Can you say; “Can I please see the FDA Form 482?” Let Dr. D ask a more basic question, do you know the actual purpose of a Form 482? The Form 482 is the vehicle employed by FDA to announce their presence for an establishment inspection in the United States. The Notice of Inspection form will be presented by the investigator(s), along with their credentials when they show up on your door step for a cup of coffee and an inspection. From the very second the investigator enters into a medical device manufacturer’s lobby, an escort should accompany this individual at all times, including trips to the use the restroom. Dr. D strongly suggests that all device manufacturers have a scripted SOP for managing agency inspections and all other kinds of regulatory visits, including notified body audits.

Remember, during the “incipient” (look-it-up) stages of an FDA establishment inspection the tone is set for the entire inspection. It is important that professionalism be exuded by all employees during the inspection. It is imperative that all employees are reminded that FDA is on-site and random gossip pertaining to work-related issues could be the kiss of regulatory death during an inspection. That being said, Dr. D hopes you enjoy this week’s guidance.

For starters, FDA is tasked with providing regulatory oversight for well-over 150,000 domestic establishments (food, drug, medical devices, biologics, dietary supplements, etc.). For the medical device industry, the number of establishments has increased to more than 40,000 domestic establishments. Considering the significant number of establishments requiring FDA oversight, Dr. D hopes the readers can come to the quick conclusion that establishments manufacturing high-risk medical devices, a.k.a., Class III – PMA devices, have the highest priority when it comes to agency inspections. For the readers of DG that are tasked with manufacturing Class I devices, relax – but not too much. The FDA’s authority to perform establishment inspections comes directly from the Act.

Food, Drug and Cosmetic Act 21 USC §374 

“704(a)(l): For purposes of enforcement of this Act, officers or employees duly designated by the Secretary, upon presenting appropriate credentials and a written notice to the O\1ler, operator, or agent in charge, are authorized (A) to enter, at reasonable times, any factory, warehouse, or establishment in which food, drugs, devices, or cosmetics are manufactured, processed, packed, or held, for introduction into interstate commerce or after such introduction, or to enter any vehicle being used to transport or hold such food, drugs, devices, or cosmetics in interstate commerce; and (B) to inspect, at reasonable times and within reasonable limits and in a reasonable manner, such factory, warehouse, establishment, or vehicle and all pertinent equipment, finished and unfinished materials, containers, and labeling therein… “

QSIT

For those of you not familiar with the acronym QSIT, it represents the FDA’s approach to establishment inspections; Quality System Inspection Technique. In short, FDA has an inspection script that they are trained and adhere to in support of the inspection process. As the doctor is sure most of the readers are aware, the FDA can announce a planned inspection, in advance, or just show up at the front door unannounced. Regardless the agency will be well-prepared for the inspection, so it is critical that all medical device manufacturers are always in a state of compliance and ready to support an inspection. From an agency perspective, the inspection process can be broken down into six parts:

• Preparing for an inspection;
• Initiating the inspection;
• Performing the inspection;
• Collecting and documenting objective evidence;
• Closing the inspection; and
• Issuing the inspection report and follow-up actions.

Preparing for an inspection

As previously stated, agency inspections (domestic) will be either announced or unannounced. Regardless, your job as a medical device quality and/or regulatory professional is to always have your organization prepared for such a visit. Prior to the agency’s visit, the assigned investigator(s) will: (a) review your organization’s compliance history; (b) review applicable guidance documents; (c) obtain a listing of all products cleared and approved for entry into the US market; (d) review inspection guidelines; and (e) prepare an inspection tool kit. Simply stated, the FDA will be prepared so device manufacturers should be at least equally prepared. As previously stated, Dr. D strongly recommends the scripting of a procedure that provides guidance for your organization for FDA inspections. In fact, a procedure should be scripted to cover all regulatory inspections and notified body audits. Additionally, every-single employee from the CEO down to the janitor needs to be trained to ensure the entire organization properly conducts themselves during an FDA inspection. If your organization has a few malcontents, lock these folks up in the janitor’s closet.

Initiating the inspection

Regardless of the inspection being announced or unannounced, the process commences when the investigator(s) arrive in the lobby. They will announce themselves and ask for the “most responsible person” or as Dr. D likes to say: “Chief Jailable Officer” (CJO). The FDA will present their credentials and issue the Form 482 “Notice of Inspection.” Once the investigator(s) enter the building, they should be escorted to a conference room that will be dedicated to the inspection. As part of the introductions, the investigator(s) will discuss the parameters of the inspection with the management team. Under no circumstances should FDA be permitted to travel through the facility without an escort that has been properly trained. Additionally, a competent individual should be identified as the inspection scribe. This individual or group of individuals will be tasked with the recording of the inspection minutes.

Performing the inspection

During the inspection process the investigator(s) will ask for a ton of documentation to review. Dr. D strongly suggests establishing a backroom to ensure all documentation is adequately reviewed before placing it in front of the investigator(s). Yes, in a perfect world such a secondary review would not be necessary; however, Mr. Murphy is alive and well in the medical device industry. 

 Furthermore, as the inspection begins all SOPs given to the investigator(s) to review should be logged. In fact, Dr. D strongly recommends making two copies: (a) one for the FDA; and (b) a retain copy for the device manufacturer’s records. During the inspection, the investigator(s) will ask for a plant tour and will probably want to visit critical manufacturing areas. Please ensure that any FDA facing person does not suffer from that dreadful disease known as; “The deer in the headlights disease.” In fact, all answers made to the investigator(s) should be short, sweet, and to the point. Sometimes a simple yes or no will do. Remember to remind all personnel that if they do not have an answer to an investigator’s question, they should state; “I do not know but will get the answer and get back to you.” Finally, make sure your organization’s Subject Matter Experts (SME) only respond to questions pertaining to their functional areas of expertise. 

Collecting and documenting objective evidence

Please keep in mind the fundamental purpose of an agency inspection is to collect objective evidence of compliance or non-compliance. As part of the inspection, the investigator(s) will ask to see records that support compliance and may even ask for product samples. If product samples are requested, ensure that the entire transaction is properly documented, including a packing slip. It is an acceptable practice to ask the FDA to pay for sample devices collected during an inspection. The salient point that needs to be driven home is that the evidence collected can be used against the device manufacturer if the agency determines additional regulatory action is required. Unlike a notified body audit, evidence collected by the FDA can be admissible in the federal courts as evidence in a criminal case; or during the negotiation of a consent decree.

Closing the inspection

During the inspection closeout, the FDA will discuss the results of the inspection and observations noted with the management team. One thing to keep in mind, this is not the forum to vehemently argue the validity of an observation. In fact, if the observation is minor the best practice is to acknowledge the observation and promise to correct the observation so the investigator(s) can annotate onto the Form 483 “Inspectional Observations” the commitment by management to correct. Finally, if the FDA is walking away with samples, they will leave you with a Form 484 “Receipt of Samples.” From an inspection standpoint, it does not get much easier: (a) Form 482 – Notice of Inspection; (b) Form 483 – Inspectional Observations; and (c) Form 484 – Receipt of Samples.

Issuing the inspection report and follow-up actions

The last step performed by the investigator(s) is the writing of the Establishment Inspection Report (EIR). The EIR will be a summary of the inspection and a compilation of noted inspectional observations. Depending on the outcome of the inspection, the FDA can pursue additional regulatory action. On the positive side if a medical device establishment receives no Form 483 observations or a small number of minor observations, a voluntary compliance statement made by the establishment and the formal correction of the observations is all that is required. However, if a firm promises to correct observations and during the next agency inspection it is noted that the previous observation(s) were not corrected or the correction deemed ineffective, then receipt of a warning letter can be expected. Other regulatory tools the agency can employ to drive compliance are:

• Follow-up inspections;
• Regulatory meetings;
• Warning letters;
• Product seizures;
• Product injunctions;
• Consent decrees; and
• Criminal and civil penalties.

Takeaways

For this week’s DG, the doctor will leave the readers with four takeaways. One – a medical device manufacturer’s best defense during an FDA inspection is to always be in compliance with the quality system regulation and all applicable parts of the regulation. Two – device manufacturers should always have a written procedure that delineates all of the organization’s requirements for entertaining a regulatory inspection. Three – never place an individual suffering from the dreaded “deer in the headlights disease” in front of the FDA. Four – if the CJO does not look good in an orange jumpsuit with stainless-steel bracelets, then compliance will always be this individual’s best friend. Five – lock all malcontents in the broom closet (just kidding – just keep them away from FDA).

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success. 

References:

1. Code of Federal Regulation. (2013, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. Investigations operations manual. (2013). Chapter 5 Establishment Inspections. Retrieved September 8, 2013, from http://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM150576.pdf.