cleaning validation seminar surabaya , 20 august 2015...that this document can stand alone as a...

DOCUMENTATION

CLEANING VALIDATION SEMINARSurabaya , 20 August 2015

Sayekti Sayekti SulisdiartoISPE Indonesia Affiliate

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FITHRUL FARMASIINDUSTRI.COM

FARMASIINDUSTRI.COM

OUTLINE

Documentation

SOP’s-Cleaning Process

- Cleaning Validation

Protocol Cleaning Validation

Report Cleaning Validation

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FARMASIINDUSTRI.COM

Cleaning ProcessStandard Operation Procedure

• 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 consists of :


Cleaning ProcessSOP’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 / Covering / Storage

• Materials, Handling, Location

• Post-Cleaning Documentation

• Re-Tagging, Cleaning & Use Log

• Equipment Expiration

• Dating Requirements, Re-Cleaning Requirements

• Pre-Use Inspection

• Verification of Expiration, Integrity of Wraps / Covers

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Cleaning ProcessSOP 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 ProcessRecords 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 ProcessSpecial 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 ProcessChallenges 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 /

forms8


Cleaning ProcessTips 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 ValidationCleaning validation SOP -1

• Defining on how cleaning process will be validated

• General SOP’s shoud be prepared / developed

Cleaning Validation SOP’s

• Responsible person who performed and approved the validation study

• Acceptance criteria• Revalidation timing

SOP’s should address

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Cleaning ValidationCleaning validation SOP -2

• Equipment Characterization ( New and Existing)

• Standard Operating Procedure Development for Cleaning

• Developing and Maintaining Limits Calculations

• Cleaning Validation Analytical Methods : Validation and Recovery Studies

• Engineering Studies / Cycle Development • Developing Cleaning Validation Protocols

and Reports• Collecting and Testing Cleaning Validation

Samples

Possible topics to

incude( in a single or

several different SOP’s)

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Cleaning Validation ProtocolsWriting 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 ProtocolsWriting Protocols-2


• 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.)13


Cleaning Validation ProtocolsWriting Protocols -3


• 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 toChallenge 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 ConditionsShould Be considered ?

Worst-Case RationaleHold times before cleaning Residues may dry on surfaces or, if

hygroscopic may pick up moisture

Personnel / Shifts May provide representative data with regard to person-to-person or shift-to-shift robustness

Process parameters Reducing process parameters (eg. 5 minutes less wash time) will ensure that full parameter is always successful

Starting soil conditions such as maximum campaign length and/or maximum batch size

Will ensure that any condition that is less severe in terms of soil load will be successful

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Cleaning Validation ProtocolsTypical 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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• 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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• 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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• 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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• 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

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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 uncontrolled areas and back again 25


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 datacollected 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 Protocol– Objective– Scope– Reference inclusive SOP– Responsibility– Material and method– Procedure– Acceptance criteria:

training, deviation, batch, …..

– Work sheet/equipment: cleaning procedure, raw data record, sampling, analytical procedure, etc.

• Cleaning Validation Report– Introduction– Summary: method– Results: table– Conclusion– Recommendation– Appendices: analytical raw

data, chromatogram, 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 YouTerima Kasih

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