What to Expect When They're Inspecting - Part 1

Holly Scott

FDA 101 - Fundamentals that can influence the outcome of an FDA Inspection

The next time you attend an industry function like BIO, BioEast, or an AABB conference, start up a conversation about FDA inspections with those seated at your luncheon table. It's more than likely that everybody will describe a different inspection experience and that no two perceptions will be the same.

FDA is NOT your enemy and you don't have to make them one! Do not refuse them or provide an unreasonable barrier to the inspection. Those choices will come back to haunt you!

One expects variations in the level of coverage at firms in different program areas, whether it's drugs, devices, biologics, dietary supplements, clinical research, or a food firm, because each industry area is so technically diverse. However, observation methods used by Investigators should be comparable and not diverge significantly. If two firms are manufacturing the same regulated product, and are both undergoing a routine GMP inspection, why does one receive an FDA-483 citation for an observation while the second firm receives no citation although the same observation was made? Is it a lack of continuity between Investigators, or are there other contributing factors?

The conclusion of an inspection can often be impacted by the level of firmness that officials are willing to demonstrate during inspections. This level of firmness can make the difference between receiving an FDA-483 or not receiving the same. You might say that these are the unwritten "rules" of an inspection. So, here is an interesting question: What are some of the non-GMP variables that can influence inspection results and how should you approach inspections with the purpose of improving inspection outcomes?

  1. Understand who is inspecting you.

    An FDA Field Investigator is the individual who is most likely to perform your inspection. "Inspector" is not their title, though there are many who refer to them as such, since conducting inspections is only one of their many professional duties. A "real" FDA Inspector (i.e, someone who actually holds the title of "Inspector") is a different individual altogether and is employed mainly in the area of Imports. In the case of a Pre-approval or Pre-license inspection, a firm can expect an inspection team comprised of a Field Investigator, a Reviewer from one of the Centers and the possible arrival of chemists, microbiologists, analysts, and/or any other individual with relevant product development, assay-methods, pharmtox, or process expertise. An FDA Field Investigator manifests his or her expertise during the enforcement of GMP regulations, due-diligence actions, document and procedure reviews, and compliance actions. They're also generally (and annoyingly) very good at finding those isolated—but significant—deviations that no one else seems to have noticed. With Field Investigators, you can expect their team approach to be very comprehensive.

    The FDA-482, Notice of Inspection, stipulates that FDA has the authority to enter an FDA-regulated firm at a reasonable time and in a reasonable manner in order to conduct an inspection. Generally, an organization that is about to be inspected won't know that the FDA is coming. When FDA arrives at your firm they will present their credentials (they should never display their official badge unless working with other law enforcement officials) and issue this documentation to the person onsite who will be the most responsible for assisting the FDA team during the inspection.

    However, that said, there are instances when prior notice is granted but is usually limited to medical device firms, bioresearch monitoring inspections (e.g, clinical investigators, IRB’s, etc) and organizations with a good compliance history. Even these organizations however may not be notified unless there is good reason to do so. For example, if the firm is not located within an easy commuting distance of the FDA (or one of its many branches) a prior notification might be a good option. After all, the FDA representative(s) doesn't want to drive for two hours only to find, upon arrival, that the QA Manager went on vacation and left no one in charge. Again however, prior notification is only an occasional courtesy and is exclusive to companies with a good compliance history. .

    Tip #1 - The basic first rule of what to expect when they're inspecting is not to expect them. Instead, be prepared to receive them professionally and courteously whenever they arrive at your door. Set a positive tone for the inspection. Have an SOP in place for handling regulatory inspections so the receptionist doesn't have to play the role of "deer in the headlights."

  2. Refuse them at your own risk!

    How do you handle the initial reception of the FDA Investigator? Do you receive them professionally? Do you delay or even refuse their entry for a variety of reasons? Unbelievably, there are still companies that will refuse an inspection. Documented refusal is not limited to just an outright repudiation of the Investigator's authority. There are more subtle ways that a firm unknowingly refuses an inspection. For example, FDA could arrive at a firm anytime between their normal operating hours under the "reasonable time and manner" precept and unless the organization's management presents an extenuating circumstance (i.e, usually a personal emergency) which will not allow for the inspection to continue, the inspection should be allowed to proceed.

    I, for instance, was attempting to conduct an inspection of a human tissue distributor that was located about 1.5 hours away from our district office. I arrived at the firm at 11am, presented my credentials to the receptionist and announced my purpose for being there. Unfortunately, the manager of the firm had stepped away for an early lunch. "Could you come back after 1:30?" the receptionist asked. I considered the length of time that I had already driven and, due to past experience, calculated a 2.5-hour wait time, which at that point I wasn't willing to accept. So I politely suggested that she call her manager to notify him that I was there and to ask him if he might return earlier. I, of course, was willing to wait for a more reasonable 30 minutes. I further stated that if he did not acquiesce, she should request permission to receive the FDA-482, and allow the inspection to proceed. I also did not fail to explain that I could easily limit the first two hours of the inspection to a review of their written SOPS only (basic desk work) and then proceed with more critical functions once her manager had returned.

    In this case, the refusal to delay the inspection for 2.5 hours was reasonable. Could I have left the facility, commuted the 1.5 hours back to my office and written up the refusal for referral to Compliance branch for action — Absolutely! I swallowed my pride however, went for lunch, wandered around town and then returned to the firm at 1:30pm to proceed with the inspection. It was about 5:30pm when the manager asked me when I was going to "wrap it up." I replied that we'd conclude the inspection around 8:00pm and as soon as I had completed writing up their FDA-483!

    My point here is that management needs to be flexible. In this case, the manager was not flexible and it cause a significant delay. Since I was not going to allow him to shorten the planned inspection duration, his inflexibility resulted in an inspection that was more comprehensive than it normally would have been especially given the limited functions for which the company was responsible.

    In another instance, I was attempting to conduct a "for cause" inspection but the owner of the firm became hostile and refused to let me enter. I tried to convince him to allow me to proceed but my words were to no avail. So, two days later, I returned to the firm with an armed U.S. Marshall in tow and the inspection proceeded. Not surprisingly, the inspection resulted in significant regulatory action.

    Tip #2 - FDA is NOT your enemy and you don't have to make them one! Do not refuse them or provide an unreasonable barrier to the inspection. Those choices will come back to haunt you!

  3. There is no such thing as passing an FDA inspection!

    If you have ever heard a peer state that their firm "passed" an inspection they have been misinformed. I couldn't possibly quantify the number of times that I was asked by firm personnel if they were going to "pass" the inspection. Let me set the record straight! An FDA inspection is not a pass or fail endeavor, nor is the conclusion of the inspection ever defined or labeled as such. I defy anyone to produce a FDA Guidance Document, a 21 CFR Regulation, an FDA Technical Inspection Guide, an Investigations Operations Manual, or a Compliance Program Guide that provides a methodology that would allow an organization to "pass" an FDA inspection. Yet over the years, I've been witness to GMP courses and industry-sponsored conferences in which the entire focus of the course/conference was centered on "How to Pass an FDA Inspection." The mere mention of "passing" an FDA inspection causes a spike in my blood pressure!

    Many years ago at a major regional conference that was sponsored by a consulting firm, I attended a breakout session focused on the idea of "passing" an inspection. The surprised expression on the presenter's face when it was my turn to introduce myself was priceless. "Why are you in this course?" he said to me. To which I gave a chuckle and replied, "I'm spying on you." Although the response met with muffled laughs from the class, I wasn't lying. I wanted to know what Industry's perspective was. When the speaker presented "How to Pass an Inspection and Inspector Tactics," it was all I could do to stay silent in order to maintain professionalism.

    So I suffered through the session, as many of us do, listening to the presenter drone on about what he believed MY perspective was and how I was going to approach an inspection. How odd that one should teach about "passing" an FDA Inspection and the covert tactical methods that an FDA Inspector will apparently employ when 1) they were never employed by FDA and had never performed an FDA inspection, 2) they failed to understand that compliance levels are not rewarded with "pass" or "fail" grades and that 3) they really were not privy to the motives of an FDA Investigator. I asked myself how many of the inspections that had been conducted in his organization must have been violative for him to have become an expert on "inspector tactics." Perhaps I should have changed the title on my business card to "Holly M. Scott, Stealth Investigator!" In all seriousness, however, it left me wondering...how is it that so many professionals have missed the point?

    An Investigator isn't out to "catch" you. On the contrary, they don't want to catch you. "Catching" a firm means that conditions exist that put consumers at risk and nobody wants that. An Investigator's sole purpose is to verify that a firm is ensuring their products' quality, sterility, purity, safety, and potency. The point is that the FDA, and firms which maintain a compliance-oriented culture, do not have divergent goals.

    There are varying degrees of GMP compliance that a firm can demonstrate during an inspection and the following assessment "rubric" is used to provide the real final grade after an inspection:

    • a. NAI - No action indicated - Indicates that a firm does not receive a FORM FDA-483, Inspectional Observations, but that there may be observations of deviations, that in the Investigator's judgment, are of questionable significance. S/he may choose not to include them on an FDA-483 form. In this case, the observation will be documented in the Discussion with Management section of the Establishment Inspection Report and any observations that deviate from published FDA Guidance documents—but not the regulations—will also be recorded in the Discussion with Management section (You cannot be cited on an FDA-483 for failure to adhere to Guidance documents). An NAI inspection is the most positive outcome that can be achieved post-inspection and should be the goal of every compliance-oriented firm.
    • b. VAI - Voluntary Action Indicated - If you receive an FDA-483, at minimum, your inspectional conclusion will be classified as VAI. Observed deviations would have been significant enough to warrant the inclusion of a written observation on the FDA-483 form. The observations may be significant or may be considered to be non-significant but with a high-enough rate of occurrence that the inclusion of the information on the FDA-483 was still warranted. I've participated in many exit discussions in which management wanted to debate the significance of an observation that they considered to be minor in nature. For example, a drug firm's QA unit failed to review temperature logs for one -80° freezer. The freezer was one out of four freezers being utilized for product storage. The logs for the freezers were complete, accurate, and there was no indication that products were being stored in temperatures that were out-of-specification. However, QA had failed to review the temperature monitoring records for the freezer in question and that freezer had contained a biological drug for over 12 months! Management argued that the deviation had not affected the product's quality and I explained that I did not disagree with his assessment but that his employees had repetitively failed to follow written procedures, a neglect for which he should have been responsible especially during the firm's scheduled quarterly QA-review of the equipment's quality control logs. I did not remove the citation.

    • c. OAI - Official Action Indicated - an instance in which the observed conditions at the firm are significant and multiple and can contribute to product quality failures. A hypothetical firm receiving an OAI would afterward receive an FDA-483. This will very likely occur after what is likely to have been a very lengthy inspection. In the case of an OAI, a Compliance Branch review would also be performed to determine which one of the following actions FDA will pursue:
      • Regulatory meeting request letter - these meetings are considered official prior notice and are documented in the FDA Enforcement Report. If the firm in question fails to correct objectionable conditions prior to the next inspection, the firm can then expect an "involuntary" loss of their product through an action of seizure. The firm would not receive a warning letter.
      • Warning letter - uploaded to www.fda.gov website to become public domain. Also, just as a note of interest, if you don't think your competitors are monitoring these 483 updates—think again. Receiving a 483 is obviously a very effective way to lose business.
      • Administrative/civil actions like seizure or injunctions;
      • Criminal actions for companies that repeatedly fail to correct violations, knowingly participate in fraudulent activity after multiple warnings, or are caught lying to the FDA (a Title 18 felony).
    • Tip #3 - Understand the possible compliance outcomes and you can more effectively interpret the progress of an inspection. Remember! There is no pass or fail! A VAI inspection resulting in the issuance of an FDA-483 can work itself into a positive outcome if the firm that received the 483 notice demonstrates to FDA that it will be proactive in performing corrective actions and use their new experience (i.e, in performing corrective actions) to improve the firm's quality system. Failing to perform corrective action after the receipt of a 483 notice will result in another FDA-483 during a subsequent inspection, at which point the firm can obviously expect an OAI conclusion. Again, it's great to understand the possible outcomes before an inspectional observation is argued; it might not be as bad as you think.
  4. "Co-manage" the inspection.

    Do not attempt to "handle" the inspection team or to direct the pace of the inspection. The only time this is appropriate is when a production schedule dictates it. If FDA wants to begin with a review of batch records and you want them to start in the lab, don't debate the issue. While the direction of the inspection may seem random to you there is usually a reason behind it. Additionally, never ask how long the Inspector thinks the inspection will last. I think I speak for all Investigators when I say that "It lasts as long as it lasts!" An Investigator simply won't know how long it will last until s/he has had the opportunity to review some of the firm's production process areas. In addition, the pace of the inspection will be driven by the firm's state-of-control, by what observations are noted and not by the QA Manager's schedule.

    Part two of this article will discuss tips for writing procedures to meet FDA expectations, how to handle the inspection when it starts to go wrong, when to act on inspectional observations, accountability, and the discussion with management during the exit meeting. It will also discuss appropriate responses to FDA-483 Observations.

Holly McNair Scott joined Biologics Consulting Group, Inc. as a Senior Consultant in September 2009 after 19 years with the Food & Drug Administration. As a Senior Consultant for BCG, she currently performs facility audits, "mock" FDA preparation PAI/Pre-license inspections, due-diligence & gap analysis audits, and other regulatory support services for dietary supplement manufacturers, drug manufacturers, manufacturers of biological products (blood, plasma, human tissue and cord blood/stem cell products) as well as clinical trial support for bioresearch sponsors/investigators. Ms. Scott also provides BLA support, compliance assessment, assistance with FDA correspondence, strategic regulatory planning, and in-house training and/or investigations.

Ms. Scott spent four years as a Consumer Safety Officer with the Center for Biologics Evaluation & Research (Rockville, MD) and 15 years as a Field Investigator with the FDA/Office of Regulatory Affairs - Florida District Office (Miami & Orlando). In 1996, Ms. Scott was selected for the FDA National Biologics Cadre, a group of Investigators specializing in the inspections & regulation of Blood, Plasma, & Human Tissue Establishments and was subsequently awarded her FDA Level II Certification which recognized her expertise in the area of biological product inspections.

As an FDA Senior Investigator, Ms. Scott's interrogative prowess and interviewing skills earned her high profile cases such as investigations into the importation and distribution of unlicensed biological products, smuggled human tissue, suspected product tampering incidents, fraudulently conducted clinical research and numerous undercover buys. In addition to the other services she now performs as a BCG Senior Consultant, Ms. Scott now utilizes these skills when assisting clients with in-house quality investigations, tampering and the analysis of clientss product websites to ascertain liability for potential FDA enforcement actions and provide recommended preventative measures.