Supplementary Training Workshop on Good Manufacturing Practices (GMP)

QUALIFICATION of EQUIPMENT
Jnos Pogny, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hu
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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 of equipment (e.g., machines, stability chamber)work correctly and actually lead to the expected results. The meaning of the word validation is sometimes extended to incorporate the concept of qualification.  REQUALIFICATION is the main part of the preventive maintenance programme of proving that any premises, (pharmaceutical utility) systems and items of equipment work 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 any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to 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 keeps on leading to the expected results.
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Qualification - Validation
Regulatory requirements DQ,IQ,OQ inputs DQ,IQ,OQ process DQ,IQ,OQ outputs

Process

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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Calibration
The 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 of measuring should be established. (see also the notes page) Verification.
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Calibration test equipment

Instrument or device used to calibrate other instruments, the calibration of which is traceable back to accepted national standards. The test equipment should have greater precision, accuracy, and repeatability, than the instruments being calibrated. These instruments should have documentary evidence of traceable calibration to at least the same standard as the site calibration.

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DESIGN

QUALIFICATION

4.3 Documentary evidence

(a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ); (b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or 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 specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance 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 in accordance with an installation plan, as per supplier and any special (purchaser) requirements.  The requirements for calibration, maintenance and cleaning developed as draft procedures should be reviewed and finally issued as authorised standard operating procedures (SOPs).
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Basic principles
 Operating requirements should be established and tests conducted to assure equipment is operating correctly, under normal and worst case conditions ( failure mode analysis)  Operator training requirements pertaining to the new equipment should be finalised and documented.

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DQ and IQ
 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 for HVAC and water systems

Do not start OQ before IQ has been completed!

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INSTALLATION

QUALIFICATION

Prequalification of vendor
 Vendor specification
    

familiarity with GMP installation, training and start-up support performance testing at the vendors site experience of current users cost analysis

 Once selected, the vendor may assist in preparing the qualification protocols

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Pre-delivery check
For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a predelivery 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 a reduction in the scope of the Installation Qualification checks.

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Checking at users
Installation Qualification requires a formal and systematic check of all installed equipment against the equipment supplier's specifications and additional criteria identified by the user as part of the purchase specifications. At the Installation Qualification, all equipment, gauges and services should be given a serial (or other reference) number and a check conducted that the installed equipment (or plant) has been installed in accordance with the current (approved) version of the Piping & Instrument Diagram (P&ID).
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IQ - Overview Statement
Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and working instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification.

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Installation of equipment
An effective Change Management procedure 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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Calibration Requirements
 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 of calibration requirements for measuring devices for the future use of the equipment

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OPERATION

QUALIFICATION

OQ - Overview Statement
Operational Qualification is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the equipment or systems will define the critical characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorised, implemented and resulting data collected and evaluated.
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OQ - Overview Statement
 It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken.  It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration 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 specialist knowledge 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 a condition or a set of conditions encompassing upper and lower processing or operating limits and circumstances; commonly referred to as "worst case" conditions. Such conditions should not necessarily induce product or process failure.  The completion of a successful OQ should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for 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 written authorisations 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 of computers and software that are used to control laboratory equipment or process data.  The overall program should be evaluated periodically to ensure that current requirements are met.

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Re-Qualification
 Modifications to, or relocation of, equipment should only follow satisfactory review and authorisation of the documented change proposal through the change control procedure. Part of the review procedure should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or inprocess product quality should be handled through the documentation system of the preventative maintenance programme.
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Qualification of in-use equipment

While it is not possible to undertake the details of an IQ for established equipment nor the detailed approach for an OQ, nevertheless there should be data available that support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and in use 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 PQ protocols and reports are required that equipment was designed, installed and operated in accordance with suppliers and users requirements.  Effective change control keeps documentation up to date.  Qualification is a sub-set of validation
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Literature
 Validation Master Plan, Installation and Operational Qualification, Non-sterile Process Validation, Cleaning Validation, Pharmaceutical Inspection Convention (PIC/S), August 2001  Model IQ/OQ protocol and report (distributed among participants of the training course)  Comparison of WHO, EU and US-FDA GMP Requirements for Pharmaceutical Equipment (distributed among participants of the training course)
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