Integrating ICH Q8 principals into the validation of computer systems

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Integrating ICH Q8 principals into the
validation of computer systems

• 2007 Annual Technology Show
• March 21, 2007
• Brian Stephens
• ABB, Inc

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Disclaimer

• The information provided in the following
  presentation are the personal ideas that Mr.
  Stephens has on the subject and do not represent
  the views held by his employer (ABB, Inc) or any
  of the industry groups with which he is
  associated with (ISPE, ASQ, PDA). The opinions
  expressed may not be universally accepted and are
  definitely meant to generate thoughts and
  opinions from the audience.

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Discussion

• Background
• Overview of ICH Q8
• Flexible regulatory approach
• Overview of PCS validation
• Integration of Q8 ideas into the validation
  process
• Caveats
• Summary

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Goals

• This presentation will describe the contents of
  ICH Q8 and offer suggestions on using the
  guidance when developing validation strategies
  adhering to the Pharmaceutical cGMPs for the 21st
  Century
• NOTE ICH Q8 is a guidance document and it is not
  required to meet its contents to satisfy FDAs
  current Good Manufacturing Practices

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Background

• ICH Official Name International Conference on
  Harmonisation of Technical Requirements for
  Registration of Pharmaceuticals for Human Use
• ICH is a joint initiative involving both
  regulators and research-based industry
  representatives of the European Union, Japan and
  the USA in scientific and technical discussions
  of the testing procedures required to assess and
  ensure the safety, quality and efficacy of
  medicines
• FDA and Pharmaceutical Research and Manufacturers
  of America (PhRMA) participate in ICH activities
  with their counterparts from Europe and Japan
• Guidelines for Quality, Safety, Efficacy and
  Multidisciplinary topics
• from the ICH website www.ICH.org

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Background

• ICH/FDA History
• 1990 FDA announced that it will join European
  and Japanese agencies and manufacturer
  organizations to form ICH.
• ICH Q8, Q9, Q10 are found to be consistent with
  and supportive of FDA goals and implementation of
  cGMP initiative, are approved as guidance in
  meeting cGMPs.
• ICH Q8 published in the Federal Register, May 22,
  2006 as guidance for Pharmaceutical Product
  Development.
• Note FDA applied for admittance to
  Pharmaceutical Inspection Cooperation Scheme
  (PIC/S) in 2006 to promote more multinational
  support for drug quality.

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Overview of ICH Q8

• Design Space  The multidimensional combination
  and interaction of input variables (e.g.,
  material attributes) and process parameters that
  have been demonstrated to provide assurance of
  quality. Working within the design space is not
  considered as a change. Movement out of the
  design space is considered to be a change and
  would normally initiate a regulatory postapproval
  change process. Design space is proposed by the
  applicant and is subject to regulatory assessment
  and approval. 
• Formal Experimental Design  A structured,
  organized method for determining the relationship
  between factors affecting a process and the
  output of that process. Also known as Design of
  Experiments.  

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Overview of ICH Q8

• Process Analytical Technology (PAT)  A system
  for designing, analyzing, and controlling
  manufacturing through timely measurements (i.e.,
  during processing) of critical quality and
  performance attributes of raw and in-process
  materials and processes with the goal of ensuring
  final product quality.   
• Process Robustness  Ability of a process to
  tolerate variability of materials and changes of
  the process and equipment without negative impact
  on quality. 

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Overview of ICH Q8

• Quality by Design
• Designs quality into the product using knowledge
  of process
• Relationship between quality attribute and
  product efficacy and performance
• Increased knowledge and control decreases
  oversight
• Framework for implementing continuous improvement
• Supports best practices approach
• Process Analytical Technology
• Flexible Regulatory Approach

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Flexible Regulatory Approach

• Description (FDA)
• Risk based regulatory decisions (reviews and
  inspections)
• Reduction of post approval submissions
• Real time quality control, leading to a reduction
  of end-product release testing
• Manufacturing process improvements within
  approved design space described in the dossier,
  without further regulatory review
• The degree of regulatory flexibility is
  predicated on the level of relevant scientific
  knowledge provided.

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Flexible Regulatory Approach

• Benefits
• Reduces regulatory costs during process
  optimization
• Promotes manufacturing practices that increase
  manufacturing output
• Improves product quality
• Promotes improved process understanding
• Identifies Critical Quality Attributes to be
  monitored
• Increases manufacturers responsibility and their
  control on defining and maintaining quality
• Supports manufacturing changes/improvements
• Promotes continuous improvement, technological
  innovation

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Flexible Regulatory Approach

• Initial costs/disadvantages
• Requires science based knowledge and results to
  support the changes
• Requires that the manufacturing company invest in
  process understanding
• Can promote out of the building thinking that
  causes regulatory problems

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Overview of ICH Q8

• To realize flexible regulatory approach, the
  developer must demonstrate an enhanced knowledge
  of product performance
• Process operations
• Process parameters
• Environmental impacts
• Supplier material impacts
• Tools for identifying the process
• Formal design experiments
• Process history
• Analytical data

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Overview of ICH Q8

• Identifying the process in a flexible regulatory
  approach environment
• Design space
• DoE results
• Documented process experience
• Includes boundary testing results
• Fully verified correlation of input/output
• Identified for each process by the manufacturer
• Subject to approval/disapproval by the FDA

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Overview of ICH Q8

• To define design space, the process must be
  understood
• Excipient properties
• Active properties
• Process conditions
• Environmental effects
• Equipment attributes
• Understanding of input variables and process
  parameters allow definition of the critical
  process parameters that affect the CQAs

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Overview of ICH Q8

• Guidance for Industry, Q8 Pharmaceutical
  Development
• Key definition Design Space - The
  multidimensional combination and interaction of
  input variables (e.g., material, attributes) and
  process parameters that have been demonstrated to
  provide assurance of quality.
• from Guidance for Industry, Q8
  Pharmaceutical Development

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Overview of PCS Validation
Document

• Traditional Validation
• Adds paperwork to the initial project validation
• Document all test results
• Document all test deviations
• Document all test deviation causes
• Document all proposed solutions for all test
  deviations
• Document the execution of the proposed solutions
• Document the results of the solution executions
• Document how the solutions met the original
  criteria
• Document that everyone approves of the new results

Document
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Overview of PCS Validation
Document

• Traditional Validation
• Adds paperwork for any changes made to the
  system
• Document all specification changes
• Document all test results
• Document all test deviations
• Document all test deviation causes
• Document all proposed solutions for all test
  deviations
• Document the execution of the proposed solutions
• Document the results of the solution executions
• Document how the solutions met the original
  criteria
• Document that everyone approves of the new specs
  and test results

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Overview of PCS Validation

• Not considered a flexible approach
• Validation documents that verify that a set of
  rigid, set in stone or frozen requirements
  have been met
• Verifies a single process used in drug
  production, with little variation accepted
• Not flexible for changes
• Requires the execution of a full revalidation for
  any changes to the system
• Update specs
• Update design
• Retest system
• System downtime

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Overview of PCS Validation

• The FDA guidance document Pharmaceutical cGMPs
  for the 21st Century was introduced in 2004 to
  allow the industry to reduce regulatory barriers
  to process improvement.
  The guidance
  promotes the use of the following ideas and
  technologies to improve product quality, reduce
  manufacturing costs, increase product yields
• 1. New technology in pharmaceutical manufacturing
  (PAT)
• 2. Risk based assessment of process (Q9)
• 3. Science based regulation of product quality
  (Q8)
• 4. Modern quality management techniques for QA
  (Q8)

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Flexible Regulatory Approach - Validation

• How does the flexible regulatory approach affect
  the validation process and how can the ideas
  stated in ICH Q8 support this process?

Guidance for IndustryQ8 Pharmaceutical
Development  U.S. Department of Health and Human
ServicesFood and Drug AdministrationCenter for
Drug Evaluation and Research (CDER)Center for
Biologics Evaluation and Research (CBER)  May
2006ICH Guidance for IndustryQ8 Pharmaceutical
Development
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Q8 and Validation

• Definition of Validation (FDA) Establishing
  documented evidence which provides a high degree
  of assurance that a specific process will
  consistently produce a product meeting its
  predetermined specifications and quality
  attributes
• Product quality and performance achieved and
  assured by design of effective and efficient
  manufacturing processes.
• Definition of Continuous Process Verification
  (ICH Q8)  An alternative approach to process
  validation in which manufacturing process
  performance is continuously monitored and
  evaluated
• Summary Progress Report Pharmaceutical cGMPs
  for the 21st Century

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Q8 and Validation

• Validation process using Q8 guidance
• Use DoE as described in the ICH Q8 guidance to
  define CQAs and design space
• Document the process used to verify CQAs
• Document the CQAs and their interrelation,
  identify the CPPs for each CQA
• Identify the affect that CQA variability has on
  the process
• Form the design space for the process based on
  these findings
• Critical Quality Attributes (CQAs)
• related to end product properties such as
  identity, strength, potency, purity, and moisture
• Critical Process Parameters (CPPs)
• Controls that affect CQAs

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Q8 and Validation

• Validation process using Q8 guidance (contd)
• Identification of CQAs and CPPs via experiment
  and analysis
• Risk assessment
• Product assessment
• Process assessment
• Analyzer assessment
• Say it, do it, experience it, improve it, update
  it
• Perform validation based on the range of control
  of the process within the design space rather
  than map testing to the frozen specification
  parameters
• Verify knowledge base to verify relationship
  between CQA and CPP
• Validate the control system (algorithms
  controlling CPPs)
• Qualify analyzers
• Validate method
• Validate sampling system

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Traditional Validation Approach
Requirements
IQ, OQ, PQ
Plan
System Qualification
System Development
System Design

• Conventional validation approach to quality
• Validation focuses on system operation
• Testing the output of the system

Validation
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ICH Q8 Validation Approach
CPP Requirements
Measure CQA
Identify CQA
System Development
System Qualification
System Design

• ICH Q8 approach
• Validation focuses on system design
• Testing the quality that is being built into the
  process

System Operation
Validation
Design space
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Integration of Q8 into the Validation Process

• Guidance for Industry, Q8 Pharmaceutical
  Development
• Promotes process understanding that can identify
  opportunities to develop more flexible regulatory
  approaches that lead to faster regulatory
  actions 
• Risk-based regulatory decisions (reviews and
  inspections)
• Know and understand the critical quality
  attributes of a process, approval based on this
  knowledge of process
• Validation plans that include testing the quality
  attributes and process variables that affect the
  quality attributes (the drug process) instead of
  verifying the drug being manufactured by the
  production process

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Integration of Q8 into the Validation Process

• Guidance for Industry, Q8 Pharmaceutical
  Development
• Promotes process understanding that can identify
  opportunities to develop more flexible regulatory
  approaches that lead to faster regulatory
  actions 
• Automated real-time quality control, leading to a
  reduction of end-product release testing 
• Continuous process verification of known and
  measured critical attributes
  allows real time product release
• Proper identification and validation of critical
  quality attributes allows real time product
  release
• Proper validation of CPPs verifies the adherence
  to specified CQA parameters

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Integration of Q8 into the Validation Process

• Guidance for Industry, Q8 Pharmaceutical
  Development
• Promotes process understanding that can identify
  opportunities to develop more flexible regulatory
  approaches that leads to reduced
  testing/documentation for process changes 
• Changes to certain known process attributes
  without further
  regulatory review (design space)
• Design space variables and knowledge of their
  interaction allows
  changes that will not trigger
  revalidation activities
• Reduction of postapproval submissions
• Process knowledge leads to known results from
  process changes

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Integration of Q8 into the Validation Process

• Controls in the validation process
• Modular structure of PCS
• Isolation of control
• Aids the creation of experiments
• Data collection capabilities of PCS
• Information Managers collect massive amounts of
  data during process to help define design space
• PCS interface to PAT
• PAT performs online testing for continuous
  process verification, real time QA continuous
  process verification, real time QA
• Verifies system operates within design space
• Supports QbD principles

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Integration of Q8 into the Validation Process

• After implementation of system
• Online quality assurance checks
• Reduces off line QA checks, promotes real time
  product release
• Working within the design space is not considered
  as a change.
• Must document that change was made, must have
  science based knowledge to back up the definition
  of design space and the change

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Caveats

• Caveat 1 To take advantage of the flexible
  regulatory approach, an enhanced knowledge of the
  process must be demonstrated through documented
  science-based experiments and measurements and/or
  experience. This must verify the robustness of
  the process

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Caveats

• Caveat 2 Q8 requires sharing proprietary
  information with FDA
• Different relationship with FDA. Industry may be
  slow to embrace this relationship.
• Caveat 3 Design space still a pilot program
  for FDA
• Not totally accepted or understood. Great
  potential savings, but still a risk.
• Design space is proposed by the applicant and is
  subject to regulatory assessment and approval.
• Caveat 4 Documentation is critical
• The approach that is decided upon must be
  recorded, that approach must have controls to
  verify that it is being adhered to.

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Summary

• Adhering to ICH Q8 promotes process understanding
  and the identification of critical quality
  attributes that can define information required
  to meet the goals of the Pharmaceutical cGMPs
  for the 21st Century
• Adhering to ICH Q8 documents design space
  parameters, quantifies CQAs.
• Assists the operation of Quality Systems
• Supports the use of risk based assessment in
  validation
• Allows changes (within the design space) to occur
  without imparting additional regulatory testing
  or revalidation

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Summary

• Guidance for Industry, Q8 Pharmaceutical
  Development
• When performed properly, process development will
  provide the basis for more positive developments
• Process improvement
• Process is fully understood, efficiencies (or
  problems) can be identified and improved (or
  rectified)
• Process control requirements 
• Identify controls that affect critical quality
  attributes
• Proactively change controls to improve process

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Summary

• Guidance for Industry, Q8 Pharmaceutical
  Development
• When performed properly, process development will
  provide the basis for more positive developments
  (contd)
• Process validation
• Critical process parameters are identified and
  measured
• Validation work is mostly performed during
  design/development
• No revalidation for changes made within the
  design space
• Continuous process verification
• Reduce end of process testing - RTPR
• Identify problems as they occur and immediately
  implement corrective action to save batch or
  decision to destroy batch rather than after batch
  completion opportunity to save batches,
  reduce rework and scrap

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Summary

• Validation Plan
• Emphasis on science based knowledge
• Identify proper programming/configuration
  boundaries
• Document verification of CPP - CQA relationships
• Document control of Critical Process Parameters
• Use the data collected from the Design of
  Experiments
• Create the design space
• Document the design space
• Focus on design verification that has occurred
• Document systems installation
• Execute a high level operational test
• Do not depend on a handful of tests, use the
  entire body of process and control knowledge to
  verify control of operation

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Brian C. Stephens brian.c.stephens_at_us.abb.com 919.
365.3822