What to Expect When They're Inspecting - Part II

Holly Scott

Note: The views expressed in this article are those of the author and do not necessarily represent those of his/her employer, GxP Lifeline, its editor or MasterControl, Inc.

The first segment of this series focused on some of the non-traditional variables that can have an effect on any FDA inspection and how to achieve a positive outcome regardless of the inspectional conclusion. That article generated some blog discussion on FDA's objectivity. I wanted to clarify some of those issues. FDA Investigators are trained to be objective in all situations and will approach their inspection in this manner. However, firm management needs to understand that when intentional barriers to an effective inspection are presented or the FDA Investigator is met with a less-than-cooperative attitude, the realistic conclusion is that management is trying to hide objectionable GMP conditions, leaving the Investigator no choice but to be even more thorough to ensure there are no safety or quality risks to the consumer. It isn't that an FDA Investigator is showing bias or being subjective, they're "Investigators" - it's their job to do so.

Does an uncooperative management affect the neutrality of an Investigator performing an inspection, or cause the firm to receive any unwarranted FDA-483 citations? Absolutely not!

Does an uncooperative management affect the neutrality of an Investigator performing an inspection, or cause the firm to receive any unwarranted FDA-483 citations? Absolutely not! Can it result in a more thorough inspection, causing FDA to review functional areas not originally intended because of attempts by management to stall, withhold, or obstruct FDA from conducting an effective inspection? Of course it can, but it doesn't mean any deviations noted on the FDA-483 are unjustified.

When I discuss aspects of FDA inspections and the ways in which firm management can influence the outcomes, I simply want firms to be aware of the possible impact of their decisions, whether the result is positive or negative. It isn't subjectivity and it isn't personal, it's reality. Hopefully, this will provide a clear postscript to Part I.

This is a good conduit into Part II of this series where I focus on issues that can arise during the inspectional process. These scenarios were chosen based on questions I've been asked and emails I often receive from colleagues or clients on various inspectional topics.

  1. Managing the anxiety of observed deviations.

    Not having been on the Industry side of the table, I can't say with conviction that I understand how management must feel during the issue of an FDA-483, or during the course of an inspection when one observation leads to another, and another, until the FDA-483 citations start to add up, and the firm is embarrassed by a seemingly ineffectual quality program.

    • a. Always maintain your composure in the presence of the inspection team.

      All seems to be going well with an FDA inspection...until it doesn't. The observed deviations are multiplying and management doesn't like it. The Investigators could be speaking a foreign language for as much as you understand their justification for citing you on some of their observations. When you simply can't agree, what do you do? Any discussion of observed conditions is perfectly acceptable, warranted, and even encouraged, but an outright argument isn't going to mitigate the situation. Take the time to calmly and factually discuss the observation. The Investigator is there to obtain enough information for FDA Compliance to make the determination that a firm is compliant with the relevant FDA regulations. The reasons firm management will give to justify non-compliance is of no consequence. There are a multitude of them so refrain from making excuses. It is what it is. Instead, use the opportunity to explain your understanding of the regulations and allow the Investigator to respond.

      If after discussion the Investigator stands firm and includes the observation on an FDA-483, you can certainly state you do not agree the citation is warranted (make sure you are on solid ground!), but do not continue to argue your position into the ground. You've given your reasons for not agreeing to the citation; it will be documented in the EIR (Establishment Inspection Report), and the bottom line is that the Investigator is going to include it on the FDA-483. Since every firm should respond to the FDA-483 in writing, include any unresolved concerns in this correspondence so it becomes part of the official record, and request that FDA provide you additional guidance on the citation.

    • b. Solving Conflict with the Investigator

      What do you do when you have legitimate questions about the manner in which FDA is managing the inspection or when it seems clear that the Investigator is keener to assert authority than to entertain any reasonable dialogue about inspectional observations?

      In the event that firm management sincerely believes that the barrier to an effective inspection is an unreasonable or argumentative demeanor exhibited, it has every right to address this concern on a professional level. However, choose the right approach. Don't address concerns regarding the Investigator's conduct in front of the entire QA staff. Pull the Investigator aside at the appropriate time and raise the issue. Perhaps, like all of us at some point, s/he's had a terrible day and is unable to keep emotions in check, so offer the benefit of the doubt.

      Examine your own attitudes and the behavior of your staff during the inspection. Ask the Investigator if s/he has any concerns with something that may have been said or that may have occurred during the inspection that has warranted any frustrations. More often than not, you'll find a one-on-one discussion with your Investigator will effectively address any issues and will probably benefit you in the long run.

      If after your attempt at a personal discussion, his/her manner has not improved to a more professional approach, bring your concern up during the close out discussion. Be factual and unemotional. Since the close-out meeting is documented in the Discussion with Management section of the EIR, the issue should at least have a reference to it, making it part of the official record. As a last resort, the Investigator's Supervisor can be contacted through the phone number listed on the FDA-482 (Notice of Inspection). I caution you to exhaust other efforts first and to approach this conversation with a factual example of your concerns. Do not call simply to complain because you didn't "like" the Investigator. That will get you nowhere fast. Few people "like" FDA so it isn't exactly an inventive complaint. Moreover, the agency is not inspecting your firm to expand their circle of friends. If your complaint is valid, it will be handled in the appropriate manner. A firm is not going to be later "punished" by FDA because you took this step.

      In my experience as an Acting Supervisory Investigator, I had to address issues of this nature on a few occasions. Unfortunately, it happens. If your complaint is found to have any merit, the Supervisor may send a replacement Investigator with equal expertise, or in the case of a multiple day inspection, send an additional investigator to join the inspection to moderate the situation.

  2. Acting on observations made during the inspection.

    It is the policy of FDA to bring any GMP deviations to the attention of management, contemporaneously as they are observed by the inspection team. An investigator will not silently perform inspection and wait until the close-out meeting before verbally discussing his/her findings, so there should be no surprises during the close-out meeting.

    This approach presents numerous opportunities for the firm to perform immediate corrective action, when possible to do so. Since the Investigator is required to report any corrective action that is performed during the inspection in the EIR, it is beneficial to the firm to make them prior to the conclusion of the inspection so they can be verified. An experienced Investigator is going to know when an observation can be reasonably expected to be corrected and will understand that it is not always possible to correct observed deviations during the inspection (some actions need to follow a change control process, quality/management review, a deviation investigation, etc.). In this case, every effort should be made to address the FDA-483 observations and provide assurance of corrective action or a corrective action plan in the initial follow-up correspondence.

    With an effective response, you will receive a letter from FDA that basically thanks you for your cooperation during the inspection and explains that all reported corrective actions will be verified during the next inspection. If you received an FDA-483, this is the letter you WANT to receive from the Agency. Your inspection is still classified as VAI and you have some work to do but you have sufficient time needed to perform the required corrective action.

    Remember that not all inspectional observations are citable on the FDA-483. FDA-483 citations include observations specifically required by a regulation. For instance, published FDA Guidance Documents contain references to both GMP regulations and also recommended practices. If a firm is observed not to be adhering to recommended practices, the investigator will discuss this in detail and should report it in Discussion with Management Section of the EIR, but cannot include it as an FDA-483 citation.

  3. Making a good "last" impression.

    Most of us were taught by our parents that first impressions are lasting impressions and how important it is during a job interview to make a good first impression. Likewise, how you receive FDA into your firm sets the tone for an inspection - this is the investigator's first impression. But equally as important in this case is the last impression. In this case dear old Dad was wrong; it's not the first impression that matters the most, but the last impression. Since the inspection is concluded with a general discussion of the inspectional findings or the issuance of an FDA-483, this is a chance to make a good "last" impression. This is the opportunity to address any outstanding issues and to impress upon the investigator that firm management takes any observations seriously and is anxious to make any necessary improvements. Regardless of what transpires during an inspection, the close-out meeting is an important indicator of a firm's intentions and management statements are reported comprehensively in the EIR (or it should be).

    When an investigator recommends an inspectional conclusion (NAI, VAI, OAI - as discussed in Part I of this series) to Compliance Branch, it is largely influenced by actions performed during the inspection and statements made by management during that close-out meeting, as well as promises (or lack thereof) to perform any additional necessary corrective actions. Whether firm management agrees with all of the citations or not, the attitude conveyed to the Investigator should be one of willingness to do what is necessary to remain compliant so it is reported through the EIR to the Compliance Officer. This review of the EIR will resolve any further debate on the legitimacy of the citations.

    My own close-out experiences include death threats, hostile attitudes and hostile posturing by CEOs while refusing to accept the FDA-483. One firm's President literally positioned his face approximately 10 inches from mine and attempted to stare me down until his face turned red. I thought he was going to have a heart attack! I simply suggested that he step out of the room and compose himself while I continued to read the FDA-483 items to the other firm representatives.

    During one of my more eventful drug inspections, my vehicle was actually tampered with until it was impossible for me to drive safely. I was lucky enough to be inspecting the firm with another Investigator-colleague of mine so there was a safe ride home and a witness! We both suspected then (as I still do) that the firm's VP was responsible for the crime; we suspected him because of his behavior and other circumstances that "had" to transpire for the tampering to take place. Now...when I said that FDA isn't onsite to make friends, I wasn't suggesting that they're trying to make enemies! It's an FDA-483, not a life sentence, for goodness' sake.

    These examples are certainly rare and occurred over the course of my 19-year career with FDA. I include them because they clearly aren't the most stellar examples of making a good last impression and each instance resulted in further action on the part of FDA. I could easily list hundreds of examples of perfectly successful inspections and close-out meetings where the sincerity of management was beyond question but they wouldn't be nearly as much fun to read about.

    Inspections often don't go the way they're planned. A QC manager rarely expects to be cited on an FDA-483 and the FDA Investigator doesn't expect to have an argument at the close-out meeting. So, to conclude this segment of What to Expect When They're Inspecting - is to not expect it will go the way you planned. Adapt to it and handle the unfortunate turn so it doesn't get out of hand. The way your personnel handle themselves under the pressure of a violative inspection is indicative of the state of control your firm employs and how effective your corrective actions will be. Use the inspectional close-out meeting wisely!

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 clients' product websites to ascertain liability for potential FDA enforcement actions and provide recommended preventative measures.