Instrument Qualification DQ, IQ, OQ, PQ vs. Validation and Routine MaintenanceCalibration

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Instrument Qualification (DQ, IQ, OQ, PQ) vs.
Validation and Routine Maintenance/Calibration

• Tom Layloff
• Management Sciences for Health
• www.msh.org
• The views expressed here are those of the author
  and not necessarily those of MSH

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Drivers

• Society
• Litigious
• Risk-free
• ICH

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Regulators Want

• Assurance Of Product Safety, Efficacy And Quality
• Assurance Of Reliable Data And Information
• Repeatable
• Reproducible

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Analytical Instrument Users Want

• Versatile And Reliable Instruments Which Meet
  Their Requirements.
• Make Them The Envy Of All Other Analysts.
• Best Toy On The Block.
• Their Budgeted Instrument Request Delivered
  Yesterday.
• More
• Sensitivity
• Selectivity
• Resolution
• Accuracy
• Precision

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Instrument Manufacturers

• Successful Analytical Instrument Manufacturers
  Want To Sell Lots Of Equipment To Satisfied
  Users.
• Successful Analytical Instrument Manufacturers
  Constantly Monitor The Law, Regulation, And
  Guidances Seeking To Identify As Soon As Possible
  New Analytical Instrument Requirements.

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Instrument Company Success

• A Successful Instrument Manufacturer Must
  Anticipate The Availability Of Funds And Drivers
  For Additional Data.
• The Societal Values Must Be Served.
• Instrument Companies Which Do Not Adequately
  Address The Needs Of The Testing Community Do Not
  Survive.

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USER REQUIREMENT SPECIFICATION (URS)

• Sales And Marketing Personnel Visit With Users To
  Identify Needs And Bells And Whistles.
• Minimum Performance Requirements Must Be
  Identified.
• Focus Groups May Aid In Refining The URSs.

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The Road Forward

• The URSs Drive The Development Of Functional
  Requirement Specifications (FRS) Which Establish
  The Design Qualification (DQ).
• The FRS Are Developed Into The Detailed Design
  Specification (DDS). The DDS Establishes The
  Basis For The Installation Qualification (IQ).
• The DDS Provide The Basis For Construction.

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FDA CMC Guidance

• Methods validation is the process of
  demonstrating that analytical procedures are
  suitable for their intended use. The methods
  validation process for analytical procedures
  begins with the planned and systematic collection
  by the applicant of the validation data to
  support the analytical procedures.

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Instrument ValidationToms Revision

• Instrument validation is the process of
  demonstrating that analytical instruments are
  suitable for their intended use. The validation
  process for analytical instruments begins with
  the planned and systematic collection by the
  applicant of the validation data to support the
  analytical applications.

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21 CFR 211.160 (b)(4)

• The calibration of instruments, apparatus,
  gauges, and recording devices at suitable
  intervals in accordance with an established
  written program containing specific directions,
  schedules, limits for accuracy and precision, and
  provisions for remedial action in the event
  accuracy and/or precision limits are not met.
  Instruments, apparatus, gauges, and recording
  devices not meeting established specifications
  shall not be used.

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GUIDELINE ON GENERAL PRINCIPLES OF PROCESS
VALIDATION, MAY, 1987

• 1. Equipment and Process
• a. Equipment Installation Qualification
• b. Process Performance Qualification
• Installation qualification - Establishing
  confidence that process equipment and ancillary
  systems are capable of consistently operating
  within established limits and tolerances.

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Coup De Grâce

• It is important that the manufacturer prepare a
  written validation protocol which specifies the
  procedures (and tests) to be conducted and the
  data to be collected. The purpose for which data
  are collected must be clear, the data must
  reflect facts and be collected carefully and
  accurately.
• In assessing the suitability of a given piece of
  equipment, it is usually insufficient to rely
  solely upon the representations of the equipment
  supplier,
• Information obtained from these studies should be
  used to establish written procedures covering
  equipment calibration, maintenance, monitoring,
  and control.

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Continuing 1

• Installation qualification studies establish
  confidence that the process equipment and
  ancillary systems are capable of consistently
  operating within established limits and
  tolerances. After process equipment is designed
  or selected, it should be evaluated and tested to
  verify that it is capable of operating
  satisfactorily within the operating limits
  required by the process.

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Two Prongs of Equipment Purchasing/Receipt

• Good Business Practices ISO Standards
• Purchased Goods Must Conform to The Purchasers
  Requirements and Specifications
• cGMP
• Equipment Must Be Fit For Intended Use
• Equipment Must Conform to Requesters
  Specifications
• Performance Assessment

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ISO 9001-2000

• 7.4 Purchasing
• 7.4.1 Purchasing process
• The organization shall ensure that purchased
  product conforms to specified purchase
  requirements. The type and extent of control
  applied to the supplier and the purchased product
  shall be dependent upon the effect of the
  purchased product on subsequent product
  realization or the final product. The
  organization shall evaluate and select suppliers
  based on their ability to supply product in
  accordance with the organization's requirements.
  Criteria for selection, evaluation and
  re-evaluation shall be established. Records of
  the results of evaluations and any necessary
  actions arising from the evaluation shall be
  maintained (see 4.2.4).

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• 7.4.2 Purchasing information
• Purchasing information shall describe the product
  to be purchased, including where appropriate
• a) requirements for approval of product,
  procedures, processes and equipment,
• b) requirements for qualification of personnel,
  and
• c) quality management system requirements.
• The organization shall ensure the adequacy of
  specified purchase requirements prior to their
  communication to the supplier.

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• 7.4.3 Verification of purchased product
• The organization shall establish and implement
  the inspection or other activities necessary for
  ensuring that purchased product meets specified
  purchase requirements. Where the organization or
  its customer intends to perform verification at
  the supplier's premises, the organization shall
  state the intended verification arrangements and
  method of product release in the purchasing
  information.

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ISO 17025 Section 4.6.2

• (a) All incoming supplies and reagents that can
  affect the quality of test results shall be shown
  to be suitable for their intended use through
  acceptable control sample testing or other system
  suitability testing prior to their release for
  routine use or supplier certifications may be
  accepted after the reliability of the supplies
  has been established. A program to periodically
  monitor the supplies must be implemented to
  assure the continued adherence to those standards.

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Fused Silica Capillary 1

• The small improvement are overshadowed by
  the fact that most of the adverse quality issues
  of two decades ago remain. variations in
  capillary bore and outer dimensions, ovality,
  random brittleness, and surface activity.

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Fused Silica Capillary 2

• Although fused-silica capillary enables
  separation methods unimaginable prior to its
  introduction, most manufactured capillaries are
  highly variable in quality and less than optimal
  for any application.

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Fused Silica Capillary 3

• Not only have fused-silica capillary columns
  revolutionized GC, but the newer separation
  science technologies capillary electrophoresis
  (CE), capillary LC, and capillary
  electrochromatography (CEC)perhaps would not
  have been explored without the availability
• Steve Griffin, LCGC North America, 2002, 20,
  928-938.

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Waters 717 plus Autosampler

• Precision   lt0.5 RSD (5 µL to 100 µL)
• Linearity   gt0.99 coefficient of correlation
• Carryover  lt0.1 from previous injection
• Cross Contamination lt0.1 from previous sample
• Injection Range 0.1 µL - 2000 µL (in 0.1 µL
  increments)

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Agilent Standard Autosampler

• 0.1 - 100 µl
• Typically lt0.5 RSD from 5-100 µl,
• typically lt1 RSD from 1 - 5 µl 
• Up to 1500 µl
• Typically lt0.5 (injection volume lt1000 µl),0.5
  (injection volume gt1000 µl) 
• 0.1 - 900 µl  l
• Typically gt0.5 (injection volume lt5 µl),
• lt0.5 (injection volume 5 - 900 µl)
• Up to 1800 µl
• lt0.5 up to 1800 µl
• Up to 5000 µ 
• lt0.5 (injection volume lt 2000 µl),
• 1 (injection volume gt 2000 µl)

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Uncertainty in HPLC Analysis

• It is impossible to run all autosamplers at a
  rsd better than 0.5. In fact, it is difficult
  to keep them in good enough shape to provide an
  overall rsd of nmt 1.0. Experience shows a
  reasonable uncertainty of 2 or more from the
  autosampler.
• Autosamplers-A Major Uncertainty Factor in HPLC
  Analysis Precision, S. Kuppers, B. Renger, and
  V.R. Meyer, LC-GC Europe, February, 2000.

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Waters 1500 SERIES HPLC PUMPS

• Programmable Flow Rate Range 0.00 - 10.00 mL/min,
  in 0.01 mL increments
• Flow Precision lt 0.1 RSD or 2 seconds SD, six
  replicates, based on retention time or volumetric
  measures, at 1 mL/min, 1000 - 2000 psi
  backpressure
• Flow Accuracy 1.0 or 30 uL/min, whichever is
  greater, at 1 mL/min, degassed methanol, 1000 -
  2000 psi backpressure (each pump individually)
• Maximum Operating Pressure 6000 psi (41,370 kPa,
  401 bar)
• Delay Volume (1525 pump)lt200 uL (without manual
  injector or column heater and with one GM 150
  mixer)
• Gradient Compositional Accuracy (1525) 0.5 of
  setting at 1 mL/min and 1000 psi backpressure
  (MethanolMethanol with propylparaben) with one
  GM 150 mixer

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Pump Specifications 2

• Gradient Compositional Precision (1525) lt0.5 RSD
  of setting at 1 mL/min and 1000 psi backpressure
  (Methanol Methanol with propylparaben) with one
  GM 150 mixer (based on 6 replicates of
  compositional accuracy)
• Acoustic Noise lt70 dB (A) at operator position
• Operating Temperature Range 4 C - 40 C
• Operating Humidity Range 20 - 80,
  non-condensing
• Physical Size (W x H x D) (without bottle holder)
  
• 12 inches x 17 inches x 24 inches
• 30.5 cm x 43 cm x 61 cm
• Weight
• 1515 pump 45 lbs. or 20.4 kg
• 1525 pump 60 lbs. or 27.2 kg

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Agilent 1100 HPLC Pump

• Pump Flow
• Precision lt0.3 RSD (typically lt0.15 RSD)
• Range Setpoints from 0.001 to 5.0 ml/min, in
  0.001 ml/min increments
• Pressure
• Operating range 0 - 40 MPa (0 - 400 bar, 0 - 5880
  psi)
• Pulsation lt2 amplitude (typically lt1 ) at 1
  ml/min isopropanol at all pressures gt1 MPa (gt 10
  bar, gt147 psi)
• Gradient
• Delay volume 180 - 480 µl (600-900 µl with mixer)
  dependent on back pressure
• Composition precision lt0.20 SD, at 0.1 and 1
  ml/min
• Recommended pH range 1.0 - 12.5
• Solvents with pH lt2.3 should not contain acids
  which attack steel

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Influence of Poor Peak Shape on Integration This
slide courtesy of Waters, Inc.

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BMW Z Decisions
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BMW Z3
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Invicta S1

• Engine
• 4.6 Liter V-8
• DOHC Per Bank
• 320 bhp at 5,900 rpm
• 300 lb-ft at 4,800 rpm
• Performance (claimed)
• Top Speed 180 mph
• 0-60 mph in 5 sec.
• 0-100 mph in 11 sec.

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Bottom Lines

• The World Is Infinitely Complex.
• It Is Impossible To Validate The Intricate
  Minutiae In Complex Systems.
• Appropriate Performance Parameters Must Be
  Established In SOPs To Demonstrate Fitness For
  Use.
• Control Samples Which Challenge The Typical
  Analytical Method Validation Dimensions Should Be
  Used.

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What Do We Want From Our Instrument?The
Performance Required For Method Validation

• Accuracy
• Precision
• Specificity
• Detection limit
• Quantitation limit
• Linearity
• Range
• Robustness
• Typical Validation Characteristics ICH and, USP
  lt1225gt