Unveiling the Nitty-Gritty of FDA Inspection

  • Date: May 10, 2010
  • Source: Admin
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The U.S. Federal Food, Drug, and Cosmetic Act has provided the FDA with the authority to demand evidence of safety for new drugs, issue standards for food, and conduct factory inspection. By inspections, FDA makes sure that the food, cosmetics and drug are safe, efficient and secure to be used by humans and animals. The U.S. Food and Drug Administration is held responsible for

  • Protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation, and
  • Advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

The objective of inspection – the FDA initiates its inspection with the objective to “….identify dangerous or otherwise violative units in order to protect the consuming public”

Scope of FDA Audit - FDA enjoys broad , yet limited authority to inspect equipment, materials, products, labeling and certain records.

What FDA Regulates
For different industry, regulations of the FDA get changes simultaneously. For the following four industries (Biologics, Cosmetics, Drugs, and Foods), FDA gives a closer look to:

Biologics Cosmetics Drugs Foods
  • Product and manufacturing establishment licensing
  • Safety of the nation's blood supply
  • Research to establish product standards and develop improved testing methods
  • Safety
  • Labeling


  • Product
  • OTC and prescription drug labeling approvals
  • Drug manufacturing standards


  • Labeling
  • Safety of all food products (except meat and poultry)
  • Bottled water

Types of FDA Inspection
FDA inspection can broadly be divided in two distinct categories – Surveillance and Compliance inspections. While the former category can be described as a routine inspection category, the latter takes place with a specific objective.

Surveillance Inspection:
As mentioned in the graph, surveillance category can again be divided into two separate subcategories

  1. Pre-announced/ Routine Inspections
    In case of pre-announced FDA inspection, the investigator contacts the firm to be inspected. From local District Office, the FDA investigator contacts responsible person at site.
    For domestic manufacturers, generally, FDA notifies the firms five days before the inspection whereas for foreign manufacturers, the notification is sent two to three months in advance.
  2. Unannounced/ Directed Inspections
    FDA often conducts unannounced or directed inspections. Therefore, being prepared for FDA investigator's surprise audit is the only solution to escape from FDA's warning letters. Make sure that all employees of your firm, starting from receptionist to management are ready to face the investigators. In fact, keeping one or two conference room unoccupied for the meeting would be advisable.

Compliance Inspection:
Same as the surveillance inspection, compliance inspection can also be divided in two categories:

  1. For-Cause Inspection
    The for-cause inspection starts taking place only under the below mentioned circumstances, where
    • Sponsor reports concerns about investigator
    • Study has major impact on medical practice
    • Patient complaint
    • Investigator conducts too many studies
    • Safety or efficacy findings are inconsistent with other investigators
    • Investigator works outside of specialty area
    • Lab results are outside range of biological expectations
  2. PMA
    Premarket Approval (PMA) is the most stringent FDA scientific and regulatory review process for products whose safety and efficacy warrants a higher level of review. In case of checking cGMP compliance or conducting follow-up from previous inspections, FDA comes for Premarket Approval inspections.

Is Refusal To FDA Inspection An Option?
Refusal to FDA inspection can fetch severe legal consequences as refusal is considered to be violation of US law and if refused, FDA can obtain warrant against the firm. In case of foreign firms, refusal to FDA inspection results into detention.

FDA's Inspection Authorization:
FDA has authorization to enter the premises and to copy documents required by the regulations. However, authorization of FDA works only if the agency pays its visits

  • At reasonable times
  • Within reasonable limits and,
  • In a reasonable manner

Items to be Available for Review and Inspection

CMC, History Section Production Related Qualifications Equipment Quality Related
  • Development Reports
  • SOPs
  • Change Control Investigations (i.e., nonconformances, failures, deviations)
  • Field Alerts
  • Process validation protocols & reports where done
  • System validations (e.g., water, gas, steam computer)
  • Critical Process Parameters (CPP)


  • Batch production records
  • Raw material usage
  • Cleaning validation
  • Environmental Monitoring


  • Complaints
  • Investigations
  • Failures
  • Reworks/reprocess laboratory
  • Raw data
  • Methods validation
  • Stability

How many investigators show up during Investigation?
Generally, inspections are performed by one person. If more than one person participates, it may be for training purposes or because some of the participants have specialized knowledge that the FDA believes is necessary to perform a thorough inspection.

Steps for Investigations
Usually, FDA has 10 separate steps to follow. These steps are -

  1. Selecting site(s)
  2. Investigator contacts Site
  3. FDA and Site agree on Visit Date
  4. FDA presents Notice of Inspection
  5. FDA requests data and documents
  6. FDA interviews Site Staff
  7. FDA conducts “Exit Interview”
  8. FDA presents Notice of Observations
  9. FDA writes Inspection Report
  10. FDA classifies Inspection

At the end of the evaluation, FDA classifies inspection and sends a letter to the inspected site.

How FDA Prepares for Inspection
Before conducting the inspection, investigators also prepare themselves thoroughly with the whereabouts of the firm. In doing that, they follow certain procedure:

  • Take help of the IOM, i.e., the Inspection Operations Manual, which is the primary guidance document on FDA inspection policy and procedures for field investigators and inspectors.
  • Get acquainted with a firm's operation and compliance history through
    • Registration and listing information
    • Complaints
    • Past establishment inspection reports (EIR)
    • Follow-up items for the last inspection
    • Applicable guidance documents
    • Database…MDRs, Recalls, Corrections, Removals, User reports

Preparation of Firms to Face FDA Inspection
Prepare for the FDA inspection long before you receive any notice that your firm will be inspected. Your preparation should include

  1. Completing written procedure
  2. Preparing logistics
  3. Train Personnel
    • Decide in advance the level of involvement of “front-line” employees
    • Train security / receptionist to receive the FDA
    • Follow all standard procedures
  4. Be familiar with
    • Investigations Operations Manual
    • Compliance Program
    • Guidance Manual 7382.845
    • Drug Manufacturing Inspections
    • Program 7356.002
    • Guide to Inspections of Quality
    • Systems (QSIT Guide)
    • Regulatory Procedures Manual
    • ORA Field Management Directives
    • FDA laws, regulations, and guidelines such as Good Manufacturing Practices (cGMP's), Good Clinical Practices (GCP), Good Laboratory Practices (GLP), Federal Food, Drug, and Cosmetic Act (FD&C Act), Code of Federal Regulations (CFR), Nutrition Labeling and Education Act of 1990 (NLEA)
  5. Identify key players during FDA Inspection – President, management representatives, regulatory affairs, Quality assurance, operations, engineering, R&D are the key people for the firm to face FDA inspection.
  6. Assign Roles and Responsibilities to key players & experts, escort, technical spokespersons, daily scribe, document logger, messengers / runners
  7. Know the Inspection Levels

    Levels of Inspection Type of Inspection Subsystem Coverage


      CAPA+ P &PC or Design Controls


    Baseline (Comprehensive)
      Four Major Subsystems (with linkages)


    For Cause and Compliance Follow-up
      As directed by CP7382.845


    For Cause
      As directed

  8. Know What are the General areas to be Inspected - FDA, in general, inspects certain areas to check whether the company is in compliance with
    • Quality System / Good Manufacturing Practices
    • Medical Device Tracking Regulation
    • Corrections and Removals regulation
    • Registration and Listing regulation
    • Current good manufacturing practice for finished pharmaceuticals (210 and 211)
    • Good Laboratory Practice For Nonclinical Laboratory Studies
    • Medical Device Reporting (MDR)
    • Medical Device Tracking
    • Corrections and Removals
    • Registration and Listing
    • Company organization including key personnel and qualifications
    • Standard Operating Procedures
    • Extent of automation
    • Calibration procedures
    • Master Production and Control Documents
    • Analytical capabilities
  9. What is high priority for Inspection?
    Other than the general areas of interest, FDA has some classified and high prioritized areas of inspection. These are-
    • Class III devices that have never been inspected
    • Compliance Follow Up / For Cause Inspections
    • Manufacturers of high risk devices
      • Special Assignment from CDRH or CDER
      • Devices with a higher frequency of recalls and MDRs
      • Devices that are driven by software and those with rapidly evolving technological changes
      • New devices
    • Single Use Device Re-processors

FDA Inspection Technique
FDA's inspection technique has witnessed a sea-change in the procedures. While the previous inspection technique used to be haphazard and dependent upon the inspector's discretion, the current Quality Systems Inspection Technique (QSIT) is responsible to make the procedure more sophisticated and organized. In comparison to the previous “Bottom-up” Review of Records, then Subsystems process, the current “Top-down” Review of Selected Subsystems, then Records has helped the process to be lean and less time consuming.

Close out Meeting
The investigator will make written notes of observations that, in his or her opinion could be violations. Commonly, such observations are about SOPs, record-keeping and validation. Such observations are recorded on FD-483, usually listed in order of significance. You should ask the investigator(s) to include your corrective actions taken during the inspection. A copy of the 483 will be given to you, and you should also keep in mind that it is available to your competitors under the Freedom of Information Act (FOIA). You are not required to respond to FD-483, but it is in your best interest to do so in writing.

Post-Inspection Functions

  1. Internal meeting – immediate
  2. Draft response to 483
  3. Send response to local FDA district office
  4. Request Establishment Inspection Report (EIR) through Freedom of Information office.
  5. Send follow-up response

Terms and Acronyms

  • FD&C Act: Food, Drug & Cosmetic Act
  • 482: FDA Form 482, Notice of Inspection
  • 483: FDA Form 483, Notice of Inspectional Observations
  • EIR: Establishment Inspection Report
  • IOM: Investigations Operations Manual
  • QSIT: Quality System Inspection Technique
  • ORA: Office of Regulatory Affairs
  • CAPA: Corrective and Preventive Action
  • P&PC: Production and Process Controls
  • GMP: Good Manufacturing Practices
  • CDRH: Center for Devices and Radiological Health
  • CDER: Center for Drug Evaluation and Research

Unfold the nitty-gritty of FDA inspection with the help of successful webinars conducted by ComplianceOnline. CDs available for the below mentioned webinars

Surviving an FDA Inspection: Understand the Do's and Don'ts and the Ground Rules

Preparing for an FDA Inspection

How to Manage an FDA Inspection

How to Prepare for an FDA Inspection - A Practical Prospective

What to Expect during an FDA Inspection, and How to Handle It

The Secret of Study Conduct Documentation to ensure a successful Audit: What the FDA Inspectors looks for

How to Prepare for, Manage, and Follow-up to an FDA Inspection



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