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?