cleaning and computerized validation
TRANSCRIPT
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CLEANING VALIDATION
The principlesThe principlesThe principlesThe principles and approaches to cleaningand approaches to cleaningand approaches to cleaningand approaches to cleaning validation :validation :validation :validation :
Protocols and reports
Personnel and equipment
Use of detergents
Microbiology
Sampling
Analytical methods and
Acceptable limits
CLEANING VALIDATION
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FDA 21 CFR 211.67 (a)
Equipment and utensils shall be cleaned, maintained, andsanitized at appropr iate inter vals to pr event malfunctio ns orc on tam inat io n t hat w ould a lte r t he s afe ty, id enti ty, s tr eng th ,qua lit y, o r p ur ity o f t he dr ug pr oduc t bey ond t he o ffi cia l or o therestablished requirements.
WHO, Annex 4, 4.11
It is of crit ical impor tance that par ticular attention is paid to
the val idat io n o f a naly tic al tes t meth ods , automated s ys te ms
and cleaning procedures.
CLEANING VALIDATION
GMP REQUIREMENTS
The objectives of GMP include prevention of possible
contamination and cross-contamination
Pharmaceutical products can be contaminated by a
variety of substances
contaminants (e.g. microbes, previous products (both API and
excipient residues), residues of cleaning agents, airborne
materials (e.g. dust and particulate matter), lubricants and
ancillary material, such as disinfectants
also contamination from decomposition residues from product
or detergents
INTROINTROINTROINTRO
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Cleaning procedures must strictly follow carefully
established and validated methods of execution.
This applies equally to the manufacture of
pharmaceutical products and active pharmaceutical
ingredients (APIs).
Validation of cleaning methods provides documented
evidence that an approved cleaning procedure will
provide clean equipment, suitable for its intended use
INTRO
There should be validated written SOPs detailing the
cleaning process for equipment and apparatus.
Cleaning policy and cleaning validation procedure to
cover:
contact surfaces (products, drug products and API);
cleaning after product changeover;
between batches in campaigns (when the same formula is
being manufactured over a period of time and on differentdays;
bracketing products for cleaning validation; and
periodic evaluation and revalidation of the number of batches
manufactured between cleaning validations.
INTRO
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Not necessarily for non-critical cleaning, e.g. between
batches of the same product (or different lots of the same
intermediate in a bulk process), or of floors, walls, the
outside of vessels, and following some intermediate steps.
However, cleaning intervals and methods should be
determined.
At least three consecutive applications of the cleaning
procedure should be performed and shown to be successful
to prove that the method is validated
INTRO
Approved by QC or QA and to cover, e.g.
disassembly of system;
pre-cleaning;
cleaning agent, concentration, solution volume, water quality;
time and temperature;
flow rate, pressure and rinsing;
complexity and design of the equipment;
training of operators; and
size of the system.
CLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLS
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The cleaning validation protocol should include:
objectives, responsible people;
description of the equipment including the make, model, serial
number or other unique code;
time intervals; bioburden; cleaning procedures;
equipment used for routine monitoring (e.g. conductivity
meters, pH meters and total organic carbon analysers);
number of cleaning cycles; sampling procedures (e.g. direct
sampling, rinse sam pl ing, in process monitoring and sam pl ing
locations)
analytical methods;
acceptance criteria (with rationale for setting the specificlimits) including a margin for error and for sampling efficiency;
revalidation requirements.
CLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLS
Cleaning agent used, scientifically justified and based
on:
the solubility of the materials to be removed;
the design and construction of the equipment and surface
materials to be cleaned;
the safety of the cleaning agent;
the ease of removal and detection;
the product characteristics;
the minimum temperature and volume of cleaning agent and
rinse solution; and
the manufacturer's recommendations
CLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLS
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No need for individual validation for very similar cleaning
procedures for products and processes.
Worst case validation study may be acceptable and
should be justified. This study referred as bracketing as
it addressing critical issues relating to the selected
product, equipment or process such as:
smal lest batch si ze, smal lest number of maximum dail y doses,
hardest to clean product
equipment that contribute most to cross contamination of the
next product
Allowed only where products are similar in nature orproperty and processed on the same equipment; and
identical cleaning procedures used.
CLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLSCLEANING VALIDATION PROTOCOLS
Bracketing
Use o f wo rs t ca se (e .g . sma ll es t ba tch si ze, s mall es t nu mb erof m axim um da ily do ses, har des t to c lean ) p ro duc t as a m ark erf or e as ie r o th er p ro du cts
Group ing of products
For ex am ple g roup in g b ase d on; those p rodu cts cap ab le o f cau sing thelargest possible problems if contaminated , or i f they contaminate otherproducts; drug solubil ity and; equipment.
Identification of items of equipment that con tribute most toc ro ss c on ta mi na ti on o f t he n ex t p ro du ct
Iden tif ica tion of wor st ca se lo ca ti ons in equ ip men t , i .e. th ed es ig n o f t he e qu ip me nt s ho ul d b e c ar ef ul ly ex am in ed .
Critical areas (those hardest to clean) should be identified,p ar ti cu la rl y i n l ar g e s ys te ms t ha t e mp lo y s em i- au to ma ti c o r f ul lyautomatic c lean- in -p lace (CIP) systems.
CLEANING VALIDATIONCLEANING VALIDATIONCLEANING VALIDATIONCLEANING VALIDATIONPROTOCOLSPROTOCOLSPROTOCOLSPROTOCOLS
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The relevant cleaning records (sign edsign edsign edsign ed by the operator,by the operator,by the operator,by the operator,
checkedcheckedcheckedchecked by production andby production andby production andby production and reviewedreviewedreviewedreviewed by qualityby qualityby qualityby quality
assurance)assurance)assurance)assurance) and source data (original results)and source data (original results)and source data (original results)and source data (original results) should be
kept.
The results of the cleaning validation should be
presented in cleaning validation reports stating the
outcome and conclusion.outcome and conclusion.outcome and conclusion.outcome and conclusion.
CLEANING VALIDATION REPORTSCLEANING VALIDATION REPORTSCLEANING VALIDATION REPORTSCLEANING VALIDATION REPORTS
Personnel or operators who perform cleaning routinely should
be trained and should be effectively supervised.
CLEANINGCLEANINGCLEANINGCLEANING VALIDATIONVALIDATIONVALIDATIONVALIDATION ---- PERSONNELPERSONNELPERSONNELPERSONNEL
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Only procedures for the cleaning of surfaces of the equipment
that come into contact with product need validation.
non-contact parts of the equipment which product or any
process material may migrate also need to consider
Critical areas should be identified such as large systems
employing semi-automatic or fully automatic clean-in-place
systems
Dedicated equipment for:
products which are diff icul t to cl ean,
equipment which is difficult to clean,
products wi th a high safety ri sk where it is not poss ible to achievethe required cleaning acceptance limits using a validated cleaning
procedure.
CLEANINGCLEANINGCLEANINGCLEANING VALIDATIONVALIDATIONVALIDATIONVALIDATION----EQUIPMENTEQUIPMENTEQUIPMENTEQUIPMENT
There should be one process for cleaning a piece of
equipment or system as it depends on the products
being produced, whether
cleaning occurs between batches of the same product, or
cleaning between batches of different products.
The design of equipment may influence the effectiveness
of the cleaning process.
Consider design when preparing the cleaning validation
protocol
CLEANING VALIDATIONCLEANING VALIDATIONCLEANING VALIDATIONCLEANING VALIDATION----EQUIPMENTEQUIPMENTEQUIPMENTEQUIPMENT
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Released by quality control and meet food standards or
regulations
Composition known
Easily removed with r insing - demonstrated - with
acceptable limits defined
If persistent residues (e.g. cationic detergents) - avoided
Acceptable limits for detergent residues after cleaning
should be defined
Consider also detergent breakdown
CLEANINGCLEANINGCLEANINGCLEANING VALIDATIONVALIDATIONVALIDATIONVALIDATION----DETERGENTSDETERGENTSDETERGENTSDETERGENTS
Need to include measures to prevent microbial growthand remove contamination
Documented evidence of microbial proliferationprevention of
routine cleaning
storage of equ ipment
Equipment stored in a dry condition after cleaning (nostagnant water)
Control of bioburden through adequate cleaning and
appropriate storage of equipment The validation procedures also must include the period
and conditions
storage of unclean equipment before clean ing
between cleaning and equipment reuse
CLEANINGCLEANINGCLEANINGCLEANING VALIDATIONVALIDATIONVALIDATIONVALIDATION----MICROBIOLOGYMICROBIOLOGYMICROBIOLOGYMICROBIOLOGY
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Clean as soon as possible after use
especially topical products, suspensions and bulk drug or
where the drying of residues will directly affect the efficiency
of a cleaning procedure
Two methods of sampling:
direct surface sampling and
rinse samples
Combination of the two - most desirable
CLEANING VALIDATION-SAMPLING
Direct surface sampling (direct method)Direct surface sampling (direct method)Direct surface sampling (direct method)Direct surface sampling (direct method)
Most commonly used method
Use swabs (inert material) - type of sampling materialshould not interfere with the test
Factors to be considered include:
supplier of the swab,
area swabbed, number of swabs used, whether they are wet ordry swabs,
swab handling and swabbing technique
location from which the sample is taken (including worst caselocations, identified in the protocol)
composition of the equipment (e.g. glass or steel)
Critical areas (hardest to clean) should be identified
e.g. in semi-automatic/fully automatic clean-in-place systems
Use appropriate sampling medium and solvent
CLEANING VALIDATION-SAMPLING
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Rinse samples ( indirect method)Rinse samples ( indirect method)Rinse samples ( indirect method)Rinse samples ( indirect method)
Allows sampling of:
a large surface
areas that are inaccessible or that cannot be routinely
disassembled
Provides an "overall picture"
Useful for checking for residues of cleaning agents
Should be used in combination with other sampling
methods such as surface sampling
It is important to ensure chosen solvent has appropriate
recovery for residues being quantified
CLEANING VALIDATION-SAMPLING
Analytical method must be validated before the cleaning
validation is performed
Validated analytical methods able to detect residuals
or contaminants: specif ic for the substance(s) being assayed
at an appropriate level of cleanliness (sensitivity)
Suitable methods that are sensitive and specifi c should
be used for: chromatographic methods (e.g. high pressure liquid
chromotography (HPLC), gas chromotography (GC), and highpressure thin-layer chromatography (HPTLC) ). Others include(alone or in combination), e.g. total organic carbon (TOC), pH,conductivity, ultraviolet (UV) spectroscopy, and ELISA
CLEANING VALIDATION
ANALYTICALANALYTICALANALYTICALANALYTICAL METHODSMETHODSMETHODSMETHODS
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Acceptance criteria established for contaminant levels in
the sample should be:
Practical, achievable and verifiable
The rationale for the residue limits established should be
Logical, based on knowledge of materials
Each situation assessed individually
There should be no residue from:
Previous product
Reaction by-products and degradants
Cleaning process itself (e.g. detergents or solvents)
CLEANING VALIDATION
ACCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITS
Limits may be expressed as:
a concentration in a subsequent product (ppm),
limit per surface area (mcg/cm2222), or
in rinse water as ppm.
Limits for carry-over of product residues should meetdefined criteria:
Visually cleanVisually cleanVisually cleanVisually clean No residue visible on equipment after cleaning.Spiking studies to determine the concentrat ion at whi ch mostactive ingredients are visible. (May not be suitable for high
potency, low -dosage drugs.)
No more thanNo more thanNo more thanNo more than 10101010 ppmpp mpp mpp m of one product will appear in anotherproduct (basi s for heavy met als in star ting materials) .
No more thanNo more thanNo more thanNo more than 0.10.10.10.1%%%% of the normal therapeutic dose of oneproduct wi ll appear in the maximum daily dose of a subsequentproduct.
CLEANING VALIDATIONACCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITS
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Certain allergenic ingredients and highly potent material
should be undetectable by the best available analytical
methods
e.g. penicillins and cephalosporins
e.g. anovulent steroids, potent steroids and cytotoxics
Dedicated manufacturing facilities needed
CLEANING VALIDATION
ACCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITSCCEPTABLE LIMITS
Verifying that manufacturing equipment and product formulation are
finalized
Installation qualification, operational qualification, and preventive
maintenance of instruments
Validation of analytical methods
Evaluation of cleaning procedures themselves
PRIOR PREPARATION FORPRIOR PREPARATION FORPRIOR PREPARATION FORPRIOR PREPARATION FOR OFOFOFOF CLEANINGCLEANINGCLEANINGCLEANINGVALIDATIONVALIDATIONVALIDATIONVALIDATION
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COMPUTERIZED SYSTEM
VALIDATION
The validationThe validationThe validationThe validation of computerized systemsof computerized sy stemsof computerized systemsof co mputerized systems include:include:include:include:
System specifications
Functional specifications
Security
Back-ups
Validation:
Hardware
Software
INTRO
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Computer systems should be validated at the level
appropriate for their use and application.
Computer systems used in planning, specification,
programming, testing, commissioning, documentoperation, monitoring and modifying.
The purpose: is to ensure an acceptable degree of
evidence (documented, raw data), confidence
(dependability and thorough, rigorous achievement ofpredetermined specs), intended used, accuracy,
consistency and reliability
Both the system specifications and functional
specifications should be validated. Periodic (or continuous) evaluation should be performed
after the initial validation.
INTRO
INTRO
Should be written procedures for: perf ormance moni toring, change control, programme and
data security, calibration and maintenance, personneltraining, emergency recovery and periodic re-evaluation
During validation, consider: networks
manual back-ups
input/output checks
process documentation, monitoring
alarms, and
shutdown recovery
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Also known as Control document
Control document should state
objectives of a proposed computer system
the data to be entered and stored
the flow of data
how it interacts with other systems and procedures
the information to be produced
the limits of any variable
the operating programme and test programme
System elements that need to be considered in computer
validation include:
hardware (equipment)
soft ware (procedures)
people (users )
COMPUTERIZED SYSTEM VALIDATION
SYSTEMSYSTEMSYSTEMSYSTEM SPECIFICATIONSPECIFICATIONSPECIFICATIONSPECIFICATION
COMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEM VALIDATIONVALIDATIONVALIDATIONVALIDATION
FUNCTIONALFUNCTIONALFUNCTIONALFUNCTIONAL SPECIFICATION (PERFORMANCESPECIFICATION (PERFORMANCESPECIFICATION (PERFORMANCESPECIFICATION (PERFORMANCESPECIFICATIONSPECIFICATIONSPECIFICATIONSPECIFICATION))))
Provide instructions for:
testing, operating, and maintaining the system
names of the person(s) (development and operation)
When using computer systems, consideration:
location
power supply (Fluctuations in the electr ical supply caninfluence computer systems and power supply failure canresult in loss of memory).
temperature
magnetic disturbances
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GMP requirements for computer systems:
Verification and revalidationVerification and revalidationVerification and revalidationVerification and revalidation
Af ter a suitable period of running a new system
Independently reviewed and compared with the systemspecif ication and functional specif ication
Change controlChange controlChange controlChange control
Alterations made in accordance with a def ined procedure
Provision for checking, approving and implementing thechange
ChecksChecksChecksChecks
Data checked periodically
Confirm accurate and reliable transfer
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATION
FUNCTIONAL SPECIFICATION (PERFORMANCEFUNCTIONAL SPECIFICATION (PERFORMANCEFUNCTIONAL SPECIFICATION (PERFORMANCEFUNCTIONAL SPECIFICATION (PERFORMANCE
SPECIFICATION)SPECIFICATION)SPECIFICATION)SPECIFICATION)
Security is important in production as well as in quality
control
Data entered or amended - only by authorized persons
Security systems to prevent unauthorized entry or
manipulation of data
SOPs for entering data, changing or amending incorrect
entries and creating back-ups
Security procedures should be in writing
Security should also the control access of devices used to
store programmes, such as tapes, disks and magnetic strip
cards.
COMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEM VALIDATIONVALIDATIONVALIDATIONVALIDATIONSECURITYSECURITYSECURITYSECURITY
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Traceability is of particular importance and should be
able to:
identify the persons who made entries
identify the persons who made changes
identify the persons who released material
identify the persons who performed other critical steps in
production or control
Independent verification and release for use by a second
authorized person
e.g. for entry of a master processing formula.
SOPs for certain systems or processes validated
e.g. action in case of system failure or breakdown includingdisaster recovery procedure in the event of a breakdown
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATION
SECURITYSECURITYSECURITYSECURITY
Regular back-ups of all files and data
Secure storage (prevent intentional or accidental damage)
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONBACK UPS
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Validation process should include:
Planning
Validation policy
Project plan and SOPs
Define computer-related systems and vendors
Vendor and product evaluated
System designed and constructed
Consider types, testing and quality assurance of the software
After installation of the system it should be qualified.
Extent of qualification depends on complexity of the
system
COMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEMCOMPUTERIZED SYSTEM VALIDATIONVALIDATIONVALIDATIONVALIDATION
PROCESSPROCESSPROCESSPROCESS
Qualification includes:
Installation
Evaluation of the system
Performance
Change control, maintenance and calibration, security,
contingency planning, SOPs, training, performance
monitoring and periodic re-evaluation
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONPROCESSPROCESSPROCESSPROCESS
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Validation of hardwareValidation of hardwareValidation of hardwareValidation of hardware
Appropriate tests and challenges to the hardware
No influence of static, dust, power-feed voltage
fluctuations and electromagnetic interference
Hardware is considered to be equipment
focus on location, maintenance and calibration as part of the
qualification
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATION
PROCESSPROCESSPROCESSPROCESS
Validation ofValidation ofValidation ofValidation of hardwarehardwarehardwarehardware
It should prove:
Appropriate capacity
Operational limits
e.g. memory, connector ports, input ports
Performance under worst-case conditions
e.g. long hours, temperature extremes
Reproducibility/consistency
e.g. by performing at least three runs under differentconditions
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONPROCESSPROCESSPROCESSPROCESS
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Validation ofValidation ofValidation ofValidation of hardwarehardwarehardwarehardware Written qualification protocols; results in qualification
reports kept
Revalidation in case of significant changes
Validation may be performed by the vendor butultimate responsibility remains with the company
If records kept by supplier, manufacturer still has tohave sufficient records to allow assessment of theadequacy of the validation
A mere certification of suitability from the vendor, forexample, will be inadequate
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATION
PROCESSPROCESSPROCESSPROCESS
Validation of SoftwareValidation of SoftwareValidation of SoftwareValidation of Software
Software:
is the term used to describe the complete set of
programmes used by a computer, and which should be
listed in a menu
Records are considered as software
Focus should be placed on:
accuracy, security, access, retention of records, review, double
checks, documentation and accuracy of reproduction
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONPROCESSPROCESSPROCESSPROCESS
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Validation of SoftwareValidation of SoftwareValidation of SoftwareValidation of Software
Key computer programmes to be identified:
language, name, function (purpose of the programme)
input (determine inputs), output (determine outputs)
fixed set point (process variable that cannot be changed by the
operator), variable set point (entered by the operator)
edits (reject input/output that does not conform to limits and
minimize errors, e.g. four- or five-character number entry),
input manipulation (and equations) and programme overrides
(e.g. to stop a mixer before time)
Identification of authorized personnel to write, alter or have access to programmes
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATION
PROCESSPROCESSPROCESSPROCESS
Validation ofValidation ofValidation ofValidation of SoftwareSoftwareSoftwareSoftware
Points to be considered may include:Points to be considered may include:Points to be considered may include:Points to be considered may include:
Consistency in performance: Within pre-established limits)
Function: Matching the assigned operational function (e.g.generate batch documentation, di ff erent bat ches of materialused in a batch listed)
Worst case: Validation under different conditions (e.g. speed,data volume, frequency)
Repeats: Sufficient number of times (e.g. replicate data
entries) Documentation: Protocols and reports
Revalidation: In case of significant changes made
COMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONCOMPUTERIZED SYSTEM VALIDATIONPROCESSPROCESSPROCESSPROCESS
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WHO Technical Report Series, No. 937, 2006. Annex 4
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfo
rmation/Guidances/default.htm
REFERENCES