating Effective SOPs
• Too tight vs Too loose control limits
– Excessive investigations
– Limited reproducibility
• Too much vs Too little detail
– Using clockwise 50cm circular motions and the amount of
pressure that it takes to see if a pineapple is ripe, wipe the white,
lint-free wipe 25 times then reverse to a counter-clockwise
motion in the same position for an additional 25 circles. When
complete, move 50cm to the left, repeat, it will take 125 - 50cm
circles to clean the full circumference at the top level, when the
full circumference has been wiped in this manner, move down
50cm and repeat for the next row …
– Rinse, wash, rinse
• Defining scope and applicability of SOP
• Determining extent of cross-referencing vs including documents /
forms 8
 Cleaning Process
Tips for Evaluating Existing SOPs

• Observe process
• Review the actual cleaning performed against the SOP
• Are all tools / steps identified ?
• Ensure critical process control steps have a measurable or
observable parameter
• Consider how the parameter is assured – is documentation the
answer?
• Observe several different operators performing the cleaning tasks -
look for variability in current practices
• Revise the SOP to reflect current practices
• Retrain all operators accordingly

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 Cleaning Validation
Cleaning validation SOP -1

• Defining on how cleaning process

Cleaning will be validated
Validation SOP’s • General SOP’s shoud be prepared /
developed

• Responsible person who performed

SOP’s should and approved the validation study
address • Acceptance criteria
• Revalidation timing

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 Cleaning Validation
Cleaning validation SOP -2

• Equipment Characterization ( New and

Existing)
Possible • Standard Operating Procedure Development
topics to for Cleaning
• Developing and Maintaining Limits
incude Calculations
( in a single or • Cleaning Validation Analytical Methods :
Validation and Recovery Studies
several • Engineering Studies / Cycle Development
different • Developing Cleaning Validation Protocols
and Reports
SOP’s) • Collecting and Testing Cleaning Validation
Samples

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 Cleaning Validation Protocols
Writing Protocols -1
Understand Your Objectives

• Focussing your decisions to this point:

– What equipment is the subject of your study and what
boundaries will be observed?
– What residues will you be assessing? Can you assess them in
a single trial or will multiple trials be required?
• Active / Excipient
• Micro
• Particulate
– What groupings / bracketings of equipment / products have
been created and which will be used as part of the validation
rationale?
– What analytical methods / sampling methods will be in use?
Make sure you identify them clearly for each analyte along
with the procedure(s) to be followed
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 Cleaning Validation Protocols
Writing Protocols-2
Understand Your Objectives

• Focussing your decisions to this point:

– What locations on the equipment will be sampled? Do you have
your sampling map prepared?
– What is the maximum time after use before cleaning? Will the
maximum be explored?
– What are your limits? Do you have a clear list of all calculations
that need to be included for the interpretation of your results?
– What documentation of cleaning will be included as part of the
validation record?
– Will your study include an equipment expiration study or will that
be a separate study?
• What is the time after cleaning before next use?
• What are the conditions of storage? (covers, environment,
etc.)
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 Cleaning Validation Protocols
Writing Protocols -3
Understand Your Objectives

• What key parameters will you be studying / observing

(T.A.C.T.)?
– Will you simply be monitoring them or do you intend to
challenge them?
– Will you need to have multiple operators / shifts performing the
cleaning procedures?
– Will you be witnessing the cleaning?
• How will your equipment be soiled?
– Routine production – single batch
– Routine production – campaign (# of days / # of batches)
– Intentional worst-case soiling – is a justification available for
this being worst-case

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 Worst-Case Conditions to
Challenge In Validation Studies

• Worst-case conditions are typically included in validation

• Worst-case conditions can help us assure that our
procedures / process are robust
• By demonstrating robustness, we are including an
inherent safety factor that will help to assure that if we
see minor changes in soil load, or person to person
differences that our process will still be successful

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 What Worst Case Conditions
Should Be considered ?

Worst-Case Rationale
Hold times before cleaning Residues may dry on surfaces or, if
hygroscopic may pick up moisture

Personnel / Shifts May provide representative data with

Process parameters
regard to person-to-person or shift-to-shift
robustness
Reducing process parameters (eg. 5
minutes less wash time) will ensure that
full parameter is always successful

Starting soil conditions such as Will ensure that any condition that is less
maximum campaign length severe in terms of soil load will be
and/or maximum batch size successful

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 Cleaning Validation Protocols
Typical Contents -1
• Scope / Purpose
– define the equipment, procedures, practices to be
challenged; be sure to include references to any
groupings / bracketing of equipment / products that
will also be considered validated based on a
successful outcome
• Responsibilities
– participants in the validation and their roles in the
studies
• Background
– optional section to describe any pre-work leading to
this point; references may be included to cycle
development, prior trials or linked validation studies

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 Cleaning Validation Protocols
Typical Contents -2
• Experimental Design
– this section should define the key decisions and
rationales, such as:
• Equipment design or definition / boundaries
• Soil selection criteria
• Analytical method selection / sampling method
• Sampling site selection
• Worst-case conditions to be challenged (soil load,
hold times, cleaning parameters, etc.)
• Limits to be applied

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 Cleaning Validation Protocols
Typical Contents -3

• References
– Include those documents that support the accomplishment of the
validation, avoid extraneous generic references
– Cleaning SOPs
– Training programs
– Rationales
– IQ / OQ performance of cleaning equipment and automation
– Analytical method / sampling method SOPs
– Analytical method validation summary report
– Recovery study summary report
– Failure Investigation / OOS procedure to be followed

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 Cleaning Validation Protocols
Typical Contents -4

• Validation Procedure
– Details of each data sheet to be executed and
attached to the validation, including all
documentation to be completed and attached
• Acceptance Criteria
– Include limits (or their source) and all calculations
required for the interpretation of results

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 Cleaning Validation Protocols
Typical Contents -5
• Revalidation conditions / parameters
• Monitoring conditions / parameters
• Data sheets for execution
– Common
• Visual Assessment
• Rinse Samples
• Swab Samples
• Deviation Summary
– Optional
• Instrument and Calibration Checklist
• Equipment Boundaries
• Personnel’s Training record
• Analytical Methods Validation / Recovery Studies
• Post-Sampling Activities 1 2
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 Meaning of Consecutive Successful

• Validation guidelines often refer to requirement for “consecutive

successful trials”
• Consecutive successful in these cases means consecutive trials
without intervening failures – it does not mean without intervening
production
• Defend the timing of your cleaning evaluations as part of your
strategy
• When you have a failure, be sure you understand and investigate
whether they are:
– Extrinsic failures – not process related, therefore repeat only the
failed run (e.g., utility breakdown )
– Intrinsic failures – process related, therefore repeat the entire
validation
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 Issues with Campaign Manufacture

• Don’t cut into campaigns to shortcut the time needed

for validation
– Applies to both process validation and cleaning
validation
– If you intend to manufacture a 6 batch campaign,
make sure that a 6 batch campaign is what you
validate in your cleaning validation study

• Validation should reflect real life. Consider collecting

data later as part of the life cycle under monitoring
programs.

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 Storage of Clean Equipment

• Equipment should be stored dry and covered or closed

• Microbial propagation depends on
– Conditions of storage (eg. Temperature and relative
humidity of environment, quality / cleanliness of
covers, degree of cleanliness and dryness of
equipment)
– Location of storage (eg. Clean equipment storage
room, in the room in which cleaning is conducted or in
a production room that is used for other purposes
before equipment reuse)
– Genus and species of contamination
– Starting population
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 Storage of Clean Equipment
• Clean Equipment storage areas must be designed
appropriately – location and room pressure/ air flow
patterns.
• Other precautions include:
– Consider whether reuse of cover material is wise
– Keep equipment away from aerosols or dust
generating activities
– Keep foot traffic in clean equipment storage area to a
minimum
– Ensure that personnel entering to retrieve
equipment have on clean gloves, gowns, booties,
etc.
– Prevent relocation from clean manufacturing to
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uncontrolled areas and back again
 Storage Time for Equipment
• Residues to consider include:
– Particulate (eg environmental dust)
– Bioburden
– Endotoxin
– Product

Could be a problem if :
• equipment stored in the production space
during other processing , or
• when the equipment is stored in same room as
cleaning takes place (dirty equipment is brought
in)
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 Cleaning Validation
Reports

• Approval Page - corresponding signatures to those approving the

protocol pre-implementation
• Purpose / Scope – reiterate the goals and boundaries of the
validation; referencing supported groupings / bracketing may again
be appropriate
• Background – reiterate any pertinent relational information with
regard to other studies
• Description – provide sufficient description of the system to ensure
that this document can stand alone as a summary to the executed
protocol
• Procedures / Test Methods / Equipment – define those elements
used to execute the protocol – remember that these now represent
the validated operational / process state

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 Cleaning Validation
Reports

• Results - provide a summary of results and state whether acceptance

criteria were met; use tables and graphs to present data effectively;
reference deviations that occurred and point to the deviation section;
provide evidence of how the acceptance criteria were met
• Deviations – list the deviations and their resolutions, state the impact
to the validation and/or to follow-on production, if any
• Revalidation – state the conditions under which revalidation would be
required (e.g., change in key process parameter, change in cleaning
agent, modification to equipment, formulation, etc.)
• Conclusion – state whether the initial goals of the protocol were met;
reiterate any groupings / bracketing that are supported by the
validation; clearly state any procedure amendments or requirements
as a result of the qualification

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 Review and Approve Reports

• Ensure that all groups agree with the validity of the data
collected and the conclusions reached

• Ensure that all acceptance criteria have been met

• Ensure that all groups agree that the pertinent regulatory

and policy requirements have been met – especially if
there were any failure investigations as a result of OOS
or deviations

• Ensure that all groups understand any directions for

future production / recommendations (e.g., procedures
to be followed for cleaning, additional disassembly
procedures, inspectional requirements, etc.)
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 Documentation of Cleaning Validation
Summary
• Cleaning Validation • Cleaning Validation
Protocol Report
– Objective – Introduction
– Scope – Summary: method
– Reference inclusive SOP – Results: table
– Responsibility – Conclusion
– Material and method – Recommendation
– Procedure – Appendices: analytical raw
– Acceptance criteria: data, chromatogram, etc.
training, deviation, batch,
…..
– Work sheet/equipment:
cleaning procedure, raw
data record, sampling,
analytical procedure, etc.

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 Maintenance of the Validated State

Programs that maintain the validated state:

– Preventive Maintenance
– Calibration
– Change Control
– Monitoring
– Revalidation

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 Thank You
Terima Kasih
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