cleaning and computerized validation

8/21/2019 Cleaning and Computerized Validation

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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


2/23

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


3/23

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


4/23

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


5/23

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 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



6/23

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.


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


7/23

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


8/23

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


9/23

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


10/23

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



11/23

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


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


12/23

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


13/23

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


14/23

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


15/23

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


16/23

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


17/23

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


18/23

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


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


19/23

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


20/23

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



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



21/23

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



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



22/23

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



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



23/23

WHO Technical Report Series, No. 937, 2006. Annex 4

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfo

rmation/Guidances/default.htm

REFERENCES

cleaning and computerized validation

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