The FDA conducts pre-approval facility evaluations and inspections to ensure conformation with Current Good Manufacturing Practice (CGMP) requirements and to ensure accuracy and completeness of data submitted in the marketing applications for drug products.
On August 24, 2017, the FDA published a 20-page white paper for facility evaluation, entitled “Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations [ConOps],” detailing proposed strategic alignment, collaboration and vertical integration across various offices of the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA). The ConOps white paper outlines the responsibilities of CDER and ORA for pre- and post-approval, surveillance and for-cause inspections, as summarized below. Many aspects of the practice are unchanged, but the process is now streamlined.
Pre-Approval Facility Evaluations and Inspections
The FDA conducts pre-approval facility evaluations and inspections to ensure conformation with Current Good Manufacturing Practice (CGMP) requirements and to ensure accuracy and completeness of data submitted in the marketing applications for drug products. According to the ConOps white paper, CDER leads pre-approval facility evaluations with ORA participation, while ORA leads pre-approval facility inspections with CDER participation. The process for pre-approval inspections for biotechnology applications, wherein CDER currently leads many inspections, will remain unchanged for now.
Based on the ConOps white paper, upon submission of a marketing application for a drug product, the FDA assembles an integrated quality assessment (IQA) team. The IQA team provides the quality assessment, a plan for pre-approval facility evaluation and possibly a plan for pre-approval inspection. The Office of Process and Facilities (OPF) of CDER performs an initial facility risk assessment based on the application and a site dossier, provided by CDER’s Office of Surveillance (OS), which includes information on facility inspection history, recalls, shortages, customer complaints, a listing of all products manufactured at the site, etc. After receipt of the initial facility risk assessment, the IQA team may recommend a facility inspection; and CDER and ORA collaborate to decide if an on-site inspection is needed and, if so, to identify areas of concern. An ORA investigator, with participation of CDER, leads the inspection and documents objectionable findings, if any, in a Form 483 (when significant issues are identified) and completes the establishment inspection report. After a review of the findings, the IQA team evaluates the report and addresses outstanding issues through regulatory meetings or information request, discipline review or complete response letters, and provides an overall recommendation on approvability of the application.
Post-Approval Facility Inspections
The FDA conducts post-approval facility inspections that are focused largely on the process validation life cycle, any post-approval manufacturing changes or changes in perceived risk. According to the ConOps white paper, post-approval facility inspections will be led by ORA with CDER participation.
In summary, the IQA team, sometimes with ORA personnel, determines whether a post-approval facility inspection is needed, using a life cycle dashboard developed by the IQA team, and identifies any areas of concern. If the inspection team observes any critical conditions, the OPF, CDER’s Office of Compliance (OC) and OS may get involved, the inspection may expand to a surveillance inspection, and appropriate regulatory action may follow. The inspection team documents any objectionable findings and issues a Form 483 for significant issues. OPF completes its final assessment and recommendations within 45 days and initiates any follow-up action within the next 10 days, as needed, then updates the risk profile in the life cycle dashboard for further aiding inspections.
Surveillance Facility Inspections
To identify quality problems or any adverse trends, and develop strategies to mitigate them, the FDA routinely conducts surveillance facility inspections focused on manufacturing facilities of marketed prescription and over-the-counter drug products, as well as in-process materials or drug substances used in marketed drug products. According to the ConOps white paper, ORA leads the surveillance facility inspections with CDER participation, if requested by ORA.
The OS maintains a manufacturing facility catalog containing a risk-based site selection model that helps assess the relative quality risks and a prioritized list of the highest risk facilities for inspection. If ORA observes critical conditions during inspection, Office of Manufacturing Quality (OMQ) may get involved as well, and prompt regulatory action or further inspections may follow. The investigator documents any findings and issues a Form 483 at the close of the inspection. Within 45 days of the close of a surveillance inspection, ORA completes the establishment inspection report, which features the classification of the facility according to the Field Management Directive (FMD) 86 classification: official action indicated (OAI), voluntary action indicated (VAI) or no action indicated (NAI). Within two days of closing the inspection, ORA informs CDER if a facility is potentially OAI and refers the matter to OMQ within 45 days of closing the inspection. OMQ makes a final classification and issues a decisional letter within 90 days of closing the inspection. If an inspection is classified as final OAI, OMQ and ORA take the appropriate enforcement action. Alternatively, if OMQ determines that no enforcement action is necessary, they notify the ORA of the downgraded classification along with the reason(s) for downgrade within 40 days. If no further action is recommended, either because of NAI or VAI classification or because of downgraded initial OAI classification, ORA issues an FMD-145 decisional letter within 90 days of closing the inspection. Depending on the specific facts, further inspections may also follow. The OS also examines trends in quality issues and identifies a subset of firms for follow-up engagement.
For-Cause Facility Inspections
The FDA routinely initiates for-cause facility inspections in response to a new registrant or a specific event or information that brings into question the compliance and/or quality of a manufacturing practice, facility, process or drug. According to the ConOps white paper, ORA leads for-cause facility inspections with CDER participation, when appropriate.
The ORA, OPF, OS or OC can initiate requests for for-cause facility inspections. Following the request, depending on specific facts, one of these offices determines if a for-cause inspection is warranted, setting forth the areas of required coverage. ORA performs the on-site inspection, with CDER participation, if requested. If objectionable conditions are observed, the investigator issues a Form 483. ORA completes an establishment inspection report within 45 days of closing the inspection; and the initiating office completes a final assessment or classification in the following 45 days. ORA does not issue an FMD-145 letter unless the initiating office concurs. If the inspection team uncovers major deficiencies, other offices (e.g., OPF, OS, OC) may get involved, and prompt regulatory action or further inspections may follow. The initiating office completes a final assessment or classification and recommends appropriate action. OS updates the site dossier for the facility with information gained from the inspection.
Drug manufacturers should make sure that they conform to CGMP and be aware of any changes in perceived risk of drugs being manufactured and adapt their practices accordingly. Additionally, drug manufacturers should watch for surveillance facility inspections, as they are randomly scheduled.
For Further Information
If you have any questions about this Alert or would like more information, please contact Frederick (Rick) R. Ball, Carolyn A. Alenci, any of the attorneys in our Pharmaceutical, Medical Device, Pharmacy and Food industry group or the attorney in the firm with whom you are regularly in contact.
- Approved on June 6, 2017, by Janet Woodcock, the director of CDER, and Melinda K. Plaisier, the associate commissioner for Regulatory Affairs, but issued by the FDA on August 24, 2017.
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