The US Food and Drug Administration (FDA) earlier this week published its 2017 version of a chapter of its investigations operations manual on establishment inspections, offering an inside look at how inspections are conducted and what companies should expect.
The 127-page chapter offers the basics for how FDA inspectors should go about conducting what it calls, a "careful, critical, official examination of a facility to determine its compliance with laws administered by FDA."
At its outset, the chapter notes certain inspectional precautions that FDA inspectors should be aware of, including the potential for microbiological contamination.
"When inspecting areas where sterility is maintained or sterile rooms are located (especially in pharmaceutical or device firms), follow the sterile program required of the firm's employees," the manual says. "In general it is unnecessary to enter sterile rooms except in the most extraordinary circumstances. These areas are usually constructed to provide visual monitoring. Take no unsterile items with you (notebook, pencils, etc.). In this type of situation you can enter your observations in your regulatory notes immediately after leaving the sterile area."
In addition to explaining the reportable observations that can be identified in an inspection, the manual also discusses the use of FDA 483s, which the agency notes should include five characteristics: "1. Each observation should be clear and specific. 2. Each should be significant. Length is not necessarily synonymous with significance. 3. Observations should not be repetitious. 4. The observations should be ranked in order of significance. 5. All copies of the FDA-483 should be legible."
The chapter also discusses how inspectors should meet with high-ranking management officials at the site, what to do if they are hostile or uncooperative, and how investigators "should make every reasonable effort to discuss all observations with the management of the establishment as they are observed, or on a daily basis, to minimize surprises, errors, and misunderstandings when the FDA 483 is issued."
In-depth inspections of all manufacturing and control operations "is usually not feasible or practical,” the chapter notes on pharmaceutical inspections, though it says a "risk-based systems audit approach is recommended in which higher risk, therapeutically significant, medically necessary and difficult to manufacture drugs are covered in greater detail during an inspection."
In terms of discerning whether action taken by a drug firm during an inspection constitutes delaying, denying, limiting or refusing an inspection, the manual says: "Use reasonable discretion ... If you are unsure whether an action taken by a firm constitutes delaying, denying, limiting, or refusing drug inspection, contact your supervisor."
In the case of a refusal, which the agency says can take several forms, the inspector must show that the inspection was attempted in “reasonable time, reasonable manner, and reasonable limit to show you exercised prudence to avoid refusal. You must have presented your credentials and given the responsible individual a properly prepared and signed Notice of Inspection, FDA 482."
And in reviewing the agency’s files on a manufacturing site, the manual tells inspectors to “identify products which: 1. Are difficult to manufacture, 2. Are complex dosage forms, 3. Require special tests or assays, or cannot be assayed, 4. Require special processes or equipment, 5. Are new drugs and/or potent low dosage drugs, 6. Are misbranded, unapproved, fraudulent, or compounded drugs containing ingredients that have been withdrawn or removed from the market for safety or effectiveness reasons, or compounded drugs that contain bulk active ingredients that are not components of FDA-approved drugs."
As far as medical device manufacturing site inspections, the chapter notes that the majority are related to a quality system (QS) or good manufacturing practice (GMP), "but often the reason for the inspection will vary. For example, inspections may be conducted to assist the pre-market clearance process (PMA or Class III 510(k)), to specifically address MDR [medical device report] concerns, or to assure in-depth coverage of an aspect of manufacturing (sterility)."
In terms of MDR data most useful in preparing for an inspection, the chapter points to "specific MDRs for the manufacturer (i.e., query by establishment's short name) for the time frame since the last inspection, or MDRs for the generic devices manufactured by that establishment (i.e., query by product code) for some reasonable time frame. This data assists you in determining potential problem areas in the manufacture or design of the device, or lot or batch specific issues. MDR information can be accessed through the Total Product Lifecycle Reports (TPLC)."
As far as sample collection during device inspections, the manual notes that because of the limited funds available for samples and the relatively high cost of device samples, "it is essential you consider, in consultation with your supervisor, the following factors before collecting a physical sample of a device: 1. If follow-up to a QS/GMP deviation, will sampling demonstrate the deviation and/or a defective product? Documentary Samples may be more suitable for QS/GMP purposes. 2. Likelihood of the analysis showing the device is unfit for its intended use. 3. Samples costing over $250.00. 4. Laboratory capability to analyze the sample."