Handling deviations & unexpected results during method validation
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
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).
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?