FDA is responsible to make sure that pharmaceutical products in the market are safe, effective and of high quality. FDA regularly inspects drug manufacturers located in the US and abroad to assess their compliance with cGMP.
An FDA inspection can create serious problems for pharmaceutical manufacturers when it comes to complying with the laws. During this inspection, the FDA will go through a very specific process and will determine whether or not the manufacturer has adequate procedures, documentation and quality systems in place in order to comply with the law.
This article outlines how FDA inspections are conducted at manufacturing facilities, including preparation, the inspection process, results and any subsequent actions taken.
The purpose of the inspection is to verify that a company's drug manufacturing processes consistently produce drugs that satisfy the previously defined specifications as discussed. However, the inspection also goes beyond just these items, it verifies that quality is built into every phase of the production process.
1. Pre-Approval Inspection (PAI): The purpose of this inspection is to grant marketing approval for a new product, to ensure:
- Manufacturing facilities can produce products according to NDA/ANDA/BLA submissions.
- Analytical methods have been validated.
- Manufacturing and Quality Systems are able to produce consistent products.
2. Routine cGMP Inspection: The purpose of this inspection is to verify that facilities are meeting ongoing compliance requirements to cGMP. Routine cGMP inspections are performed at least every two to three years for domestic facilities, or more frequently for high-risk facilities.
3. For-Cause Inspection: These inspections are performed as a result of a specific event(s), such as product recall(s), complaint(s), or observations made during previous inspections. The focus of these inspections is narrow and issue-based.
4. Follow-Up Inspection: These inspections are performed to verify that a facility has properly implemented the corrective actions promised as a result of a previous inspection(s).
5. Foreign Inspections: Any overseas facility that ships drug(s) to the U.S. market, must be inspected to ensure that products shipped to the U.S. meet the same quality standards as product(s) shipped from facilities that are located in the U.S.
The most common inspection trigger is an application for approval of both new drug applications and abbreviated new drug applications (NDA and ANDA). Other common triggers are:
- Recall of a product or complaints regarding its quality.
- Reports of adverse events occurring with the product.
- An event where goods had been declared to be adulterated (import alerts) that raised issues of data integrity.
- Reports of major deviations from 21 CFR 314.81.
- Being consistently ready to respond to inspections as part of your compliance with cGMPs.
- Product Submission
- Annual Report
- History of Previous Inspections
- Any observations made during a previous inspection (483 observations) and corresponding responses submitted by the company
- Details regarding the process of manufacturing, layout of facility and the control strategies that company implements.
This information is important for investigators to focus on the most important aspects of the inspection.
A short introductory meeting will then take place, which includes:
- The reason for the inspection and describes its scope
- Each company providing names and telephone numbers of their quality representatives
- Establishes logistics like meeting rooms, escorts to escort the investigators through the company and provides the investigators access to review documents as needed.
Once this meeting concludes, the official inspection start.
- Equipment (e.g., design, maintenance and cleanliness)
- Personnel’s practice of gowning and hygiene
- Flow of materials through and designation of critical areas
- Environmental control systems (HVAC, air differential measurements and filtration systems)
The first impression that an investigator has when they see an establishment, will be noted immediately any visual concerns that they may have such as leaks, residues or unlabeled products.
- Batch manufacturing records (BMRs).
- Standard operating procedures (SOPs).
- Quality control data like analytical results and stability reports.
- Validation and qualification documents for equipment, process and cleaning.
- Deviation records, corrective action preventative action records (CAPA) and records of change control.
- Training and calibration logbooks.
The inspector verifies that records are accurate, current, attributable, legible and comprehensive. This is referred to as the ALCOA principle for data integrity.
In many cases, the inspector will request that operators demonstrate how to do certain tasks, for example cleaning and setting up equipment, verification of line clearance, sampling procedures and record entry practices.
Operators must provide honest and consistent answers based on the documentation available. The FDA inspector has been trained to identify any discrepancies that exist between activities stated in the written SOP and the actual procedures that an operator follows.
During this meeting, each observation is discussed and the opportunity is provided to senior leadership to respond and clarify their response. The overall tone of the meeting sets the framework for what will occur following the conclusion of the inspection.
1. Data integrity - Falsified, missing or incomplete records as well as unverifiable electronic system entries.
2. Quality System - Lack of appropriate handling of deviations and corrective and preventative action (CAPA).
3. Process validation - absence of or outdated validation protocols.
4. Equipment maintenance and calibration.
5. Contamination prevention and cleanliness.
6. Employee training on personal hygiene, product handling etc.
7. Supplier qualification and management of materials.
FDA's primary objective during inspections is to verify that the company has systems in place to reduce the likelihood of non-conformance.
A. No Action Indicated (NAI): There were no deficiencies found during inspection in compliance with federal regulations that would require enforcement action during the inspection.
B. Voluntary Action Indicated (VAI): There were some less severe deficiencies identified by the inspector which do not require any enforcement penalties but do require corrective action.
C. Official Action Indicated (OAI): Serious deficiencies were observed in the facility which may result in one or more of the FDA's enforcement actions like warning letters, import alerts or seizure of facility or products.
If the violations are serious enough the FDA has enforcement options, including:
- Import bans (import alerts)
- Product withdrawal and seizure
- Consent decrees or criminal prosecution
In all cases when companies take timely and effective action they can often avoid these types of enforcement actions.
Here are examples of how leading facilities are always prepared for inspections:
In the EIR, the inspector will provide details on:
- The type of inspection performed and the findings of that inspection
- If any corrective actions were discussed during the inspection, these would be noted on this document
- The final classification level assigned to the establishment (NAI, VAI or OAI)
The EIR will be sent to the company after the review has been completed. This will conclude the formal inspection process.
Inspections performed by FDA are not an event to fear but they provide a chance for you to show your dedication to quality, safety and transparency.
The trust is involved in everything about pharmaceutical manufacturing. Companies can feel comfortable during an FDA inspection if they have a strong quality system, they document truthfully and they incorporate compliance into their day-to-day operations.
An inspection that goes well for you is not only a regulatory win but it’s a way for you to demonstrate that your processes effectively protect patients and that you follow the industry’s highest standards for pharmaceutical quality.
An FDA inspection can create serious problems for pharmaceutical manufacturers when it comes to complying with the laws. During this inspection, the FDA will go through a very specific process and will determine whether or not the manufacturer has adequate procedures, documentation and quality systems in place in order to comply with the law.
Purpose of FDA Inspections
The FDA conducts inspections of their facilities to determine if they meet the requirements of the Federal Food, Drug and Cosmetic Act (FDCA), if they are following cGMP guidelines set out in 21 CFR Part 210 and 211 and if they are producing products that meet an acceptable level of quality, safety and efficacy as well as maintaining adequate records to support compliance with both future audit and product traceability or other records required under applicable law.The purpose of the inspection is to verify that a company's drug manufacturing processes consistently produce drugs that satisfy the previously defined specifications as discussed. However, the inspection also goes beyond just these items, it verifies that quality is built into every phase of the production process.
Types of FDA Inspections
The FDA conducts inspections based on the purpose, timing and compliance history of the facility.1. Pre-Approval Inspection (PAI): The purpose of this inspection is to grant marketing approval for a new product, to ensure:
- Manufacturing facilities can produce products according to NDA/ANDA/BLA submissions.
- Analytical methods have been validated.
- Manufacturing and Quality Systems are able to produce consistent products.
2. Routine cGMP Inspection: The purpose of this inspection is to verify that facilities are meeting ongoing compliance requirements to cGMP. Routine cGMP inspections are performed at least every two to three years for domestic facilities, or more frequently for high-risk facilities.
3. For-Cause Inspection: These inspections are performed as a result of a specific event(s), such as product recall(s), complaint(s), or observations made during previous inspections. The focus of these inspections is narrow and issue-based.
4. Follow-Up Inspection: These inspections are performed to verify that a facility has properly implemented the corrective actions promised as a result of a previous inspection(s).
5. Foreign Inspections: Any overseas facility that ships drug(s) to the U.S. market, must be inspected to ensure that products shipped to the U.S. meet the same quality standards as product(s) shipped from facilities that are located in the U.S.
Advance Notification and Inspection Triggers
FDA inspections may either be announced or unannounced. Usually, routine or pre-approval inspections will be announced to the company several days before such an inspection takes place. Conversely, for-cause or follow-up inspections are generally conducted unannounced.The most common inspection trigger is an application for approval of both new drug applications and abbreviated new drug applications (NDA and ANDA). Other common triggers are:
- Recall of a product or complaints regarding its quality.
- Reports of adverse events occurring with the product.
- An event where goods had been declared to be adulterated (import alerts) that raised issues of data integrity.
- Reports of major deviations from 21 CFR 314.81.
- Being consistently ready to respond to inspections as part of your compliance with cGMPs.
Structure of an FDA Inspection
The FDA conducts its inspections utilizing procedures outlined within the Investigations Operations Manual (IOM) and Compliance Programs Guidance Manuals (CPGMs). There are five primary phases to conduct a typical inspection.1. Preparation Phase
Before engaging with the facility, FDA investigators will access the following information regarding the company:- Product Submission
- Annual Report
- History of Previous Inspections
- Any observations made during a previous inspection (483 observations) and corresponding responses submitted by the company
- Details regarding the process of manufacturing, layout of facility and the control strategies that company implements.
This information is important for investigators to focus on the most important aspects of the inspection.
2. Arrival and Introductory Meeting (Form 482)
Upon arrival at the company, FDA investigators will present their official credentials, as well as disburse the Form 482, Notice of Inspection to the management of the company.A short introductory meeting will then take place, which includes:
- The reason for the inspection and describes its scope
- Each company providing names and telephone numbers of their quality representatives
- Establishes logistics like meeting rooms, escorts to escort the investigators through the company and provides the investigators access to review documents as needed.
Once this meeting concludes, the official inspection start.
3. Facility Tour and Initial Observations
The first step of an FDA investigator's inspection is to walk through the facility. At this time the investigator will document his observations of:- Equipment (e.g., design, maintenance and cleanliness)
- Personnel’s practice of gowning and hygiene
- Flow of materials through and designation of critical areas
- Environmental control systems (HVAC, air differential measurements and filtration systems)
The first impression that an investigator has when they see an establishment, will be noted immediately any visual concerns that they may have such as leaks, residues or unlabeled products.
4. Document Review and Record Checking
All FDA inspections focus on the review of documentation. During the inspection process, inspectors will review:- Batch manufacturing records (BMRs).
- Standard operating procedures (SOPs).
- Quality control data like analytical results and stability reports.
- Validation and qualification documents for equipment, process and cleaning.
- Deviation records, corrective action preventative action records (CAPA) and records of change control.
- Training and calibration logbooks.
The inspector verifies that records are accurate, current, attributable, legible and comprehensive. This is referred to as the ALCOA principle for data integrity.
5. Interviews and Observations
The inspector interviews and observes employee positions at all levels of responsibility (from operators to QA managers) in order to verify that the employee understands and is following procedures correctly.In many cases, the inspector will request that operators demonstrate how to do certain tasks, for example cleaning and setting up equipment, verification of line clearance, sampling procedures and record entry practices.
Operators must provide honest and consistent answers based on the documentation available. The FDA inspector has been trained to identify any discrepancies that exist between activities stated in the written SOP and the actual procedures that an operator follows.
6. Daily Summary Meetings
The FDA conducts summarization meetings, known as wrap-up meetings each day during the course of multi-day inspections. The purpose of these meetings is to summarize findings, clarify information requests and create an opportunity for investigators to explain their findings.7. Exit Meeting (Form 483)
At the conclusion of the inspection, FDA investigators conduct a formal exit meeting with the senior leadership team and the quality managers. All observations made during the inspection are recorded on Form 483.During this meeting, each observation is discussed and the opportunity is provided to senior leadership to respond and clarify their response. The overall tone of the meeting sets the framework for what will occur following the conclusion of the inspection.
Common FDA Inspection Focus Areas
Over the years, the FDA has inspected hundreds of companies and has noted to see a variety of similarities. The most prevalent areas of non-compliance include:1. Data integrity - Falsified, missing or incomplete records as well as unverifiable electronic system entries.
2. Quality System - Lack of appropriate handling of deviations and corrective and preventative action (CAPA).
3. Process validation - absence of or outdated validation protocols.
4. Equipment maintenance and calibration.
5. Contamination prevention and cleanliness.
6. Employee training on personal hygiene, product handling etc.
7. Supplier qualification and management of materials.
FDA's primary objective during inspections is to verify that the company has systems in place to reduce the likelihood of non-conformance.
Inspection Outcomes
It can be concluded from the evaluation of findings following the exit meeting of the FDA's Inspection that there may be one of three outcomes:A. No Action Indicated (NAI): There were no deficiencies found during inspection in compliance with federal regulations that would require enforcement action during the inspection.
B. Voluntary Action Indicated (VAI): There were some less severe deficiencies identified by the inspector which do not require any enforcement penalties but do require corrective action.
C. Official Action Indicated (OAI): Serious deficiencies were observed in the facility which may result in one or more of the FDA's enforcement actions like warning letters, import alerts or seizure of facility or products.
How to Respond to Form 483
Once a company has received a Form 483, it should take the following actions:- Respond to the form 483 within 15 working days.
- Include detailed corrective and preventative action (CAPA) information in their response.
- Submit evidence for completion of these actions or provide a strict timeline for completion of any remaining actions.
FDA Warning Letters and Enforcement Actions
The Food and Drug Administration (FDA) issues a warning letter to any company when it found inadequate corrective actions or violation is severe and requires such action. The warning letter is publicly available and specifies the violations and requires that the company correct the violations by a certain date.If the violations are serious enough the FDA has enforcement options, including:
- Import bans (import alerts)
- Product withdrawal and seizure
- Consent decrees or criminal prosecution
In all cases when companies take timely and effective action they can often avoid these types of enforcement actions.
How to Prepare for an FDA Inspection
Preparation for an FDA inspection can not be a last minute effort but a continuous activity.Here are examples of how leading facilities are always prepared for inspections:
- Daily compliance with Current Good Manufacturing Practices (cGMP) - will treat every batch as if it is audit ready.
- Regularly train employees on conducting the inspection and recording accurately.
- Conduct mock inspections at least once per year.
- Logically organize your records and make them easy to find and access.
- Ensure the integrity of data in paper and electronic records.
- Handle all deviations within specified time frame and document corrective and preventive actions (CAPA) properly.
- Keep your facility clean and well maintained because first impression counts.
Current Trends in FDA Inspections
Recent trends in FDA inspections include:- Risk-based inspection approaches are developed from the FDA site selection model.
- Remote or hybrid inspections are being performed through virtual document review.
- A strong focus on data integrity and electronic records to meet 21 CFR Part 11 and other regulations.
- Global harmonization with other organizations such as the European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA) and World Health Organization (WHO) is being increased to implement regulations effectively.
What Happens After an Inspection is Conducted
The next step in the process of an inspection conducted by an inspector from the Food and Drug Administration will include preparing an Establishment Inspection Report or EIRIn the EIR, the inspector will provide details on:
- The type of inspection performed and the findings of that inspection
- If any corrective actions were discussed during the inspection, these would be noted on this document
- The final classification level assigned to the establishment (NAI, VAI or OAI)
The EIR will be sent to the company after the review has been completed. This will conclude the formal inspection process.
Inspections performed by FDA are not an event to fear but they provide a chance for you to show your dedication to quality, safety and transparency.
The trust is involved in everything about pharmaceutical manufacturing. Companies can feel comfortable during an FDA inspection if they have a strong quality system, they document truthfully and they incorporate compliance into their day-to-day operations.
An inspection that goes well for you is not only a regulatory win but it’s a way for you to demonstrate that your processes effectively protect patients and that you follow the industry’s highest standards for pharmaceutical quality.
Frequently Asked Questions (FAQs) on FDA Inspections
Q1. What is the purpose of an FDA inspection?
Answer: The purpose of FDA inspections is to determine compliance of the facility with current good manufacturing practices (cGMP) and ensure the manufacturing of high quality pharmaceutical products.Q2. How often does the FDA inspect pharmaceutical companies?
Answer: The FDA performs inspections of pharmaceutical facilities every 2 to 3 years. The frequency of the FDA inspections is based on the risk of the product, type of product and the compliance history of the manufacturing facility.Q3. What is Form FDA 482?
Answer: Form 482 is the FDA’s official "Notice of Inspection" document issued to the company when an FDA inspector starts an inspection.Q4. What is Form FDA 483?
Answer: FDA Form 483 lists observations made during the inspection where the facility is possibly out of compliance with one or more regulations.Q5. What happens after receiving an FDA 483?
Answer: The company must respond to the observations on Form 483 with corrective actions and preventive actions within 15 days of receiving the form.Q6. What is the difference between NAI, VAI and OAI?
Answer: An inspection classification of NAI (No Action Indicated) indicates that there were no observations of violations of the regulations and all the applicable regulations have been met. VAI (Voluntary Action Indicated) indicates that the inspector observed only minor violations. OAI (Official Action Indicated) indicates that the inspector observed significant violations and the inspector is obligated to take action against the facility based on those violations.Q7. Can FDA inspections be unannounced?
Answer: Generally, FDA inspections are not scheduled, however, follow-up or for-cause inspections will often be made with no previous notice given.Q8. How should a company prepare for an FDA inspection?
Answer: Companies should remain compliant every day, conduct regular internal audits and train their employees. Ensure all the records maintained by the facility are current, accurate and are available to the FDA inspector at the time of the inspection.
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