Transcript EQUIPMENT AND ITS QUALIFICATION Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines.

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.
Basic Principles of GMP
Equipment
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Equipment
Objectives
 To review the requirements for equipment
– selection
– design
– use
– Maintenance
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Validation
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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Equipment
Principle
 Equipment must be
– located
– designed
– constructed
– adapted
– maintained
to suit the operations to be carried out
13.1
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Equipment
Principles
 Equipment layout and design must aim:
– to minimize risks of error
– to permit effective cleaning and maintenance
 To avoid:
– cross-contamination, dust and dirt build-up
– any adverse effect on the quality of products
 Equipment must be installed to:
– minimize risks of error
– minimize risks of contamination
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13.1, 13.2
Equipment
Balances and Measuring Equipment
 Appropriate range and precision available
 In production and quality control
 Calibrated
– scheduled basis
– checks
– records maintained
13.5
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Equipment
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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Equipment
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
13.11 – 13.13
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Equipment
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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Equipment
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))
13.6, 13.8
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Basic Principles of GMP
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Equipment
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 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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Validation
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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Validation
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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Validation
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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Validation
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 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 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. 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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Validation
Stages of qualification
Design qualification
Installation qualification
Operational qualification
Performance qualification
3.11
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Validation
Stages of qualification
Design qualification
Installation qualification
Operational qualification
Performance qualification
Change control
3.11.
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Validation
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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Validation
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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Validation
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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Validation
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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Validation
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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Validation
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?
 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 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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Validation
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
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7.1 – 7.2
Qualification 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 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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Validation
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 Plan
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Worst 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 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” 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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Validation
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
• Does function/operation directly impact product quality?
• Does function/operation create (electronic) data which are the basis for
GMP related activities?
• Would malfunction impact directly on product quality
• Does a measuring instrument control or measure quality critical processing
steps/parameters?
• Does operation/installation cause contamination risk or product or
environment
• Are materials of construction in direct contact with the product?
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)
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Example of Document Matrix
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Requalification
 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 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
 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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Qualification 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
Annex 6
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