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Prepare for and
Handle FDA Validation
    Inspections

            William E. Hall, Ph.D.
  President, Hall & Pharm. Associates, Inc.
Some Potential Triggers for an
     Inspection of Your Validation
               Program
—  ‘For Cause’ inspection – e.g. from atypical number
  of complaints or when field samples are subpotent

—  As result of findings in a ‘Systems’ inspection
—  On-site observations of deficiencies – e.g. operators
  not apparently trained, poorly written procedures,
  problems in the batch records
Phases of Activities
—  Pre-Inspection Activities
—  Activities During the Inspection
—  Post-Inspection Activities
Pre-Inspection Activities
—  Internal Audits – should be doing them anyway
  —  Are they by area or by subject (such as validation)?
  —  Could do a ‘gap analysis’ or a risk assessment of
      validation program
  —  Perform using same team that will host the
      inspection (QA/QC, Reg Affairs, Production,
      Engineering)
Value of Self Audits or
       Mock Inspections
—  Gives you a chance to identify and fix problems
—  Allows for ‘continuous improvement
—  Permits identification of poor or incomplete
  documentation
Pre-Inspection Activities
Review of Critical Documentation
—  Validation Master Plan – A good place to start.
   —  Is it current?
   —  Does it follow traditional or new ‘life cycle’ approach?
       —  If ‘life cycle’ how is the monitoring data being collected and evaluated?
   —  Helpful to have a diagram showing the chronological sequences of
       events in the execution or implementation of the validation program,
       e.g. design           equipment qual        process qual      monitoring

—  Change Control Documentation
   —  Have any of the changes been indicated to have impact on the
       validation status of processes, equipment, or critical utilities. If so,
       have the appropriate follow-up activities (such as revalidation) been
       completed and signed off?
   —  Review ‘as built’ drawings-do they accurately reflect any changed
       made to equipment?
Pre-Inspection Activities
Review of Critical SOPs for Accuracy

—  Do you know what are your critical SOPs in relation
  to your SOPs?
  —  Calibration program (part of PM program) for critical
    gages and instruments-take a ‘walkabout’ and see if
    the stickers on critical instruments is current, i.e. are
    any of the calibrations past due?
Pre-Inspection Activities
Review of Critical Documentation

—  Review of Training Program & Records
  Ø  Are they up-to-date?
  Ø  Include laboratory personnel as well
  Ø  Have you captured the expertise of outside services
    that calibrate, clean, advise (consultants)? i.e. do you
    have a file of resumes on hand
Pre-Inspection Activities
Written Procedure for Handling the Inspection Itself

—  Does one exist? Maybe not for smaller companies
—  If not, there is still time to write one
—  Allocation of resources during the inspection-who,
  what, when, where?

—  Practice what you are going to do- ”How do you get
  to Carnegie Hall?” Practice, practice, practice!
Pre-Inspection Activities
Review of Critical Quality Systems that interface
with Validation

—  Change Control Procedure
—  Recall Procedure
—  Annual Product Review Procedure
—  Deviations/Exceptions Procedure
—  Preventative Maintenance (PM) Program
Pre-Inspection Activities
Review Equipment Qualification Documentation

—  Design Qualification
—  Installation Qualification
—  Operational Qualification
—  Performance Qualification
Pre-Inspection Activities
Review Process Validation Documents

—  Were there failures or deviations during the
  execution of the validations?
  Ø  Review findings, follow-ups, actions
—  Are there Summary Reports and Protocols readily
  available?
Activities & Responsibilities
   During the Inspection
—  The inspection of the validation program or some
  elements of it will probably occur during a regular GMP
  or Quality Systems inspection

—  Therefore, the actions would be the same, namely:
  —  Follow the SOP for handling inspections
  —  Provide documents to inspector(s) in a timely fashion
  —  Notify all employees that FDA is on-site and they should
      follow protocol when asked questions; remember that “I
      don’t know the answer to your question, but I will locate
      someone who can answer it” is a valid response.
  —  Provide document reviewers prior to handing original
      documents to inspector(s)
Activities & Responsibilities
   During the Inspection
—  Make lists of documents & doc numbers requested by FDA
    and make 2 copies of every document (one to be retained)
—  Request a daily debriefing of the day’s findings by the
    inspector(s); during that debriefing, it is reasonable to
    inquire about the next day’s inspection activities.
—  Make sure the proper person answers the questions of the
    inspectors (i.e. the person having the most intimate
    knowledge of the issue)
—  Create flow diagrams of the various manufacturing
    processes (if they don’t already exist); numbered steps and
    diagrams will facilitate the inspection and help inform the
    inspector as to how the overall process is carried out.
    Identify critical processes and provide a rational for
    determining critical steps.
                                   More…………
Activities & Responsibilities
   During the Inspection
Have the validation-related information available such
as:

—  Validation documentation for critical utilities, e.g.
  Purified Water system

—  Preventative Maintenance (PM) program
Activities & Responsibilities
   During the Inspection
—  Create good listening habits-Reading between the
  lines-try to figure out the reason for the questions
  and how the answers might lead to further
  questions, i.e. the ‘art of understanding’

—  Recognize the critical importance of taking good
  and copious notes during the inspection

—  Involve upper management in the findings and
  directions of the ongoing inspection
Post-Inspection Activities
—  Take very good notes during the exit interview, as
  this will be a preview of events to come. Ask
  questions of the inspector(s) to gather information
  on any observation that you are not completely sure
  of the meaning. Gather all the details.

—  You will be left with any FDA 483 comments, but
  will not receive the EIR (Establishment Inspection
  Report) for quite some time. This is the detailed
  findings of the inspector.
Post-Inspection Activities
—  Appoint a group of subject matter experts (SMEs) to a
  committee, who will be charged with responding to the
  FDA findings. The group should be chaired by the QA or
  Compliance representative and should meet
  immediately (if not sooner).
—  Evaluate the regulatory report (citations) and develop a
  response with an appropriate time-line for completion of
  corrective actions. A “working master plan” is
  appropriate and should include time lines and the name
  of the person responsible for completing the activity.
—  Seek additional information and clarification by picking
  up the phone and contacting the investigator-this is
  welcomed by the investigator(s)/inspectors(s).
Post-Inspection Activities
—  Prepare a proactive written response to the
  citations and submit to management for approval.
Case Study # 1
During an inspection of your validation program, an
inspector indicates that he is interested in seeing
more information to assure that the manufacturing
equipment is being properly cleaned and maintained.
What type of documentation would you suggest to the
inspector so that he/she could choose specific
documents to review?
Case Study # 2
During review of your validation data related to blend
sampling, an inspector notes that you have no
rationale for the sample sites, number of samples,
and justification for your sampling program. What
suggestions would you make, what groups or
departments should be contacted, and how would you
proceed?
Case # 3
An inspector indicates to you, as the host, that he is
not particularly pleased with some of the Corrective &
Preventative Action (CAPAs) investigations that he is
reviewing. Specifically, he has a problem with the root
cause analysis and the fact that the CAPA’s have not
all been closed out after a considerable period of
time. Who should be involved in responding and
answering the inspectors specific concerns and how
should they proceed?
Case Study # 4
An inspector arrives at your facility and immediately
begins a detailed inspection in a specific
manufacturing area and of records for a specific
batch of product. During the initial discussions, she
mentions that the FDA has received laboratory data
from testing of shelf samples that seem to indicate
that a certain batch of product has fallen below
specifications before the expiry date has been
reached. How would proceed? What is the potential
impact of the product validation as well as product
still on the market and how would you evaulate this
situation?
Case Study # 5
In reviewing your cleaning validation program, an
inspector is spending considerable time reviewing
your rationale for doing product grouping and “worst
case” approach to your cleaning validation studies.
Can you see any way to salvage the situation and give
the inspector more confidence in your approach prior
to his exiting the facility?

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Fda validation inspections

  • 1. Prepare for and Handle FDA Validation Inspections William E. Hall, Ph.D. President, Hall & Pharm. Associates, Inc.
  • 2. Some Potential Triggers for an Inspection of Your Validation Program —  ‘For Cause’ inspection – e.g. from atypical number of complaints or when field samples are subpotent —  As result of findings in a ‘Systems’ inspection —  On-site observations of deficiencies – e.g. operators not apparently trained, poorly written procedures, problems in the batch records
  • 3. Phases of Activities —  Pre-Inspection Activities —  Activities During the Inspection —  Post-Inspection Activities
  • 4. Pre-Inspection Activities —  Internal Audits – should be doing them anyway —  Are they by area or by subject (such as validation)? —  Could do a ‘gap analysis’ or a risk assessment of validation program —  Perform using same team that will host the inspection (QA/QC, Reg Affairs, Production, Engineering)
  • 5. Value of Self Audits or Mock Inspections —  Gives you a chance to identify and fix problems —  Allows for ‘continuous improvement —  Permits identification of poor or incomplete documentation
  • 6. Pre-Inspection Activities Review of Critical Documentation —  Validation Master Plan – A good place to start. —  Is it current? —  Does it follow traditional or new ‘life cycle’ approach? —  If ‘life cycle’ how is the monitoring data being collected and evaluated? —  Helpful to have a diagram showing the chronological sequences of events in the execution or implementation of the validation program, e.g. design equipment qual process qual monitoring —  Change Control Documentation —  Have any of the changes been indicated to have impact on the validation status of processes, equipment, or critical utilities. If so, have the appropriate follow-up activities (such as revalidation) been completed and signed off? —  Review ‘as built’ drawings-do they accurately reflect any changed made to equipment?
  • 7. Pre-Inspection Activities Review of Critical SOPs for Accuracy —  Do you know what are your critical SOPs in relation to your SOPs? —  Calibration program (part of PM program) for critical gages and instruments-take a ‘walkabout’ and see if the stickers on critical instruments is current, i.e. are any of the calibrations past due?
  • 8. Pre-Inspection Activities Review of Critical Documentation —  Review of Training Program & Records Ø  Are they up-to-date? Ø  Include laboratory personnel as well Ø  Have you captured the expertise of outside services that calibrate, clean, advise (consultants)? i.e. do you have a file of resumes on hand
  • 9. Pre-Inspection Activities Written Procedure for Handling the Inspection Itself —  Does one exist? Maybe not for smaller companies —  If not, there is still time to write one —  Allocation of resources during the inspection-who, what, when, where? —  Practice what you are going to do- ”How do you get to Carnegie Hall?” Practice, practice, practice!
  • 10. Pre-Inspection Activities Review of Critical Quality Systems that interface with Validation —  Change Control Procedure —  Recall Procedure —  Annual Product Review Procedure —  Deviations/Exceptions Procedure —  Preventative Maintenance (PM) Program
  • 11. Pre-Inspection Activities Review Equipment Qualification Documentation —  Design Qualification —  Installation Qualification —  Operational Qualification —  Performance Qualification
  • 12. Pre-Inspection Activities Review Process Validation Documents —  Were there failures or deviations during the execution of the validations? Ø  Review findings, follow-ups, actions —  Are there Summary Reports and Protocols readily available?
  • 13. Activities & Responsibilities During the Inspection —  The inspection of the validation program or some elements of it will probably occur during a regular GMP or Quality Systems inspection —  Therefore, the actions would be the same, namely: —  Follow the SOP for handling inspections —  Provide documents to inspector(s) in a timely fashion —  Notify all employees that FDA is on-site and they should follow protocol when asked questions; remember that “I don’t know the answer to your question, but I will locate someone who can answer it” is a valid response. —  Provide document reviewers prior to handing original documents to inspector(s)
  • 14. Activities & Responsibilities During the Inspection —  Make lists of documents & doc numbers requested by FDA and make 2 copies of every document (one to be retained) —  Request a daily debriefing of the day’s findings by the inspector(s); during that debriefing, it is reasonable to inquire about the next day’s inspection activities. —  Make sure the proper person answers the questions of the inspectors (i.e. the person having the most intimate knowledge of the issue) —  Create flow diagrams of the various manufacturing processes (if they don’t already exist); numbered steps and diagrams will facilitate the inspection and help inform the inspector as to how the overall process is carried out. Identify critical processes and provide a rational for determining critical steps. More…………
  • 15. Activities & Responsibilities During the Inspection Have the validation-related information available such as: —  Validation documentation for critical utilities, e.g. Purified Water system —  Preventative Maintenance (PM) program
  • 16. Activities & Responsibilities During the Inspection —  Create good listening habits-Reading between the lines-try to figure out the reason for the questions and how the answers might lead to further questions, i.e. the ‘art of understanding’ —  Recognize the critical importance of taking good and copious notes during the inspection —  Involve upper management in the findings and directions of the ongoing inspection
  • 17. Post-Inspection Activities —  Take very good notes during the exit interview, as this will be a preview of events to come. Ask questions of the inspector(s) to gather information on any observation that you are not completely sure of the meaning. Gather all the details. —  You will be left with any FDA 483 comments, but will not receive the EIR (Establishment Inspection Report) for quite some time. This is the detailed findings of the inspector.
  • 18. Post-Inspection Activities —  Appoint a group of subject matter experts (SMEs) to a committee, who will be charged with responding to the FDA findings. The group should be chaired by the QA or Compliance representative and should meet immediately (if not sooner). —  Evaluate the regulatory report (citations) and develop a response with an appropriate time-line for completion of corrective actions. A “working master plan” is appropriate and should include time lines and the name of the person responsible for completing the activity. —  Seek additional information and clarification by picking up the phone and contacting the investigator-this is welcomed by the investigator(s)/inspectors(s).
  • 19. Post-Inspection Activities —  Prepare a proactive written response to the citations and submit to management for approval.
  • 20. Case Study # 1 During an inspection of your validation program, an inspector indicates that he is interested in seeing more information to assure that the manufacturing equipment is being properly cleaned and maintained. What type of documentation would you suggest to the inspector so that he/she could choose specific documents to review?
  • 21. Case Study # 2 During review of your validation data related to blend sampling, an inspector notes that you have no rationale for the sample sites, number of samples, and justification for your sampling program. What suggestions would you make, what groups or departments should be contacted, and how would you proceed?
  • 22. Case # 3 An inspector indicates to you, as the host, that he is not particularly pleased with some of the Corrective & Preventative Action (CAPAs) investigations that he is reviewing. Specifically, he has a problem with the root cause analysis and the fact that the CAPA’s have not all been closed out after a considerable period of time. Who should be involved in responding and answering the inspectors specific concerns and how should they proceed?
  • 23. Case Study # 4 An inspector arrives at your facility and immediately begins a detailed inspection in a specific manufacturing area and of records for a specific batch of product. During the initial discussions, she mentions that the FDA has received laboratory data from testing of shelf samples that seem to indicate that a certain batch of product has fallen below specifications before the expiry date has been reached. How would proceed? What is the potential impact of the product validation as well as product still on the market and how would you evaulate this situation?
  • 24. Case Study # 5 In reviewing your cleaning validation program, an inspector is spending considerable time reviewing your rationale for doing product grouping and “worst case” approach to your cleaning validation studies. Can you see any way to salvage the situation and give the inspector more confidence in your approach prior to his exiting the facility?