PREPARING FOR CLEANING VALIDATION · 2019. 4. 6. · size etc. VALIDATION • A CONFIRMATION of an EFFECTIVE and RELIABLE equipment cleaning procedure , • Omitted or reduced analytical

PREPARING FOR CLEANING VALIDATION

CLEANING VALIDATION SEMINARSurabaya , 20 August 2015

Sayekti Sayekti SulisdiartoISPE Indonesia Affiliate 1

FITHRUL FARMASIINDUSTRI.COM

FARMASIINDUSTRI.COM

OUTLINE

• Why cleaning validation• Cleaning validation

• Definition• Objectives• Cleaning procedure• General requirements

• Preparation for Cleaning Validation• Master Planning for Cleaning Validation

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References• Pedoman CPOB 2012• PIC/S Guide to Good Manufacturing Practice, (PE-009-11

especially Annex 15 - 2014)• ISPE Risk – Based Manufacture of Pharmaceutical Products

Volume 7 – A Guide to managing Risks Associated with Cross-Contamination (September 2010)

• PIC/S Recommendations on Validation Master Plan, Installation and Operational Qualification, Non Sterile Process Validation and Cleaning Validation (PI-006-3, 2007)

• FDA Validation of Cleaning Processes, Guide to inspections validation of cleaning processes ( 7/93)

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Why Cleaning ValidationPRODUCT CONTAMINATION

Medicinal products can be contaminated by

:

Other medicinal products

Cleaning agents

Micro-organism

Other Material eg.

dust,lubricants, air-borne

particles etc.

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Why Cleaning ValidationPREMISES AND EQUIPMENT

Any building , facilities or equipment used in the manufacture, processing, packing, or holding of a drug product shall be of:

Design and construction

Suitable size :All surfaces can be

readily contacted by cleaning process;

accessed for inspection

Suitable construction:

Coved corners, free-draining, non-reactive,

non-additive, non-absorptive materials of

construction

Suitable location :Location appropriate to

cleaning utilities / supplies; away from

walls or other interfering surfaces

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to facilitate cleaning, maintenance, and proper operations.


Why of Cleaning ValidationBACKGROUND

• When two or more products are to be manufactured in ,• one facility• one room within facility , or • using common equipment

the potential for cross-contamination becomes a significant issue

• Residues from a compound which remain after equipment cleaning or other product contact surfaces may pose a risk topatient safety

• Cleaning procedures should be developed to minimize the risk from residues .

• The cleaning procedure should be capable of reducing residues to or below

predetermined safe level base on the risk assessment of a compound

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Why of Cleaning ValidationCROSS-CONTAMINATION CASE

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Case Root causePesticide contamination -On the API manufacturer :

-Pesticide contamination of API due toin adequate control over solvent drums-No validated cleaning procedure for the drums

- On the finished product facility :- Received some shipment of this contaminated API , resulted in the contamination of FBD’s bag .- Turn led to cross contamination of the lots produced at that site- No adequate validated cleaning procedure for the FBD

Recall of a finished product Cholestyramine Resin USP


Why Cleaning ValidationGMP REQUIREMENTS

Clausul Description

4.24 Equipment and utensils should be cleaned ,stored and where appropriate sanitized or sterilized to prevent contamination or carryover of a material that would alter the quality of product …..

4.25 Where equipment is assigned to continuous production or campaign production of successive batches of the same product and intermediates , equipment should be cleaned at appropriate intervals to prevent buildup and carryover of contaminants ( degradants or objectionable levels of microorganism )

4.26 Non-dedicated equipment should be cleaned between productions of different products to prevent cross-contamination

4.27 Equipment should be identified as to its contents and its cleanliness status ….

4.28 Log books should be kept for major or critical equipment recording ,as appropiriate ,any validation , cleaning including the dates and identity of people who carried these operations out

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Chapter IV : Equipment ( CPOB 2012 )


Why Cleaning ValidationCOMMON CASES……..

• Equipment A• Equipment B• Equipment

CProduct x

• Equipment A• Equipment B• Equipment C

Product y• Equipment

A• Equipment

B• Equipment

CProduct z

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The same equipments may be used for processing different products

To avoid contamination of the following medicinal product, adequate cleaning procedures are essential


Cleaning ValidationDEFINITION

DEFINISI• Tindakan pembuktian

yang didokumentasikan bahwa – prosedur pembersihan

yang disetujui – akan senantiasa

menghasilkan peralatan bersih yang sesuai untuk pengolahan obat

PRINSIP• KETANGGUHAN

PRODUK terhadap– Kontaminasi silang (al.

produk lain, air-borne partikel, debu )

– Kontaminasi mikroba– Kontaminasi deterjen

• Pemakaian ulang peralatan

• Persyaratan _ sesuai CPOB

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Glossarium CPOB 2012


Cleaning ValidationOBJECTIVES

CLEANING• “ Removal ” of contaminants

associated with – Previous products,– Other Material eg.

dust,lubricants, air-borne particles etc.

– Residues of cleaning agents and

The “ Control “ of – potential microbial

contaminants

On the equipment surfaces which contact with the product during production process . taking into consideration batch size, dosing, toxicology , equipment size etc.

VALIDATION• A CONFIRMATION of an

EFFECTIVE and RELIABLE equipment cleaning procedure ,

• Omitted or reduced analytical monitoring in the routine operations

• Provide equipment which is suitable for processing of the following product

• Taking into consideration batch size, dosing, toxicology , equipment size etc.

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Note a risk-based employment


Fundamentals of CleaningCleaning depends upon process parameter control…T imeA ctionC oncentration /

ChemistryT emperature

Cleaning also depends upon the conditions of cleaning…W aterI ndividual Performing Cleaning

N ature of SoilS urface Being Cleaned

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Cleaning ValidationCLEANING PROCEDURE -1

Written procedures (SOPs) of equipment cleaning process are required • For each major equipment :

– Cleaning between different batches of the same product

– Cleaning between product changes – Cleaning for dedicated equipment when it is

difficult to clean or hazardous

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Equipment Categories

Major Equipment -equipment critical to the manufacturing process (usually has a unique identification number)

Minor Equipment -apparatus and utensils (such as scoops, hoses, beakers) which perform a support function

Attributes of Each CategoryGenerally large and significant

contributor to overall contamination

May be dedicated

Generally small but may be used for highly concentrated materials

Not a significant contributor, but we can’t leave them out of our program

May or may not be dedicated

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Cleaning ValidationCLEANING PROCEDURE -2

SOP’s for cleaning of equipment shall be strictly followedand shall :

– Assign responsibility for cleaning – Describe in sufficient details ,

• Schedules• Methods• Equipment• Materials to be Used

To prevent ,• contamination that would alter the identity, strength,

quality, efficacy and/ or safety of the drug product beyond

the official or established requirements15


Cleaning ValidationCLEANING PROCEDURE - 3

In addition to Responsibilities, Schedules, Methods, Equipment, Materials to be used , other details should include:

– Methods of Disassembling and Reassembling to ensure proper cleaning and maintenance

– Instructions for removal or obliteration of previous batch identification

– Instructions for the protection of clean equipment from contamination prior to use

– Inspection of equipment for cleanliness immediately before use

– Establishing the maximum time between the completion of processing and equipment cleaning

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Cleaning ValidationCLEANING PROCEDURE - 4

• Records of cleaning process performed should be kept and the following informations are readily available ;

– the area of equipment cleaned– the persons who carried out the cleaning – when the cleaning was carried out– the SOP defining the cleaning process– the product which was previously processed on the

equipment beeing cleaned– training record and level of experience of the cleaning

operator

• The cleaning records should be ,• signed by the operator who performed the cleaning , • the person who responsible for Production ,and • reviewed by Quality Assurance

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Cleaning ValidationGENERAL REQUIREMENTS -1

• For Cleaning validation process , requiring :– Cleaning validation protocols

• Sampling• Analytical methods• Limits ( “acceptable level” )

– Final report– Approval by management

• IQ / OQ Elements to consider,– Examination of equipment design especially when using CIP– Assure proper identification of process equipment to ensure

correct implementation of cleaning procedures

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• Cleaning validation should confirm effectiveness of cleaning procedures;

• The rationales should be logical for selecting :– Limits for carryover of drug product residue,

cleaning agents and microbial contaminationShould be based on material to be cleaned

• Sufficiently sensitive validated analytical methods should be employed

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• Only cleaning procedure for product contact surfaces of the equipment need to be validated ; although non-product contact parts should be considered , such as • seals, • flanges• mixing shafts• fans of ovens, • heating elements

• Cleaning intervals should be validated for :– Time between use and cleaning ; – Time between cleaning and reuse

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• Worst-case approaches for similar materials / processes may be employed

• Typically three consecutive applications of the cleaning procedure should be performed à shown to be successfull to prove that the procedure is validated

• “Test Until Clean” is not an appropriate substitute for cleaning validation

• Products which simulate the physiochemical properties of the residues may be used where such materials are either toxic or hazardous

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Cleaning ValidationGENERAL REQUIREMENTS - 5

• “In establishing residual limits, it may not be adequateto focus only on the principal reactant since other chemical variations may be more difficult to remove…. the issue of impurities / by-products needs to be considered if equipment is not dedicated.”

• “When cleaning is between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.”

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Should be considered cleaning agent, microbe and areas in which equipment cleaned , stored etc.



• Microbiological aspects of equipment cleaning should be considered; there should be some evidence that routine cleaning and storage of equipment :• does not allow microbial proliferation; • equipment should be dried before storage

• “When variable residue levels are detected following cleaning, one must establish the effectiveness of the process and operator performance.”

• “Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. … Any indirect test method must have been shown to correlate with the condition of the equipment.”

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Cleaning ValidationGENERAL REQUIREMENTS - 7

• Manual cleaning methods should be reassessed at more frequent intervals than Clean-in-place ( CIP) systems

Revalidation • Facilities, systems, equipment and processes,

including cleaning, should be periodically evaluated to confirm that they remain valid; a review with evidence that still meet the prescribed requirements may suffice if no significant changes were made

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Types of CleaningManual CleaningEg. scrub brushes and high pressure hoses used by an operator to remove product residue

• Adaptable to varying soil loads

• Highly dependent upon training

Automated Cleaning(eg. Clean-In-Place) - cleaning

performed by a control system or microprocessor which automatically controls functions of wash, rinse and dry

Attributes of Each Type

Semi-Automated Cleaning(eg. COP – Clean-Out-of-Place) -

performed in a parts washer or sink; often requires manual intervention or disassembly; may be automated

• Often combines strengths and weakness of the above

• May depend upon accurate load placement / disassembly for proper cleaning

• Reproducible if equipment is qualified for use

• Will not recognize variability in the incoming soil condition

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Preparation for cleaning validation General Principle for Validation Approach

Cleaning Validation Required (may use Matrix approach)

Cleaning Validation Required PER

product

Cleaning Validation may not be Required

Cleaning Validation Required (may use Matrix approach)

Decreasing Solubility in Water

Incr

easi

ng T

hera

peut

ics

dos

e /

Toxi

city

(LD

50%

)

Very Soluble Slightly Soluble Practically Insoluble

Low Toxicity

Medium Toxicity

High Toxicity

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Where to start?• Collect the necessary data!

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Gathering Data -1

Data Required Required ForFormulation Attributes (eg. dosage, toxicity, concentration, excipients, degradants, impurities)

Analytical method selectionSampling method selectionLimits determinationWorst-case determination (if grouping / bracketing)Segregation requirements (if hazardous)

Equipment Characterisation (eg. materials of construction, geometry, surface area, cleaning procedure, cleaning agent, disassembly requirements, likely or “critical sites”)

Materials of Construction (MOC) for Recovery Studies Surface Area for Limits DeterminationHard to clean sampling locations or “hot spots”Sampling locations where non-homogeneous contamination is likely or critical sitesWorst-case determination (if grouping / bracketing)Segregation requirements (if highly difficult to clean effectively)

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Gathering Data - 2

Data Required Required ForProcess Attributes (eg. batch size, upstream /downstream, extreme temperatures / holds times, etc.)

Residue selectionLimits determinationSampling location selectionWorst-case determination (if grouping / bracketing)Segregation requirements (if hazardous)

Standard Operating Procedures Process parameters for validationInspection requirementsSampling locationsGrouping / Bracketing (if applicable)

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• Product grouping / bracketing rationale• Equipment grouping / bracketing rationale• Residue selection criteria• Limit selection and calculation rationale• Analytical approach (specific / direct vs. non-specific/ indirect /

screening)• Sampling method selection• Sampling site selection criteria• etc.

Scientific rationales should be documented well , as these will serve as the guideposts for future personnel or auditors navigating your cleaning validation program

Scientific Rationales Will be Needed for …

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Preparation for cleaning validationEVALUATION OF CLEANING PROCESS

Evaluate on :• How the residues cleaned ?

– Eg : disolving , physically , reduce surface tension • What are the cleaning agents ?

– Water (+ Surfactant/Acid / Base)– Organic solvent

• Cleaning method– Manual , semi-otomatic or fully automatic CIP ( Clean-in-place)

• Critical cleaning parameter– Temperature , action, cleaning agent concentration , time

• Cleaning process condition – Water quality– Personnel who performed the cleaning process – Nature of soil– Surface to be cleaned ( MOC)

GOAL APPROPRIATE CLEANING PROCESS TO BE VALIDATED

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Preparation for cleaning validationACCEPTANCE CRITERIA

Scientific Limits Determination• Determine residue limits:

– Sensitivity of analytical methods is critical to establish valid limits– Logical, practical, achievable and verifiable– Scientifically justifiable

• Three examples of limits are given: • as percentage of contamination eg. 10ppm, • associated with the nature of the substance being cleaned (in

other words, its pharmacological properties) , and • organoleptic levels eg. visually clean

• Cleaning Agents - “...no or very low detergent levels remain after cleaning...”

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Preparation for cleaning validationSAMPLING METHOD

• “There are two general types of sampling methods that have been found acceptable. – The most desirable is the direct method of sampling on the

surface of the equipment– Another method is the use of rinse solutions ”

• “The analytical method should be challenge in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc.”

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Preparation for cleaning validationANALYTICAL METHODS

Scientific Design of Analysis• Determine the specificity and sensitivity of the analytical

method(s) used to detect residuals or contaminants– Testing of rinse solutions should include testing for residues

or contaminants rather than for water quality• Challenge analytical methods in combination with the

sampling method(s) to show recovery• Sampling techniques include direct surface sampling

and sampling of rinse solutions.– “Test until clean” systems should not be used. The need for

retesting may indicate that the cleaning process is not validated.

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Master Planning for Cleaning ValidationMaster Plan Approach

• Validation Master Plan incorporates all validation activity– Qualification– Process Validation– Cleaning Validation– Computer Validation– etc

• Separate Master Plans for various topics

In this session we will talking about a Master Plan for Cleaning Validation

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Why Do We need a Master Plan?To Design an Effective Program we need

• Single source for information

• Consistent understanding by all team members

• Assessment of what needs to be done and by whom

• Effective control of strategies to ensure that they are consistent

• Less time spent by regulators in our facility

How the Master Plan addresses the need

• High Level Philosophy• Framework for consistent risk

based decision-making• Overview of actions and

projects, resource planning, scheduling

• Location to consolidate our scientific rationales

• Single source for regulatory review

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What are Typical Master Plan Sections?

1. Introduction Objective and Scope2. Description and Background3. References4. Responsibilities5. Validation Approach

– Strategy and organization– Inventory of qualification activitues to be accomplished

6. Acceptance Criteria ( as appropriate )7. Procedures &Format ( as appropriate )8. Risk / Hazard / Failure Analysis ( or may be in separate document )9. Reference on how to manage change, deviations, continued

verification10. Appendices :

– List of company guidelines (esp for larger companies)– Equipment/Product Matrix– Planning & Scheduling (a high level summary of the actions

needed and when they will be done)37


Master Plan Contents -1

• Introduction Objective and Scope– Goals of the Master Plan and brief content insight as

well as boundaries of the Validation Project and of the Master Plan

– Typical scope boundary elements:• Production areas included as appropriate:

marketed production, clinical trial materials, R&D, laboratories, contract manufacturer / packagers

• Types of Residues / Analysis included: chemical, microbiological

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• Description and Background– Overview and orientation to the facility, process,

technology or project; may include product overviews, as appropriate

– Typical elements:• Program progress to date or significant iterations• Dosage forms, primary manufacturing processes,

significant attributes of products (eg toxic, potent), production characteristics (eg batch, campaign)

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• References– pertinent internal and external documents (maybe in the

appendix)Examples include:

– Scientific rationales, SOPs, risk analyses, literature supporting key rationales or strategies

– Avoid excessive generic references (e.g., GMPs)• Responsibilities

– High level overview of key project participants– Sufficient detail here may supersede the need to

continue to reiterate responsibilities in protocols

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Example ResponsibilitiesDepartment ResponsibilitiesQA / Validation Protocol and Report Preparation

QC Methods Validation

Recovery Studies

Analysis of Samples

Engineering Surface Area Calculations

Materials of Construction IDProduction / Operations Cleaning in accordance with SOPs

Collecting samples

Important : this will be specific to your organisation’s structure, personnel and their experience

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• Validation Approach highlight the key elements of the validation program

• Scientific rationales – the basis for the selection of the validation testing and trade-offs

• Basis for the selection of validation priorities (most likely risk based – e.g., New product introductions, worst-case products, multi-purpose equipment, etc.)

• List of validations to be accomplished or already accomplished in support of the plan (may be in appendix)

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Master Plan Contents-6

• Acceptance Criteria– The acceptance criteria section typically refers to the

way in which the acceptance criteria will be calculated

– If more than one criterion is to be used the document needs to define how the terms will be applied (e.g. lowest, type of product, etc)

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• Procedures and Format– Often outlines the relevant procedures at a high level

and refers to another document for detail (either in the reference section or the appendix)

– Will often stipulate what types of documents need to be prepared and the formats to be followed

– in some cases specific documentation samples or outlines of document headings may be included

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• Risk / Hazard / Failure / Criticality / Impact Analysis– Usually best to reference a separate document to

substantiate scientific rationales , priorities ,trade-offs • Change Control, Deviation Management, Continuous

Verification– Interfaces to other quality system elements, such as

change control, deviation management etc should be provided in the document. The approach to Continuous Verification should also be outlined

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Master Plan Contents- 9

• Appendices Include such items as…– Planning & Scheduling – include or reference a project schedule

for major milestones• If referenced, ensure that a document exists• If included, keep it high level otherwise the master plan

becomes impossible to manage– Equipment/Product Matrix – Other appendices may include

• sample flow diagrams for key processes,• specimen documentation formats,• data tables of key product attributes including product-

specific limits, etc….. – The structure and content of the appendix varies greatly from

company to company46


Managing the Master Plan

• Maintain a Revision HistoryØ It is recommended to spend time on fully capturing the reasons

for change when revising the document• Circulate approved copies of the Validation Project Plan

to all involved departments (especially important for large companies)

• Keep the Master Plan up to date with regard to changes in priorities and scheduleØ Make sure there is clear responsibility for this task

• Place the Master Plan on a periodic review cycle (at least annually) Ø to ensure that scientific rationales and the approach to

validation are kept current ;Ø plan vs actual are kept on schedulle if not justification should

be define

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Summary Reports for Master Plans

• In some cases, where a plan is developed for a specific project such as the commissioning of a new plant, a summary report to the plan means for project closure between commissioning and routine operation

• In other cases, an annual summary report provide a convenient update for management on activities from prior year and providing highlights of goals for next year including:– Demonstrate closure of activities during a

regulatory inspection– Mechanism to discuss/defend project deviations

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Thank YouTerima kasih

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Documents

PREPARING FOR CLEANING VALIDATION · 2019. 4. 6. · size etc. VALIDATION • A CONFIRMATION of an EFFECTIVE and RELIABLE equipment cleaning procedure , • Omitted or reduced analytical