FDA Inspection Preparation and Management

1. FDA Inspection Preparation and Management Massachusetts Biotechnology Council April 28, 2009 David L. Chesney, Vice President Strategic Compliance Services PAREXEL Consulting Dave.chesney@parexel.com 978-848-2256

2. Basics for FDA Inspection Preparation and Management • Understand and respect FDA’s inspection authority • Be familiar with FDA Compliance Programs applicable to your industry sector • Develop a company inspection management SOP • Train staff so that they understand the process and can follow the SOP • Emphasize the need for staff to be truthful and professional in their interactions with FDA • Control the environment • Communicate clearly during and after the inspection

3. General Caution • This will be a rather quick summary of the key considerations in managing inspections. An in depth study and careful preparation on your part is needed. • FDA inspections carry legal risk for the company and individuals • For this reason, it is wise to include legal counsel in key decisions surrounding the management of FDA inspections • The guidance in this presentation is intended to help inform you about some of the issues FDA inspections present, but is not intended to be legal advice, nor to include every aspect that companies should consider in their inspection preparation. • Seek the guidance of counsel when finalizing inspection policy and procedure to ensure it is legally sound and properly crafted to protect the company in this important area.

4. FDA Inspection Authority • Section 704 of the Federal Food, Drug and Cosmetic Act (drugs and devices) – we will abbreviate as the “FFDCA” • Section 351(c) of the Public Health Service Act (licensed biologics) and 361 (tissue products) • 21 CFR 600.22 (licensed biologics) • 21 CFR 1270 (tissue products) • As a practical matter, 704 of the FFDCA is the governing law

5. FDA Inspection Authority • Section 704, FFDCA: • “Enter and inspect” • At reasonable times, within reasonable limits, and in a reasonable manner • For Rx drugs (including biologic drugs), “…inspection shall extend to all things therein (including records, files, papers, processes, controls, and facilities) bearing on whether prescription drugs, nonprescription drugs intended for human use (made in the facility are in compliance or not)…” • “Reasonable Time, Limits and Manner” not spelled out in detail

6. Reasonable Time, Limits and Manner • Time: FDA can inspect any time regulated operations are taking place. The calendar and the clock do not establish what is “reasonable”; what is happening in the facility determines what is a reasonable time. • Limits: You can insist that FDA stick to their authority and not enter areas that would pose a danger to the product, facility, employees, or the FDA personnel, without appropriate controls. • Manner: Lots of potential areas for conflict here, should be worked out in advance. A few examples include: • Samples • Photography • Access to personnel and records

7. What FDA Must Do • Show appropriate credentials • Issue a Notice of Inspection (FDA-482) to the “owner, operator or agent in charge” • Adhere to reasonable security precautions, safety rules, and standards/procedures for gowning or other protective garb while in production, warehousing or lab areas • Issue the FDA-483, if any, to the same person (or designee) who got the 482 • Issue a FDA-484, Receipt for Samples, for any product or material samples collected (does not apply to documents, only physical material)

8. Where to Look to Learn About FDA’s Inspection Procedures • The Investigations Operations Manual, http://www.fda.gov/ora/inspect_ref/iom/default.htm • Concentrate on Chapters 2, 4, 5 and some of 8 • Others of limited interest • The applicable FDA Compliance Programs; for biologic firms, some of the most important are: • 7345.848, Inspection of Biological Drug Products, (CBER regulated) http://www.fda.gov/cber/cpg/7345848.htm • 7356.002M, Inspection of Licensed Biological Therapeutic Drug Products, (CDER regulated) http://www.fda.gov/cder/dmpq/7356_002M.pdf

9. Where to Look to Learn About FDA’s Inspection Procedures • For non-biologic GMP and PAI inspections, consult: • 7356.002, Drug Manufacturing Inspections, http://www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.pdf • 7346.832, Pre-Approval Inspections/Investigations, http://www.fda.gov/cder/gmp/PAI-7346832.pdf • For GCP inspections • 7348.810, Sponsors, Contract Research Organizations and Monitors http://www.fda.gov/ora/compliance_ref/bimo/7348_810/48-810.pdf • 7348.811, Clinical Investigators – NOTE – New as of 12/8/2008http://www.fda.gov/ora/ftparea/compliance/48_811.pdf • For GLP inspections • 7348.808, GLP Inspections (nonclinical laboratories) http://www.fda.gov/ora/compliance_ref/bimo/7348_808/48-808.pdf

10. Where to Look to Learn About FDA’s Inspection Procedures • Miscellaneous other references of value include, • Several of the Compliance Policy Guides, http://www.fda.gov/ora/compliance_ref/cpg/default.htm • Parts of the Regulatory Procedures Manual, http://www.fda.gov/ora/compliance_ref/rpm/ • A few of the Field Management Directives, http://www.fda.gov/ora/inspect_ref/fmd/fmd_idx.html , in particular numbers 13A, 86, 119, and 120

11. Points to Consider for Your Inspection SOP • Ensure FDA is greeted appropriately and granted prompt access to the facility and the right people • Train reception and security personnel in what to do when FDA arrives • Establish an inspection reaction and management team (with backups) • Primary point of interface • Escorts • Scribes • Runners • Ready Room support • Communication system

12. Points to Consider for Your Inspection SOP • Decide: • Who will accept the Notice of Inspection on behalf of your company? • Where will FDA personnel be headquartered during the inspection? • What will be your company’s position on the more common, but sometimes controversial inspection issues, such as: • Photography • Signing of affidavits prepared by FDA personnel • Requests for documents outside the scope of FDA inspection authority • FDA intent to be present during swing or graveyard shift operations • Distinguish between inspections and visits by OCI Special Agents or non-regulatory visits by FDA personnel • Note: An OCI visit is not an inspection! Contact legal counsel if you are visited by OCI.

13. Points to Consider for Your Inspection SOP • Records access • Channel requests through escorts or primary point of contact • Keep a record of all requests, when requested and when fulfilled • Keep copies of all records reviewed by FDA (whether or not copies are provided to FDA), and note which specific records are copied and kept by FDA • If your system relies on hard copy documentation, provide originals for review • Provide copies of only those records FDA asks for • If you store documents electronically, FDA may ask for e-copies in a conventional format (Word, Excel, etc.) or that you print hard copies for review. Be prepared to honor each type of request. • If time permits, carefully review the document before providing it, to make sure it is responsive to the request. DO NOT MAKE ANY CHANGES. Supply EXACTLY what is in your files.

14. Points to Consider for Your Inspection SOP • Interviews with employees • FDA may want to speak to the person(s) with the best direct knowledge of the area of inquiry. This may mean operational level employees who are not necessarily managers or subject matter experts. Be sure these personnel are not overlooked in your training and SOP familiarization efforts. • Answering Questions • Some companies “over-prepare” employees to be so minimally responsive to questions that there is a risk of miscommunication. Sometimes one-syllable answers (“yes” or “no”) may not provide sufficient information to properly inform the FDA nor to adequately protect the company from regulatory risk. • Carefully monitor questions and answers so that FDA personnel are given complete and truthful answers. • If mitigating information exists, but was not requested, consider voluntarily bringing it to the attention of the FDA investigator

15. Train Staff • Include everyone, from the lowest to highest level personnel in your organization, so that each understands what is expected of them during an FDA inspection • Demystify the process. Much “folklore” exists about FDA inspections that is baseless, and ultimately explainable when the law and agency inspection procedures are understood. This defuses anxiety and helps the communication process. • Use a combination of: • Preparatory reading • Formal classroom training • Mock interviews – use an experienced facilitator if you do this • Mock inspections

16. Manage the Environment • Provide dedicated space for FDA’s use • Allow enough space for documents to be spread out and for other personnel who will be present • Conference rooms are best for this purpose • It’s generally OK to provide light refreshments such as coffee, tea, water, but be guided by FDA personnel and do not insist on providing lunch; allow FDA personnel to pay if they wish to do so. • Limit interruptions – now is not the time for the monthly fire alarm test! • Provide prompt access to personnel and records

17. Problems and Pitfalls to Avoid • Thinking you are in charge here (you aren’t; FDA is) • “Secret” signals, codes, hand gestures, etc designed to control people’s answers • Denying the obvious • Shifting blame: • “We’ve been inspected before and no one ever mentioned this issue” • “Everyone in the industry does it this way” • Complaining about the government, taxes, or FDA procedures • Asking questions of FDA personnel that could be perceived as: • Too personal (the usual stuff – religion, politics, family, personal health, finances…etc.) • Possibly soliciting a bribe

18. Problems and Pitfalls to Avoid • Refusals or perceived refusals • It is a criminal violation of the FFDCA to refuse a legitimate FDA demand for access to an area or a record the agency is entitled to see • FDA has a detailed procedure for handling refusals. The most likely outcome is an administrative inspection warrant, which is not a search warrant, but is a Court order affirming the agency’s right to inspect • Inspection warrants are typically served by FDA personnel accompanied by Deputy US Marshals • If you persist in refusing, you may be arrested by the Deputy Marshals • Partial refusals are more common than refusals to permit entry • FDA has used Inspection Warrants to compel photography in the face of refusals

19. Problems and Pitfalls to Avoid Avoiding Refusals • If you are asked by an FDA Investigator “Are you refusing me…?” you should respond as follows: • “No, I am not refusing you [whatever] but before I comply with your request I need to consult with our legal counsel and senior management. Please accommodate my request.” • Immediately involve legal counsel whenever the question of a refusal is raised by FDA personnel

20. Communicate Clearly During the Inspection • Basic rules for Answering Questions: • Be TRUTHFUL at all times!! • LISTEN to the question • ASK for clarification if you do not understand • ADMIT IT if you do not know the answer • REFER to an SOP if necessary, but only if truly necessary • ANSWER the question you are asked, not some other question! • STOP when you have answered the question • WAIT before going on; FDA is in charge of this process, not you • Always, always, always be TRUTHFUL

21. The FDA-483 • Legal basis of the 483 • The 483 is supposed to be objective, factual, legible and significant, and generally, listed “worst first” (within applicable systems) • Significance is dependent upon a number of factors, including, but not limited to: • Context in which the observation occurred • How frequently the observation occurred • How long ago the observation last occurred • The impact (or lack thereof) on product quality • The health hazard posed by the observation • Whether the risk posed by the observation is theoretical or actual • The “Turbo EIR” effect

22. The Exit Discussion of the 483 • Plan your strategy in advance and decide who will speak to what; stick to your plan during the discussion. • Goals for the meeting should be: • Ensure the 483 is factually accurate • Ensure you understand FDA’s rationale for each observation, even if you do not agree with the observation • State any disagreement you have and the reason(s) for it. Back up your position with facts and data, not supposition, speculation, or excuse making • Only commit to things you have discussed in advance and are certain you can do; withhold other commitments for the written response • Attendees at the exit meeting should be: • The CEO, or top official of the inspected site • “A-team” of senior personnel who are empowered to speak for the company • “B-team” of subject matter experts who can be brought in as necessary

23. The Written 483 Response • The law does not require that you respond to a 483 at all, either orally or in writing. But everyone does, almost without exception, and if you do not, it will be seen as very anomalous and quite negative. • A good format for a 483 response: • Brief statement of the company’s intent to comply with all laws and regulations • Point by point response to each observation, first quoting the observation, then responding to it • Start with the bottom line: What you will do about the observation. Then go on to explain the reasons behind your action. Use a “hierarchically structured” style of composition. • Recognize that FDA views the 483 observation as symptomatic of a system flaw. In the majority of cases, responding just to the specific observation is not sufficient. You need to address the root cause and the broader picture.

24. The Written 483 Response An effective outline for response to each item… • In response to this observation, we are taking the following actions: [list what you are doing] • We believe this approach is reasonable because [state]: • Your assessment of the reason(s) why the observation occurred; “root cause” • Your assessment of the impact on product quality • Your assessment of the scope of impact (other batches, other products) and how you determined the scope • We will complete these actions by [date] • We will take the following steps to ensure these actions had the intended effect [list; generally, this will be audit or monitoring]

25. The Written 483 Response Things to avoid… • Lengthy introductory narrative • Company-specific jargon or acronyms • Excuses • “The investigator was out to get us” • “You are singling us out” • “We are just a small business struggling to survive” • “Our CEO is a very good friend of [insert prominent politician’s name here]” • Speculation rather than data to support your premise • Failing to proofread your response before transmitting it

26. Summary • An FDA inspection is a predictable, and to an extent, controllable event if you: • Know your rights (and FDA’s) under the law • Understand the agency’s inspection procedures • Plan and document your procedure in advance, anticipating what is likely to occur • Train your staff so they understand the process and know what is expected of them • Provide adequate space, comfort and support to the FDA team and your personnel for the duration of the inspection • Communicate clearly and thoroughly, sticking to the facts and the data • Respond promptly and effectively to observations, following through to make sure your actions worked as intended