1. Preparing for and Handling an FDA Inspection May 19, 2016

2. ©2016 Maetrics. All Rights Reserved.2 FDA Authority4 What to Do Before an Inspection10 What to Do During an Inspection16 What to Do After an Inspection32 Inspections

3. ©2016 Maetrics. All Rights Reserved.3 FDA Authority4 What to Do Before an Inspection10 What to Do During an Inspection16 What to Do After an Inspection32 Inspections

4. ©2016 Maetrics. All Rights Reserved.4 FDA Authority  Section 704 of the FD&C Act [21 U.S.C. 374] provides the basic authority for establishment inspections Section 704 of the FD&C Act  Authorizes FDA to enter, and to inspect at reasonable times, within reasonable limits, and in a reasonable manner, establishments or vehicles being used to process, hold or transport food, drugs, devices, tobacco products, or cosmetics  Extends to what is reasonably necessary to achieve the objective of the inspection  This authority includes inspections of factories, warehouses, establishments, and vehicles, and all pertinent equipment, finished and unfinished materials, containers, and labeling therein where products are manufactured or held Section 704 of the FD&A Act

5. ©2016 Maetrics. All Rights Reserved.5 FDA Authority  Consent to inspect by company is not required  A warrant is not necessary (warrant is only necessary if litigation is on-going...e.g., FDA investigator wants to inspect specific filter used in a process because of investigation into patient deaths...)  Miranda warnings are not necessary (only U.S. Marshals, not FDA, are responsible for arresting!)  Refusal to permit an inspection is a violation of the FD&C Act Permitting Inspections

6. Inspections ©2015 Maetrics. All Rights Reserved.6 Being Prepared Improves Your Odds Click to edit Master text styles

7. ©2016 Maetrics. All Rights Reserved.7 Types of FDA Inspections 1Abbreviated QSIT – Two subsystems; Corrective and Preventive Actions (CAPA) plus Production and Process Controls (P&PC) or Design Controls 2Comprehensive QSIT - The four major subsystems; Management Controls, Design Controls, CAPA and P&PC 3Compliance Follow-up As directed by inspectional guidance and elements of QSIT Special For Cause / Risk Based Work Plan As directed by inspectional guidance and elements of QSIT

8. ©2016 Maetrics. All Rights Reserved.8 Selection of Firms to Inspect  Pre-Market and Pre-Clearance inspections under MDUFMA  Manufacturers of Class III devices that have never been inspected  Compliance Follow Up/For Cause Inspections  Manufacturers of high risk devices which can be identified by:  Special Assignment from CDRH;  Devices with a higher frequency of recalls and MDRs;  Devices that are driven by software and those with rapidly evolving technological changes; or,  New devices that have not been manufactured and distributed for very long  Single Use Device Re-processors What you make affects the Odds

9. ©2016 Maetrics. All Rights Reserved.9 FDA Authority4 What to Do Before an Inspection10 What to Do During an Inspection16 What to Do After an Inspection32 Inspections

10. SOP - Handling Regulatory Inspections What should this SOP include:  Defining Pre-Inspection Activities (When you know they are coming)  Defining Inspection Management  Daily Close-out Meetings and Next-Day Readiness  Final Close-out Meeting  Addressing the F-483, Planning, Organization, Compiling, and Response Submission to FDA ©2015 Maetrics. All Rights Reserved.10 "By failing to prepare you are preparing to fail.“ - Benjamin Franklin

11. Pre-Inspection Activities  Create an Inspection Response Team  IDENTIFY Team Representatives from  The Quality Unit  Design Development  Manufacturing  Warehousing and Distribution; Purchasing  IT  Facilities and Engineering  Validation  Identify Primary and Secondary Hosts (Part of the Response Team, Front Room Leads)  Identify Scribes (at least 4) (Part of the Response Team)  Test the Communications System  Have defined Front and Back Rooms  Set-up and functions  The Back Room Lead  The Document Request Process ©2015 Maetrics. All Rights Reserved.11 Every Firm Should Do This…

12. Pre-Inspection Activities  Review the past 482 and any regulatory letters for completion  If you are expecting a pre-approval inspection, make sure you have a copy of the filing and review it  If there are or were any recalls since the last inspection review and assure close-out  Review open complaints; are the time limits requirements met?  Review all open CAPAs; are any lingering?  Review your Quality Management Review Meeting Action Assignments  Review your internal Audit Plan and findings  Review all Out of Specification Reports; are they all closed?  Review all Out of Calibration Reports; are they all closed?  Are there job description for all GxP positions?  Review your training program compliance status—is everyone up to date? ©2015 Maetrics. All Rights Reserved.12 Every Firm Should Do This Prior To An Inspection

13. Defining Inspection Management  Two Scribes in the Front Room  The primary Scribe transcribes the proceedings  What did the Investigator say or ask?  What is he/she reviewing?  What has a SME stated?  What has the Investigator stated they will look at next, etc.?  The Host (QA Director) will enter each request on a form, written or electronically  Request goes to the Back Room for fulfillment  The Host will review every document or record that is brought to the Front Room  Quickly reviews any comments or notes for the Host from the Back Room  Ensure that this is the document or record requested before giving to the Investigator  If there is a question, Host writes the question on paper and gives to the scribe to convey to the Back Room  Host will not provide the document to the investigator until the question is adequately answered  Every SME, or other person entering the Front Room, must sign the Audit Log: Name, Date, Time ©2015 Maetrics. All Rights Reserved.13 Front Room Conduct

14. The Response Team ©2015 Maetrics. All Rights Reserved.14 A Good Team, The Best of Outcomes

15. ©2016 Maetrics. All Rights Reserved.15 FDA Authority4 What to Do Before an Inspection10 What to Do During an Inspection16 What to Do After an Inspection32 Inspections

16. I’m From The FDA ©2016 Maetrics. All Rights Reserved.16 Reception - The First Point of Contact

17. Defining Inspection Management  Inspection Host (QA Director or Manager, typically)  Greet and meet, go to designated inspection room, exchange cards  Ask for the reason for the Inspection  Ask for the FDA Form 482, Notice of Inspection, and for investigator’s credentials*  Suggest to the Inspector that you would like to provide a 15 minute Site Presentation  Site Presentation Reason and Content  Provides valuable overview of the site and surrounding area, Facilities, and Operations  History of Company  Products manufactured at site or site’s function (if not manufacturing)  Aerial shot of site and surrounding area or diagram of same** ‒What businesses are adjacent to the site? ‒Where are the major functions located at the site?  Organizational Diagram of Site Operations ‒ Who is Responsible for what? ‒Who is in charge? In case of violative actions, who is in charge at the site? ©2016 Maetrics. All Rights Reserved.17 Opening Meeting, Establishing Professional Rapport

18. Defining Inspection Management  Department Managers and Inspection Response Team  Do immediate tour of Facility ‒Facility Order ‒Facility Cleanliness, inspect all plant areas including the break rooms, lunch areas, and the restrooms! ‒Personnel Appearance and Readiness ‒Ensure all operations in process have up to date documentation!  Based on Inspection reason, additional preparation may be necessary at this point ‒For Cause: Gather information relating to the Cause - Complaints, CAPA, Recall Information ‒Pre-Approval: Gather the PMA/510(k) filing, all Related Product and Process Validation Packages ‒Bi-Annual Inspection: Review and files new products or major changes to Products, Production Schedule, all Major Change Controls since last Inspection, review all open CAPA, review open Complaints and Complaint Trends since last Inspection, and all MDR since last Inspection. Look for patterns and trends ‒Ensure all Training is up to date ‒Check status of Out of Specification Investigations, Out of Tolerance, and Out of Calibration  Inform all employees to be cautious with hallway, restroom, and break room conversations  Be aware of possible Investigator’s presence in restaurants, etc., no business talk ©2016 Maetrics. All Rights Reserved.18 While the Opening Meeting is Happening…

19. Tour ©2016 Maetrics. All Rights Reserved.19 …And this is how we manufacture that…..

20. Defining Inspection Management  A pre-defined path, before you leave the Front Room  Inform the Inspector of any Photography Policy  Determine who will accompany and who will lead the tour; minimize participation  Generally at least two escorts, one to lead; the other to scribe  Have the personnel on the path notified ahead of time  Include notification of appropriate management teams and SMEs  Have staff and SMEs nearby, but not too close  Ensure Auditor is provided with all required safety equipment  Adhere to all gowning requirements throughout the tour  Adhere to all sign-In logs throughout the tour  Make sure all Requests from the Investigator are immediately transcribed on Request Forms ©2016 Maetrics. All Rights Reserved.20 The Tour

21. The Front Room In Action ©2016 Maetrics. All Rights Reserved.21 The Inspector Questions the SME while the QA Director Oversees

22. Defining Inspection Management  Two Scribes in the Front Room  The primary Scribe transcribes the proceedings  What did the Investigator say or ask?  What is he/she reviewing?  What has a SME stated?  What has the Investigator stated they will look at next, etc.?  The Host (QA Director) will enter each request on a form, written or electronically  Request goes to the Back Room for fulfillment  The Host will review every document or record that is brought to the Front Room  Quickly reviews any comments or notes for the Host from the Back Room  Ensure that this is the document or record requested before giving to the Investigator  If there is a question, Host writes the question on paper and gives to the scribe to convey to the Back Room  Host will not provide the document to the investigator until the question is adequately answered  Every SME, or other person entering the Front Room, must sign the Audit Log: Name, Date, Time ©2016 Maetrics. All Rights Reserved.22 Front Room Conduct

23. Communications, Do’s and DON’Ts  DO  Speak the truth, always  Think carefully before responding  Clarify the question before answering, narrow the scope of the question, if possible  Respond accurately and professionally  Respond specifically and only to the question asked  DON’T  Be inaccurate or untruthful  Have an attitude or challenge the Investigator  Answer what you think the Investigator wants — clarify the question first  Answer on a topic or area that is out of your scope and expertise  Be afraid to say, “I do not know.” (That should be truthful!)  Fill durations of silence  Volunteer any SME by name ©2016 Maetrics. All Rights Reserved.23 “It is better to remain silent and thought a fool, then to speak and remove all doubt” - Anonymous

24. The Back Room ©2016 Maetrics. All Rights Reserved.24 Reality

25. Defining Inspection Management  Communications to the Back Room must be concise, clear, and accurate  All communications are recorded on paper or electronically  Absolutely no chit chat between the Front and Back Rooms - essential communication only  Requests are to be provided to the Back Room without delay and logged  Requests are to be fulfilled by the Back Room without undue delay  Requested documents or records are SME screened in the Back Room for compliance*  The FDA judges response times for requests as a reflection of the Firm’s ability to retrieve documentation and the state of their QMS  Each request is in duplicate, one stays in the Front Room, one is used by the Back Room to obtain and track all requested documents and records. If another copy is required for the Source Department, make a photocopy of the Back Room request or use email or another communication method to the Source Department retrieving the requested record  Ensure all documents are provided in triplicate and each page of each copy must be stamped  C O P Y and where appropriate C O N F I D E N T I A L  The Request Tracking Number must be entered on page 1 of each copy ©2016 Maetrics. All Rights Reserved.25 Back Room Conduct

26. Defining Inspection Management  10 Basic Steps to Request Handling  Request is initiated  Request is logged  Request is reviewed and clarified, if necessary  Request is assigned to the associated Department Manager  Requested document or record is retrieved  Document or record is photocopied x2 or x3  Each page of each copy is stamped COPY and CONFIDENTIAL, front page of each copy has REQ Number  SME reviews the document or record for compliance  Document delivered to the Front Room  Request is CLOSED and log updated ©2016 Maetrics. All Rights Reserved.26 Back Room Conduct, continued

27. Communications  Communicate in real time regarding the direction of the Inspection to:  All Department Managers  To the entire Response Team  The Back Room Lead is to prepare and distribute a daily summary of major inspection points  The Daily Summary shall contain the following fields:  Site and Auditing Body (e.g., FDA)  Day “#” Update (Day 1, Day 2, etc.)  Investigator(s) Name(s)  Reason for Inspection  Confirmed Observations (from today)  Potential Observations  Summary (List of topics/areas reviewed)  Topics/Areas for Review Tomorrow  Name of Audit Host Lead/Point of Contact ©2016 Maetrics. All Rights Reserved.27 “When all other means of communication fail, try words.” - Anonymous

28. The FDA is Here ©2016 Maetrics. All Rights Reserved.28 Your Investigator May Look Different Than This One

29. The Daily Close-Out Meeting  Request that the Investigator hold a brief daily Close-out Meeting  Listen to what the Inspector says at Close-Out Meetings  Take accurate notes, use a scribe  Ask if there are any deficiencies, any major or minor observations  Ask if there are any possible observations  Ask if the Inspector is getting everything they require, if there is any need  Ask what time to expect them in the next day, if applicable  Thank the Inspector and escort them to the exit  All Department Managers, SMEs, Response Team Members, all QA/Compliance staff remain  DO NOT LEAVE ©2016 Maetrics. All Rights Reserved.29 Best to Keep on Top of all Situations!

30. Daily Actions Post Close-Out  All Management and Response Team assemble in a designated space  Site Head, Audit Host, or Head of Compliance typically leads  Review all identified observations and possible observations  Discuss and decide what can be done to remediate each item  Can it be done NOW, before the Inspector returns the next day?  Can it be done before the close of the inspection?  Assign and execute, no one leaves until the actions are completed!  Discuss any open requests and formulate a Compliance Plan  Discuss where the inspection may go to the next day  Ensure that the target areas are in their best possible shape ©2016 Maetrics. All Rights Reserved.30 “Our real problem, then, is not our strength today; it is rather the vital necessity of action today to ensure our strength tomorrow.” - Dwight D. Eisenhower

31. ©2016 Maetrics. All Rights Reserved.31 FDA Authority4 What to Do Before an Inspection10 What to Do During an Inspection16 What to Do After an Inspection32 Inspections

32. Inspection Close and the FDA Form-483  Attendees at the closing meeting should include:  Highest ranking individual at the site  The Response Team and Critical SMEs (by invitation)  Department Heads  Maintain a sign-in roster for company attendees  The FDA Investigation Team will review inspection results, may read the F-483  Clarify any items that have been resolved with the Investigator  Ask if there will be a Closure Report (Establishment Inspection Report) and when you can expect a copy  State that you want the opportunity to redact confidential/proprietary information from the report (these are available via Freedom of Information Act)  Ask if the Investigator will recommend NAI (No Action Indicated), VAI (Voluntary Action Indicated), or OAI (Official Action Indicated). OAI may lead to a Warning Letter, Injunction, or Seizure.  Do not make any admissions of guilt to the Investigator of non-compliance ©2016 Maetrics. All Rights Reserved.32 The Closing Meeting

33. What should I do after the inspection? ©2016 Maetrics. All Rights Reserved.33  What should I do after the inspection?  Within 15 days after the closing meeting… ‒Send a letter to FDA identifying how deficiencies have been corrected, or will be corrected Response should include your root cause analysis  Provide documentation of corrections that have been completed  Provide a timetable or estimate completion date for future corrections  Important – remember to think holistically!! 15 Days Following the Inspection

34. What should I do after the inspection?  A good response to a 483 may prevent a WARNING LETTER  Responses are required to warning letters  Expectations vary based on severity ( 6 months to 12 months for the timeline)  Treat your response to the 483 like it was a warning letter  DO NOT WAIT TO START CORRECTIVE ACTIONS  Keep Objective evidence well organized  All Records should tie directly to the 483  Most Companies will create a CAPA for each observation  Make sure each 483 is covered totally  Send Regular Updates  Do not expect a reply  Replies usually mean bad things  Sit Back and Wait until next time ©2016 Maetrics. All Rights Reserved.34 After the initial response has been sent

35. Summary  The FDA has the authority to inspect your facility  Refusing to allow access is a criminal offense  Plan ahead, betting they will not show up is a bad bet  Have written procedures  Make sure the receptionist knows what to do and who to call  Have a defined tour route  Enlist a good BACK room manager  Have SMEs defined for each area  Have coaches ready to explain the context  BE PREPARED FOR THE SILENT TREATMENT  Correct what you can immediately  Send a written response within 15 days no matter what  Keep good records of the corrective actions.  Always be ready ©2016 Maetrics. All Rights Reserved.35 Be Prepared!

36. Questions ©2016 Maetrics. All Rights Reserved.36 Questions and Answers

37. Thank You! The contents of this presentation are copyright ©2016 Maetrics. All rights reserved. This presentation contains information in summary form and is intended for general guidance only. It is not intended to be a substitute for detailed research or the exercise of professional judgment. Maetrics LLC cannot accept responsibility for loss occasioned to any person, firm, company or corporation acting or refraining from action as a result of any material in this publication. On any specific matter, reference should be made to the appropriate professional advisor. ©2016 Maetrics. All Rights Reserved.37 Terry Gustafson, ASQ CSSBB, CBA Senior Manager - Solutions Delivery tgustafson@Maetrics.com | www.maetrics.com +1 317 575 6374 (direct) |+1 318 518 1425 (mobile) Maetrics | 8888 Keystone Crossing | Suite 1550 | Indianapolis | IN | 46240