Prepare for andHandle 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 ActivitiesReview 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 ActivitiesReview 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 ActivitiesReview 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 ActivitiesWritten 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 ActivitiesReview of Critical Quality Systems that interfacewith Validation Change Control Procedure Recall Procedure Annual Product Review Procedure Deviations/Exceptions Procedure Preventative Maintenance (PM) Program
Pre-Inspection ActivitiesReview 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 InspectionHave the validation-related information available suchas: 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 # 1During an inspection of your validation program, aninspector indicates that he is interested in seeingmore information to assure that the manufacturingequipment is being properly cleaned and maintained.What type of documentation would you suggest to theinspector so that he/she could choose specificdocuments to review?
Case Study # 2During review of your validation data related to blendsampling, an inspector notes that you have norationale for the sample sites, number of samples,and justification for your sampling program. Whatsuggestions would you make, what groups ordepartments should be contacted, and how would youproceed?
Case # 3An inspector indicates to you, as the host, that he isnot particularly pleased with some of the Corrective &Preventative Action (CAPAs) investigations that he isreviewing. Specifically, he has a problem with the rootcause analysis and the fact that the CAPA’s have notall been closed out after a considerable period oftime. Who should be involved in responding andanswering the inspectors specific concerns and howshould they proceed?
Case Study # 4An inspector arrives at your facility and immediatelybegins a detailed inspection in a specificmanufacturing area and of records for a specificbatch of product. During the initial discussions, shementions that the FDA has received laboratory datafrom testing of shelf samples that seem to indicatethat a certain batch of product has fallen belowspecifications before the expiry date has beenreached. How would proceed? What is the potentialimpact of the product validation as well as productstill on the market and how would you evaulate thissituation?
Case Study # 5In reviewing your cleaning validation program, aninspector is spending considerable time reviewingyour rationale for doing product grouping and “worstcase” approach to your cleaning validation studies.Can you see any way to salvage the situation and givethe inspector more confidence in your approach priorto his exiting the facility?