The US FDA conducts drug manufacturing inspections for facilities to ensure they are compliant with the Current Good Manufacturing Practice (cGMP) standards. However, navigating through these inspections requires a clear and comprehensive understanding of several aspects. These include applicable manufacturing standards, site selection model, 483 forms, and how the FDA reviews the inspections and outcomes.
Applicable Manufacturing Standards
All drugs must be manufacturers under cGMP per section 501(a)(2)(B) of the FD&C act. This applies to prescription and non-prescription drugs (e.g., drugs approved under section 505(c) or 505(j) of the FD&C Act, OTC monograph drugs, certain compounded drugs).
cGMP standards are further specified based on drug type e.g., cGMP regulations for finished pharmaceuticals (21 CFR 210, 211) and Position Emission Tomography drugs (21 CFR 212); cGMP Guidance for Active Pharmaceutical Ingredient manufacture (ICH Q7)
For application products, inspections of manufacturing facilities may be conducted prior to approval to assess cGMP compliance, ability to meet application commitments, and data integrity.
Facilities are required to register with the FDA and list their products. After a facility starts manufacturing, they are subject to routine cGMP surveillance inspections based on risk-based site selection model. If warranted by information, facilities may be subject to “For Cause” inspections.
Site Selection Model
The Center for Drug Evaluation and Research (CDER) of the US FDA uses a risk-based site selection model (SSM) to prioritize manufacturing sites for routine cGMP surveillance inspections. These inspections ensure that sites consistently manufacture drug products of acceptable quality and minimize patient and consumer exposure to adulterated drug products.
The risk factors used in the SSM determine its site score and thus its priority for inspections. These include:
- Compliance history
- Inherent product risk
- Facility type
- Time since last inspection
- Hazard signals
- Exposure
Understanding cGMP Inspections and 483s
A US FDA inspection verifies a firm’s adherence to GMP standards. By using a risk-based approach it focuses on covering areas that are most important with respect to drug quality and resulting risk to patients. According to the US FDA, between 90-95% of Drug Manufacturing Inspections are found to be compliant on inspections. Investigators utilize a 6-system risk-based approach to assess the manufacturing operations: quality, facilities & equipment, materials, production, packaging & labeling, and laboratory control. The quality system is always assessed during an inspection to ensure overall compliance with cGMP standards along with additional coverage of 2 or more systems.
Investigation reports, equipment qualification, validation of the manufacturing process, testing of incoming raw materials and finished products, and adequate analytical methods are examples of items that are covered during inspections. Any deficiencies that demonstrate violation of cGMP requirements are listed on an FDA 483.
FDA Form 483
The FDA 483 form is given to a company’s management when the inspection has been closed; it documents the significant deficiencies that are observed as part of the inspection. These observations are listed in the form in the order of significance and the details of the violations that were observed. 21 CFR Part 211 is the principal regulations that the observation is listed under; 21 CFR Part 210 and 211 are the minimum standards that are acceptable for finished drug products.
After an inspection has been concluded and if a 483 has been issued, companies must respond within 15 business days with their corrective action plan. They must ensure that this plan has been implemented in a timely manner.
How the FDA reviews inspectional findings
The Federal Register includes the notice by the US FDA on Review of Post-Inspection Responses. The FDA reviews the findings and/or evidence that was obtained from the inspections and the company’s response to these inspections. It then evaluates the information in accordance with the applicable and relevant standards (legal and technical) and assesses the situation with respect to patient risk management and the regulatory significance. The FDA can concur, downgrade, or upgrade the final cGMP classification depending on the outcome of the review; it notifies the companies of their cGMP status within 90 days of the end of inspection.
Template letters are also posted on the FDA website in addition to the cGMP site classifications. This is to increase communication between the industry (i.e., manufacturing sites, sponsors, etc.) and the public. The 3 outcomes are outlined below:
No Action Indicated (NAI)
- The company is in an acceptable state of cGMP compliance.
- A 483 was not issued.
- This outcome does not usually affect approvability of pending applications that are under review with the FDA.
- This outcome does not affect the government contracts/procurement with the facility.
Voluntary Action Indicated (VAI)
- The company is in an acceptable state of cGMP compliance.
- A 483 was issued.
- The US FDA has reviewed the company’s response.
- This outcome does not usually affect approvability of pending applications that are under review with the FDA.
- This outcome does not affect the government contracts/procurement with the facility.
Official Action Indicated (OAI)
- The company is not considered to be acceptable with respect to cGMP compliance and could be subject to regulatory or enforcement action.
- An OAI outcome does not require a 483 to be issued.
- This outcome may lead to non-approval of pending applications with the US FDA.
- This outcome may impact the government procurement/preclude contract with the facility.
FDA regulatory actions
The US FDA’s compliance toolbox includes injunction/consent decrees, seizures, administrative detention orders, import alerts, warning letters, regulatory meetings, etc. It is important to note that while most tools are for OAI inspections, some may be used for NAI/VAI outcomes.
A key observation that has been made is the misperception regarding posted Warning Letter with respect to its technical applicability and what is needed to issue a Warning Letter. Most Compliance Actions like Warning Letters do not need evidence of failing drugs that are in distribution. So, a Warning Letter does not actually mean that the drugs are failing specifications. Instead, this action is usually a warning for non-compliance so that the company can fix things before failures in distributed drugs occur. However, if a failing product has been identified, the FDA shall issue a recall and/or provide a public notice (through press release or alerts). If needed, the FDA may call for more aggressive measures.
The FDA may also bar the import of drugs from certain firms if the inspection findings warrant for this excluding certain drugs in order to minimize drug shortages. If this is the case, then additional requirements are imposed on manufacturers that are tailored to the particular issue of the drug. Recently, an Import Alert was issued to a manufacturing company where they were listed under Import Alert 66-40. Here it stated that all future shipments of drugs which originate from this facility could be refused admission into the USA until the company can demonstrate cGMP compliance. The letter stated a list of products that are not subject to the import alert as they are medically necessary.
References and Further Reading
- US FDA. Drug Compliance Programs. United States Food and Drugs Administration. 2023
- US FDA. Webinar: Overview of Drug Manufacturing Inspections; understanding FDA Inspections and Data Webinar. United States Food and Drugs Administration. 2023
- Federal Register of the USA. Review of Post-Inspections Responses. Notice by the Food and Drug Administration. 2002
- US FDA. Intas- Import Alert 66-40. United States Food and Drug Administration. 2023
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