GMP%20Inspections%20

1
GMP Inspections A Global PerspectiveAuditing
of Computerised System Suppliers

• IPCMF ISPE Conference
• Global Pharma NetworksTom Farmer
• 25th June 2004

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Overview of Presentation

• Reasons to Audit Computerised System Suppliers
• Outline Procedure for Audit
• Case Studies/Examples
• Overview of Audit Repository Centre (ARC)
• Typical Issues/Observations
• Summary and Conclusions

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Reasons to Audit Suppliers

• Business Reasons
• Risk Management
• Good Practice
• Cost/Schedule/Quality Benefits
• Regulatory
• Requirements and Expectations

4
Business Reasons

• Risk Assessment
• Regulatory Impact
• Data Integrity
• Security
• Product Quality
• Business Risk
• Risk To manufacturing/process equipment
• Corporate Reputation
• Safety Concerns
• Patient Safety
• Environmental Safety
• Supplier Audit is not part of Risk Assessment as
  such, but an integral part of the overall Project
  Management process which includes Risk Management.

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Business Reasons (Cont.)

• Good Practice
• Communication/Develop Relationships
• Helps identify misunderstandings and risks
• Set or clarify expectations and intentions with
  regard to documentation other deliverables
• Identify potential gaps in procedures (eg change
  control, configuration management) at an early
  stage, so they can be addressed with minimal
  impact.
• Cost/Schedule/Quality Benefits
• Reduce Rework
• On-Time Delivery
• Aim for Right First Time

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GMP Regulations

• EU Vol 4 Annex 11
• 21 CFR Part 210, 211 (Drugs)
• 21 CFR Part 820 (Medical Devices)
• 21 CFR Part 11 (Electronic Records Signatures)
• ICH Q7A (Active Pharmaceutical Ingredients)

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EU Regulations

• EC Guide to GMP for Medicinal Products
• Vol 4, Annex 11
• 5. The software is a critical component of a
  computerised system. The user of such software
  should take all reasonable steps to ensure that
  it has been produced in accordance with a system
  of Quality Assurance. (emphasis supplied)

ICH

• Q7A (API Manufacturing)
• Not explicit regarding requirement for supplier
  audits (ie Supplier audits/assessments not
  stated as mandatory)

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FDA Regulations

• Do not explicitly mandate computerised system
  supplier audits, with possible exception for
  Medical Devices (21 CFR 820)
• But note that for Medical Devices, computer
  system supplier could be providing components
  that are part of the finished product.

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FDA Regulations (Cont.)

• 21 CFR 820.50 (a)
• Each manufacturer shall establish and maintain
  procedures to ensure that all purchased or
  otherwise received product and services conform
  to specified requirements. (a) Evaluation of
  suppliers, contractors, and consultants. Each
  manufacturer shall establish and maintain the
  requirements, including quality requirements,
  that must be met by suppliers, contractors, and
  consultants.
• Each manufacturer shall
• (1) Evaluate and select potential suppliers,
  contractors, and consultants on the basis of
  their ability to meet specified requirements,
  including quality requirements. The evaluation
  shall be documented. (emphasis supplied)
• (2) Define the type and extent of control to be
  exercised over the product, services, suppliers,
  contractors, and consultants, based on the
  evaluation results.
• (3) Establish and maintain records of acceptable
  suppliers, contractors, and consultants.

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FDA Warning Letter Oct 2003

• 4. Your firm failed to evaluate and select
  potential suppliers on the basis of their ability
  to meet specified requirements, including quality
  requirements with all evaluations documented as
  required by 21 CFR 820.50(a)(1). You failed to
  document supplier audits and your audit procedure
  (PUR-0200) fails to describe supplier audit
  procedures FDA 483, Item 7.

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FDA Regulations

• 21 CFR Part 11
• Again, not explicit on supplier audits, but
  implied by the Validation and Training
  requirements
• Need to look to FDA guidance documents

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FDA Guidelines

• For validation, Scope and Application guideline
  specifically references
• FDAs guidance for industry and FDA staff General
  Principles of Software Validation (CDRH -
  Medical Device guidance)
• GAMP 4 Guide
• Guidance for Industry - Part 11, Electronic
  Records Electronic Signatures Scope and
  Application
• We recommend that you base your approach on a
  justified and documented risk assessment and a
  determination of the potential of the system to
  affect product quality and safety, and record
  integrity.
• Convergence in approach to computerised systems
  across the different regulatory groups (CDER,
  CBER, CDRH)

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General Principles of Software Validation Final
Guidance for Industry and FDA Staff (CDRH - Jan
2002)

• 6.3. VALIDATION OF OFF-THE-SHELF SOFTWARE AND
  AUTOMATED EQUIPMENT
• Where possible and depending upon the device risk
  involved, the device manufacturer should consider
  auditing the vendors design and development
  methodologies (empasis supplied) used in the
  construction of the OTS software and should
  assess the development and validation
  documentation generated for the OTS software.
  Such audits can be conducted by the device
  manufacturer or by a qualified third party. The
  audit should demonstrate that the vendors
  procedures for and results of the verification
  and validation activities performed the OTS
  software are appropriate and sufficient for the
  safety and effectiveness requirements of the
  medical device to be produced using that software.

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GAMP Guideline

• Section 7.1 - Determining Validation Strategy
• Suppliers should be formally assessed as part of
  the process of selecting a supplier and planning
  for validation. The decision whether to perform
  a Supplier Audit should be documented and based
  on a Risk Assessment and categorisation of the
  system components.
• Also highlights role of end-user in assisting and
  educating suppliers
• Appendix M2 Audit Guideline and Checklist

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Other Industry Guidelines

• PIC/S GOOD PRACTICES FOR COMPUTERISED SYSTEMS
  IN REGULATED GXP ENVIRONMENTS (Aug 03)
• The assurance of the reliability of a Suppliers
  software products is attributable to the quality
  of the software engineering processes followed
  during development. This should include design,
  coding, verification testing, integration, and
  change control features of the development life
  cycle, (including after sales support). In order
  for customers to have confidence in the
  reliability of the products, they should evaluate
  the quality methodology of the supplier for the
  design, construction, supply and maintenance of
  the software.(emphasis supplied) A formal,
  extensive review of the history of the Supply
  Company and the software package may be an option
  to consider where an additional degree of
  assurance of the reliability of the software is
  needed. This should be documented in a Supplier
  Audit Report.

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Other Industry Guidelines (Cont.)

• PDA TR 32 Auditing of Suppliers providing
  Computer Products and Services for Regulated
  Pharmaceutical Operations
• Includes a very detailed procedure and checklist
  for supplier audits
• Basis of audit procedure for Audit Repository
  Centre (ARC) shared audits

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Summary Reasons to Audit Suppliers

• If Predicate Rules do not explicity mandate
  Supplier Audits, why conduct them?
• Business Benefits
• Risk Management
• Good Practice
• Cost/Schedule/Quality
• Regulatory expectations
• FDA Guidelines Requirements for System
  Validation
• Implication of Industry Guidelines (GAMP, PIC/S,
  PDA etc)
• Audits are not mandatory but are considered good
  practice, and it is for the regulated user to
  determine any auditing needs, scope and
  standards. Recommend that the need for supplier
  audit/assessment be linked to Risk Assessments
  (and GAMP Categorisation)

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Summary Reasons to Audit Suppliers

• Organisations are expected to demonstrate control
  of the processes and systems that affect data
  integrity, product quality, and patient safety
• Quality cannot be inspected or tested into the
  finished product it needs to be designed and
  built in
• For software, one method to help achieve this is
  to follow a formal software development lifecycle
  (SDLC).
• Audit of suppliers helps ensure that a SDLC is in
  place and is followed.

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Approach to Supplier Audits
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Approach to Supplier Audits

• Pharma Industry has not yet formally embraced a
  single standard method for supplier audit, in
  spite of regulatory expectation to evaluate
  suppliers as part of the technical acquisition
  process.
• Possible sources
• GAMP 4 VPCS Best Practice Guide
• PDA TR32
• PIC/S
• ISO 10011 Guidelines for auditing quality systems
  Part 1 Auditing
• Other industry guidelines
• Have procedure/SOP in place, and ensure personnel
  are trained accordingly.

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Approach to Supplier Audits (Cont.)
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Approach to Audits - Initiation

• Determine Need for Audit
• Based on Risk Assessment
• System Categorisation
• System Scale and Complexity
• Define appropriate Audit Type
• Document justification for Audit (or otherwise)
• As part of Risk Assessment and/or within
  Validation Master Plan

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Risk Assessment (GAMP App M3)
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GAMP Software Categorisations
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GAMP GLP Good Practice Guide
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Audit types

• Postal Audits / Assessments
• System Audit / Detailed Audit
• Surveillance Audit / Monitoring Audit
• Joint Audits
• Shared Audits

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Approach to Audits Planning

• End User inputs
• Risk Assessment System Categorisation
• Supplier Audit Procedure and Standard Checklist
• Validation Master Plan
• System Specifications/User Requirements/Project
  Brief
• Supplier Inputs (If available)
• Supplier Profile
• Organisation Chart
• Product/Service Details
• Development Methodology
• Proposal/Quotation

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Approach to Audits Planning (Cont.)

• Preparation
• Audit Agenda
• Audit Specific Checklist
• Contact Supplier
• Agree date and timescales with Supplier
• Copy Supplier with agenda and checklist
• Confirm resource availability with Supplier

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Approach to Audits - Conduct

• Typical Agenda
• Introductions
• Company Overview Presentation (including Quality
  System Overview/Workflow Methodology)
• Office/Facility Tour
• Inspection of selected Audit Areas
• Include QMS and Procedures, Project
  Documentation, Maintenance etc
• Review Findings/Observations
• Present Findings to Supplier

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Approach to Audits Checklist/Audit Areas

• GAMP
• Company Overview
• Organisation and Quality Management
• Planning and Product/Project Management
• Specifications
• Implementation
• Testing
• Completion and Release
• Support/Maintenance
• Supporting Processes and Activities

• PDA TR 32
• Quality System
• Project Management
• Methodology
• Testing
• Configuration Management
• Manufacturing
• Document and Records Management
• Security
• Training and Education
• Maintenance

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Comment on use of checklists

• Need to be careful with use of standard
  checklists
• Key is in preparation for audit
• Tailor audit criteria and checklist based on
  supplier product and/or services
• Try to ensure that audit criteria is suitably
  descriptive within checklist
• When documenting audit execution
• Try to avoid simple yes/no type responses
• Include comments as appropriate to elaborate on
  and explain answers and observations
• Include objective evidence, by unambiguous
  reference, or attachment

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Approach to Audits Observations

• Communicate observations back to Supplier for
  response
• Consider categorisation of observations (eg
  Critical, Major, Minor, Comment only)
• Helps to set priorities for actions
• Helps justification of decision
• Highlight positives also ie where supplier
  meets or exceeds industry best practices

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Approach to Audits Report

• Audit Report to be issued for approval
• Include completed checklist, not just
  observations/findings
• Include positive observations also
• Formal Response on observations required from
  Supplier

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Approach to Audits Follow Up

• Need to ensure close out of observations by
  supplier
• Remember, past performance is a good indicator of
  future performance (but not a guarantee)
• Continuous monitoring is important, particularly
  for larger projects and customised systems
• Use audit as an opportunity to establish open
  dialog and collaboration with your suppliers

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Case Studies / Examples
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Case Study/Example 1

• Operations identify need for new automated
  system
• Projects Group prepare equipment specification
• Projects Group select Vendor/Supplier
• Main Criteria Used
• Cost (Cheapest!)
• Technology
• At FAT stage, Projects Group request input from
  Quality Unit / Validation

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Case Study/Example 1 (Cont.)

• Assessment/Audit planned executed
• Findings
• No Quality Systems/Procedures in place at
  supplier
• Poor Design Documentation (No Functional
  Specification, etc)
• Poor Change management/configuration management
• Planned FAT Testing of limited benefit from
  Validation perspective additional testing
  required.

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Case Study/Example 1 (Cont.)

• Actions
• DQ developed and executed
• Develop additional detailed test procedures for
  FAT, Site testing qualification
• Impact
• Project Schedule Impact (Project Delayed)
• Cost Impact (Internal costs as well as Supplier)

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Case Study / Example 2

• Project Group include Quality Unit /Validation at
  project definition phase.
• Postal Assessment of all prospective suppliers,
  followed by conference call with each supplier
  (ie Quality issues addressed as part of bid
  analysis, as well as technical and commercial
  issues)
• Prefered Supplier agreed by all parties
  (Operations, Projects, Quality)

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Case Study / Example 2 (cont.)

• Detailed systems audit conducted in selected
  suppliers premises at start of project
• Limited/minor issues only raised at audit
• On-going monitoring of supplier during project,
  up to system delivery to site
• On time, within budget no surprises

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Case Study / Example 3

• Replacement of Laboratory Analysers
• Categorised as GAMP Category 3 (Standard
  Software), but systems considered GxP critical
• Supplier Audit indicated by company SOP
• Issues
• Multiple Suppliers (gt 6)
• Local Supplier location not the same as System
  Development location.

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Case Study / Example 3 (Cont.)

• Following consultation with end-user, decided on
  Postal Audit (GAMP VPCS Good Practice Guide used
  as template).
• Review of responses followed up by conference
  call with supplier to clarify written replies and
  request additional information
• Reserved right to request face-to-face detailed
  audit, if deemed necessary
• Main Benefits - Cost Saving.
• Also, get involvement/feedback from system
  development group, as well as local distribution
  and support groups.

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Case Study / Example 4

• Manufacturing Control System
• Categorised as GAMP 4/5, and system considered
  GMP Critical
• Challenges
• Scale of project
• Multiple locations involved
• Quality Unit an integral part of project process.
• Aim to instill a culture of Right First Time

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Case Study / Example 4 (Cont.)

• Supplier Audit conducted as part of selection
  process
• Follow-up surveillance audits/reviews during
  implementation (monthly) to supplement suppliers
  internal quality group.
• Benefits
• Identified issues at an earlier stage, and helped
  minimise impact
• Reduced Rework/Retesting on site
• Helped ensure overall schedule targets met

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Shared Audits
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ARC (Audit Repository Centre)

• Centralised repository for audit reports,
  available to subscribing end-user companies. Not
  strictly limited to computerised system
  suppliers.
• Statistics (as at June 2004)
• Audits Available 28
• Audits Scheduled - 13
• Audits under consideration 18
• Links
• http//www.auditcenter.com/available.htm
• http//www.auditcenter.com/scheduled.htm
• http//www.auditcenter.com/consideration.htm

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ARC (Cont)

• Probably more appropriate as part of corporate
  system selection, may not be fully suitable for
  local (smaller) system implementations.
• Access to ARC report does not absolve end-user
  from responsibility need to analyse audit
  results and observations, and make decision on
  supplier acceptability.
• For project based systems, will still require
  on-going monitoring of supplier/implementer

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Typical Issues / Observations
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Considerations Client side

• Timing of Audit/Assessment
• Scope / Intent of Audit
• Supplier Preparation (for Audit)
• Follow up on Audit Observations/Findings
• Overall business benefits of Quality (and
  Operations) input at the design and procurement
  stages

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Typical Issues Supplier Side

• Training
• In-House Quality Procedures
• Regulatory Issues/GAMP/21 CFR Part 11
• Technical Training
• Change Control
• Typical focus on cost and schedule impact,
  lacking definition of re-test requirements and
  traceability
• Configuration Management
• Uncertainty as to requirements, Procedures and
  Baselines not clearly defined

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Summary and Conclusions
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Summary

• Supplier Audit does not solve all problems, and
  is not a standalone process, but is a integral
  part of the overall project management process to
  help ensure sucessful system implementation
• Use Risk Assessment to determine need for
  Audit/Assessment
• Focus on Business Benefits, as well as Regulatory
  Needs
• Improve quality of delivered systems
• Schedule Impact/Delivery to Market
• Cost Reduction (Minimise Rework)
• Teamwork Partnership
• Enhance co-operation between Quality, Projects
  Operations
• Develop relationship and Improve communication
  with supplier

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Questions?

• Contact Tom Farmer
• Mobile [phone]
• tom.farmer_at_global-networksgroup.com