EQUIPMENT AND ITS QUALIFICATION Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda .
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EQUIPMENT AND ITS QUALIFICATION
Rutendo Kuwana
Technical Officer, WHO, Geneva
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
Artemisinin based combined medicinesFebruary 23-27, 2009, Kampala, Uganda 2 |
Basic Principles of GMPBasic Principles of GMP
Equipment
13
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EquipmentEquipment
Objectives
To review the requirements for equipment – selection – design – use – Maintenance
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ValidationValidation
Objectives (2)
To discuss the principles of qualification of equipment, with specific focus on:
The different stages of qualification
Requalification and
Qualification of “in use” equipment
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EquipmentEquipment
Principle
Equipment must be – located– designed– constructed– adapted– maintained
to suit the operations to be carried out
13.1
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EquipmentEquipment
Principles
Equipment layout and design must aim:
– to minimize risks of error
– to permit effective cleaning and maintenanceTo avoid:
– cross-contamination, dust and dirt build-up
– any adverse effect on the quality of productsEquipment must be installed to:
– minimize risks of error
– minimize risks of contamination13.1, 13.2
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13.5
EquipmentEquipment
Balances and Measuring Equipment
Appropriate range and precision available
In production and quality control
Calibrated– scheduled basis– checks – records maintained
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EquipmentEquipment
Production equipment
Appropriate design– easily and thoroughly cleaned on a scheduled basis– procedures and records
No hazard to the products– contact parts of suitable non-reactive materials– non additive and – not absorptive
Defective equipment– removed, or– labelled to prevent use
13.9, 13.10
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13.11 – 13.13
EquipmentEquipment
Production equipment
Closed equipment used when possible
Open equipment, or when equipment opened, precautions taken to prevent contamination
Non-dedicated equipment cleaned according to validated cleaning procedures between different products
Current drawings of critical equipment and support systems maintained
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EquipmentEquipment
Control laboratory equipment
Equipment and instruments– suitable for the tests to be performed
Defective equipment – removed– labelled
13.7, 13.10
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13.6, 13.8
EquipmentEquipment
Washing, cleaning and drying
Equipment used for washing and drying – not the source of contamination
Equipment design should promote easy cleaning
Cleaning on scheduled basis, procedures and records
Washing and cleaning– manual– automated (Clean in place (CIP), Steam in place (SIP))
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Basic Principles of GMPBasic Principles of GMP
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EquipmentEquipment
Possible Issues
Poor design
Lack of safety
Poor quality finishes
Lack of cleaning
Lack of maintenance
No usage log or record
Use of inappropriate weighing equipment
Open-plan location of compressing machines
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Basic Principles of GMPBasic Principles of GMP
Remember to look at punches and dies
Are there specifications for these?
How are they cleaned, stored, issued for use and returned to storage?
Are they in a good condition and checked at regular intervals?
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ValidationValidation
General
Qualification policy for systems and equipment
To include instruments used in production and quality control
New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ)
In some cases: Not all stages of qualification may be required– e.g. electrical supply systems
3.1 – 3.4
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ValidationValidation
General
Qualification policy for systems and equipment
To include instruments used in production and quality control
New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ)
In some cases: Not all stages of qualification may be required– e.g. electrical supply systems
3.1 – 3.4
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ValidationValidation
General (continued)
Qualification should be done in accordance with predetermined and approved qualification protocols
The results of the qualification should be recorded and reflected in qualification reports
The extent of the qualification should be based on the criticality of a system or equipment, e.g.
– Blenders, autoclaves or computerized systems
3.10 – 3.11
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ValidationValidation
General (continued)
Qualification should be done in accordance with predetermined and approved qualification protocols
The results of the qualification should be recorded and reflected in qualification reports
The extent of the qualification should be based on the criticality of a system or equipment, e.g.
– Blenders, autoclaves or computerized systems
3.10 – 3.11
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Qualification and ValidationQualification and Validation
Definitions
Validation
Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results
It is a process using documented evidence that provides a high degree of assurance that a specific process will consistently produce the predetermined outcome.
Glossary
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Qualification and ValidationQualification and Validation
Definition
Qualification
Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results
(Validation usually incorporates the concept of qualification)
A process of establishing confidence that the equipment is capable of consistently operating within established limits and tolerances. Studies therefore done prior to use
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Qualification Vs. ValidationQualification Vs. Validation
Qualification
- confirm compliance with specified requirements or criteria (Do you have the right tool for the job?)
- Performed on one element or component of the process to be validated
- Conduct tests to establish if the component of a process has the attributes to produce a specified outcome.
Validation
- Proof. Document that the process will consistently produce a predetermined outcome.
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ValidationValidation
Stages of qualification
3.11
Design qualification
Installation qualification
Operational qualification
Performance qualification
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ValidationValidation
Stages of qualification
3.11.
Design qualification
Installation qualification
Operational qualification
Performance qualification Change control
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ValidationValidation
General
Systems: Qualified before equipment
Equipment: Qualified before routine use
Systems and equipment: Periodic requalification, as well as requalification after change
Certain stages done by the supplier or a third party
Maintain the relevant documentation, e.g.– standard operating procedures (SOPs), specifications and
acceptance criteria, certificates and manuals 3.5 – 3.9
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ValidationValidation
Design qualification
User requirements should be considered when deciding on the specific design of a system or equipment
A suitable supplier should be selected for the appropriate system or equipment (approved vendor)
4.1 – 4.2
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ValidationValidation
Installation qualification
Verifies that the correct equipment has been received and installed as per plan and protocol. Also that it is complete and undamaged (parts, services, controls, gauges and other components)
- Normally advised to prepare requirements for calibration, maintenance and cleaning at this stage
Verifies that equipment has been properly installed and calibrated including connections to utilities.
Calibrate the measuring, control and indicating devices– against appropriate, traceable national or international standards
5.1 – 5.4
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ValidationValidation
Installation qualification (2)
Documented records for the installation– installation qualification report
Indicate satisfactory installation
Include details, e.g.– The supplier and manufacturer– System or equipment name, model and serial number– Date of installation– Spare parts, relevant procedures and certificates
5.5
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ValidationValidation
Operational qualification
Systems and equipment should operate correctly – operation verified as in the qualification protocol
Verifies that the equipment operates consistently within established limits and tolerances over the defined operating ranges. Studies on critical variable to include conditions encompassing upper and lower operating limits and circumstances (i.e. “worst case conditions”)
Challenges equipment functionally to verify compliance with manufacturer’s specifications and end – user defined requirements. To include verification of operation of all system elements, parts, services, controls, gauges and other components
6.1 – 6.3
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ValidationValidation
Operational qualification (2)
Documented records (Operational qualification report)
Finalize and approve SOP (operation)
Training of operators provided – training records
Systems and equipment released for routine use after completion of operational qualification, provided that:
– All calibration, cleaning, maintenance, training and related tests and results were found to be acceptable
6.4 – 6.7
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How may runs are to be performed during Operational Qualification (OQ) testing?
How may runs are to be performed during Operational Qualification (OQ) testing?
Guidelines stress the importance of equipment qualification simulating actual production conditions, including 'worst case' situations and that "tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results."
"three consecutive batches" is recommended for process validation rather than for equipment qualification. No specific number of "runs" for equipment qualification, but multiple tests to simulate actual operating ranges and to establish consistency are expected
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Qualification of EquipmentQualification of Equipment
IF ONE TYPE AND MODEL OF EQUIPMENT IS QUALIFIED, CAN IT BE USED IN A DIFFERENT PROCESS WITHOUT ADDITIONAL
QUALIFICATION?
For IQ document whether each equipment is installed correctly and operates consistently according to established limits and
tolerances. OQ should also be performed for each different use of the equipment or system to document the suitability for that use
Not be required for additional pieces of the same type/model of equipment when used in the same process or for each piece of the same type/model of equipment used in the same process, provided
installation qualification has been performed
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ValidationValidation
Performance qualification
Verifies that the equipment performs according to design specifications and user defined requirements in a reliable and reproducible manner under normal production conditions.
Verified in accordance with a performance qualification protocol
Documented records – performance qualification report
Show satisfactory performance over a period of time i,e. carried out long enough to prove that the equipment is under control and turns out product of specified quality consistently.
Manufacturers to justify the selected period 7.1 – 7.2
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Qualification PlanQualification Plan
To ensure that requirements are met and confirm by examination and collection of objective evidence
- Challenges to equipment to be designed
- Re-create intended use
- Test, Test, Test
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Qualification PlanQualification Plan
1. Purpose
2. Scope
3. Equipment Description
4. Operational Specifications
5. Acceptance Criteria
6. Testing Results
7. Discrepancies/Corrective Actions
8. Conclusions/Final Report
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ValidationValidation
The next slide shows a typical format for:
"A qualification protocol / report"
It reflects the minimum information that should be included
This is an example – and should be used as such
Specific formats need to be designed for a specific system or piece of equipment
7.2
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Qualification PlanQualification Plan
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Worst Case ScenariosWorst Case Scenarios
Conditions that include upper and lower processing limits
Circumstances that present the highest chance of process or product failure relative to ideal situations
Identify those conditions that are likely to be experienced during routine manufacture/process
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More ExamplesMore Examples
The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment
A pharmaceutical firm used two blenders to produce a tablet. Both blenders from same equipment manufacturer, same model number and same design. Supplier told the drug manufacturer that the units were "identical." though one was older. Manufacturer did not include the older blender as part of its process validation.
Company marketed about 100 batches of tablets using the old blender. Retention samples showed some batches failed content uniformity
investigation showed out of specification batches were from one of the two "identical" blenders – the old one. The older blender had a slightly smaller capacity and different operational characteristics (RPMs) when run at the same settings as the newer blender.
Subsequently, the firm recalled its total production of the product it made using the older blender. The firm decided to qualify the old blender using production size lots.
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Qualification of “Old” EquipmentQualification of “Old” Equipment
What about "old manufacturers" who have not performed DQ, or IQ for existing, in-use systems and/or equipment?
It is not always possible to have all details for IQ or OQ for established equipment. The manufacturer should however have data that verifies the operating parameters and limits for the critical variables of the equipment. In addition, calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and used as SOPs ……. PIC/S
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ValidationValidation
Qualification of “in-use” systems and equipment
Data to support and verify the suitable operation and performance of systems and equipment
Should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records
9.1 – 9.2
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Risk assessment of operations or functions
Risk assessment of operations or functions
If any question is answered “Yes”, the operation/function should be considered as GMP relevant. During risk assessment, the probability of occurrence and detectability should be considered and measures to reduce the risk identified.
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Qualification flow Scheme(extracted from CEFIC Guidance)
Qualification flow Scheme(extracted from CEFIC Guidance)
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Example of Document MatrixExample of Document Matrix
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RequalificationRequalification
Required for:
- significant change in batch size
- change in operating parameters
- component specifications have changed
- new accessories or components are added to previously qualified equipment
- process changes that potentially impact product effectiveness or quality
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Some ExperiencesSome Experiences
What if the results are not good?
Study report destroyed and manufacturer pretends it never happened
So what should be done?
Document the study, but don’t approve it
Identify and describe any corrective actions needed or any noteworthy observations or deviations
Start another study using the findings and conclusions from the failed study
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More experiences – poor qualification reports
More experiences – poor qualification reports
Specifications not approved
Failure to provide clear, complete instructions in the protocol
Instrument calibration records or status not included
Full range of intended operating parameters not challenged
Inadequate sample sizes
Atypical data points
Unexplained deviations from protocol
Inconsistencies between final report and data collection/recording forms
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Annex 6
Qualification and ValidationQualification and Validation
WHO References
Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes
Validation of analytical procedures used in the examination of pharmaceutical materials