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2005.06.28. Dr. Pogny - WHO, Pretoria 1/33

Supplementary Training Workshop on Good

Manufacturing Practices (GMP)

QUALIFICATION ofEQUIPMENT

Jnos Pogny, pharmacist, PhD,consultant to WHO

Pretoria, South Africa, 28 June 2005

E-mail:[email protected]

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WHO GMP and Guidelines WHO good manufacturing practices (GMP):

main principles for pharmaceutical products

Section 4. Qualification and validation

Section 13. Equipment (see notes page)

Supplementary guidelines on good

manufacturing practices (GMP): Validation

(2003) Draft.

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Causes of variation Man (different operators - lack of proper training)

Machine / equipment

Measurement (lack of calibration)

Method (accuracy of validated processes/methods)

Material (batch-to-batch variation of APIs/excipients)

Manufacturing environment (T and RH)

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Qualification QUALIFICATION is the Action of proving that any

premises, (pharmaceutical utility) systems and items ofequipment (e.g., machines, stability chamber)work

correctly and actually lead to the expected results. Themeaning of the word validation is sometimesextended to incorporate the concept of qualification.

REQUALIFICATION is the main part of thepreventive

maintenance programme of proving that anypremises,(pharmaceutical utility) systems and items of equipmentwork correctly and keep on leading to the expected

results. (normal wear and tear)

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Validation VALIDATION is the Action of proving, in

accordance with the principles of GMP, that anyprocedure,process, equipment, material, activity

or (pharmaceutical utility) system actually leadsto the expected results (see also qualification).

REVALIDATION is a part of the change

control system of proving that any procedure,process, equipment, material, activity or (pharmaceutical utility) system actually keepson leading to the expected results.

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Qualification - ValidationRegulatory

requirements

DQ,IQ,OQ

inputs

DQ,IQ,OQ

process

DQ,IQ,OQ

outputsProcess

Qualification

Validation

Premises, equipment and supporting utilities must be

qualified to operate in a validated process.

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Relationship between qualification

and validation

DESIGN SPECIFICATION/QUALIFICATION

INSTALLATION QUALIFICATION

OPERATIONAL QUALIFICATION

PROCESS VALIDATION

CHANGE CONTROL

Qualification is a sub-set of validation.

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CalibrationThe set of operations that establish, under specified

conditions, the relationship between values indicated

by an instrument or system for measuring(especially weighing), recording, and controlling, or

the values represented by a material measure, and

the corresponding known values of a reference

standard. Limits for acceptance of the results ofmeasuring should be established. (see also the

notes page) Verification.

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Calibration test equipmentInstrument or device used to calibrate other

instruments, the calibration of which is traceable

back to accepted national standards. The testequipment should have greater precision, accuracy,

and repeatability, than the instruments being

calibrated. These instruments should have

documentary evidence of traceable calibration to atleast the same standard as the site calibration.

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DESIGN

QUALIFICATION

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4.3 Documentary evidence(a) the premises, supporting utilities, equipment and

processes have been designed in accordance with

the requirements for GMP (design qualification orDQ);

(b) the premises, supporting utilities and equipment

have been built and installed in compliance with

their design specifications (installation qualificationor IQ);

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4.3 Documentary evidence(c) the premises, supporting utilities and equipment

operate in accordance with their design

specifications (operational qualification or OQ);(d) a specificprocess will consistently produce a

product meeting its predetermined specifications

and quality attributes (process validation or PV,

also calledperformance qualification or PQ).(PQ is frequently applied to utility systems)

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Basic principles Throughout this presentation the term equipment is

used to represent both manufacturing machinery,equipment and QC instruments.

The equipment should be correctly installed inaccordance with an installation plan, as persupplierand any special (purchaser) requirements.

The requirements forcalibration, maintenance andcleaning developed as draft procedures should bereviewed and finally issued as authorised standardoperating procedures (SOPs).

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Basic principles Operating requirements should be established and

tests conducted to assure equipment is operating

correctly, undernormal and worst caseconditions ( failure mode analysis)

Operator training requirementspertaining to the

new equipment should be finalised and

documented.

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DQ andIQ DQ protocols and reports

GMP

VMP

National law

Engineering design and construction documents

Do not start IQ before DQ has been completed!

IQ/OQ protocols and reports Above inputs + machine manuals

Separate VMPs forHVAC and watersystems

Do not start OQ before IQ has been completed!

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INSTALLATION

QUALIFICATION

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Prequalification of vendor Vendor specification

familiarity with GMP

installation, training and start-up support performance testing at the vendors site

experience ofcurrent users

cost analysis

Once selected, the vendor may assist in preparingthe qualification protocols

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Pre-delivery checkForcomplicated orlarge pieces of equipment, a

pharmaceutical manufacturer may elect to undertake a pre-

delivery check of the equipment at the supplier's assembly

facility. This pre-delivery check cannot substitute for the

Installation Qualification. However, it is acknowledged that

the checks conducted and documented at this stage may

duplicate a number of the checks conducted at the

Installation Qualification stage, hence, there could be areduction in the scope of the Installation Qualification

checks.

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Checking at usersInstallation Qualification requires a formal andsystematic check of all installed equipment against theequipment supplier's specifications and additionalcriteria identified by the user as part of the purchasespecifications. At the Installation Qualification, allequipment, gauges and services should be given a serial(or other reference) numberand a check conducted that

the installed equipment (or plant) has been installed inaccordance with the current (approved) version of thePiping & Instrument Diagram (P&ID).

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IQ - Overview StatementIdentification and documenting ofmaintenance

requirements for each installed item and the

collection and collation ofsupplier operating andworking instructions, maintenance and cleaning

requirements, should form the minimum

documentation for a satisfactory Installation

Qualification.

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Installation of equipmentAn effective Change Managementprocedure should

be in place. All changes to the original design

criteria should be documented and after that,appropriate modifications made to Equipment

Specifications, Plant Functional Specifications and

Piping & Instrument Diagrams (P&IDs).

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CalibrationRequirements Confirmation of calibration with reference to the

appropriate national standard.

Calibration of measuring devices utilised in the

Operational Qualification stage, where confirmation of

calibration is unavailable.

Calibration of measuring devices related to installed

equipment.

Identification ofcalibration requirements for measuring

devices for the future use of the equipment

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OPERATION

QUALIFICATION

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OQ - Overview StatementOperational Qualification is an exercise oriented tothe engineering function, generally referred to ascommissioning. Studies on the critical variables(parameters) of the operation of the equipment orsystems will define the critical characteristics foroperation of the system or sub-system. All testingequipment should be identified and calibrated before

use. Test methods should be authorised,implemented and resulting data collected andevaluated.

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OQ - Overview Statement It is important at this stage to assure all

operational test data conform with pre-determinedacceptance criteria for the studies undertaken.

It is expected that during the OperationalQualification stage the manufacturer shoulddevelop draft standard operating procedures(SOPs) for the equipment and services operation,

cleaning activities, maintenance requirements andcalibration schedules.

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OQ - Essential Elements The conduct of an Operational Qualification should follow an

authorised protocol.

The plans for the Operational Qualification should identify the

studies to be undertaken on the critical variables, the sequence

of those studies and the measuring equipment to be used and

the acceptance criteria to be met.

Studies on the critical variables should incorporate specific

details and tests that have been developed from specialistknowledge of the process and how the equipment will work

(defined in design criteria and specifications).

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OQ - Essential Elements Where applicable, simulated product may be used to conduct

the OQ. Studies on the critical variables should include acondition or a set of conditions encompassing upper and

lower processing or operating limits and circumstances;commonly referred to as "worst case" conditions. Suchconditions should not necessarily induce product or processfailure.

The completion of a successful OQ should allow the

finalisation of operating procedures and operator instructionsdocumentation for the equipment. This information should beused as thebasis for training of operators in the requirementsfor satisfactory operation of the equipment.

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OQ - Essential Elements Draft cleaning procedures developed at the IQ stage

should be finalised. Where applicable, these procedures

should be validated as part of the PQ phase. The completion of satisfactory IQ and OQ exercises

should permit a formal "release" of the equipment/plant

for the next stage in the validation exercise (Process

Validation). The release should take the form of writtenauthorisations for both Installation Qualification and

Operational Qualification.

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OQ - Essential Elements Some OQ testing should be performed following

equipment maintenance

Current regulations require the validation ofcomputers and software that are used to control

laboratory equipment or process data.

The overall program should be evaluated

periodically to ensure that current requirementsare met.

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Re-Qualification Modifications to, orrelocation of, equipment

should only follow satisfactory review andauthorisation of the documented change proposalthrough the change control procedure. Part of thereview procedure should include consideration ofre-qualification of the equipment. Minor changesor changes having no direct impact on final or in-

process product quality should be handledthrough the documentation system of the

preventative maintenanceprogramme.

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Qualification of in-use equipmentWhile it is not possible to undertake the details of anIQ for established equipment nor the detailedapproach for an OQ, nevertheless there should bedata available that support and verify the operating

parameters and limits for the critical variables of theoperating equipment. Additionally, the calibration,cleaning, preventative maintenance, operating

procedures and operator trainingprocedures for theuse of the equipment should be documented and inuse as standard operating procedures (SOPs).

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Main points again Equipment is one of the potential causes of

variation.

DQ, IQ, OP and PQprotocols and reports arerequired that equipment was designed, installed and

operated in accordance with suppliers and users

requirements.

Effective change control keeps documentation upto date.

Qualification is a sub-set of validation

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Literature Validation Master Plan, Installation and

Operational Qualification, Non-sterile ProcessValidation, Cleaning Validation, Pharmaceutical

Inspection Convention (PIC/S), August 2001

Model IQ/OQ protocol and report (distributed amongparticipants of the training course)

Comparison ofWHO, EU and US-FDA GMPRequirements for Pharmaceutical Equipment(distributed among participants of the training course)

Documents

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