FDA Inspection for Pharmaceutical Industry

What is FDA inspection?

• The Food and Drug Administration (FDA) conducts inspections and assessments of regulated facilities to determine a firm's compliance with applicable laws and regulations, such as the Food, Drug, and Cosmetic Act. This typically involves an investigator visiting a firm’s location.

What should I expect during the FDA inspection?

• FDA may conduct an inspection of your operation for a variety of reasons, such as a routinely scheduled investigation, a survey, or a response to a reported problem. The investigator will present credentials and a "Notice of Inspection" (FDA Form 482) upon arriving at your plant. A knowledgeable person in your firm, such as the plant or production manager, preferably designated ahead of time, should accompany the investigator at all times. 
• It is in your best interest to fully understand FDA's inspection procedures. When you are unsure of certain actions taken by the investigator, don't hesitate to ask questions. Usually, the investigator will examine your production process, look at certain records and collect samples. 
• After the inspection, the investigator will discuss with your firm's management any significant findings and concerns; and leave with your management a written report of any conditions or practices, which, in the investigator’s judgment, indicate objectionable conditions, or practices. 
• This list of "Inspectional Observations," also called an FDA Form 483, can be used by your firm's management as a guide for corrective action since the FDA representative will not usually recommend specific corrective measures. Your firm can and should respond to the FDA-483 during the discussion with the investigator. In fact, corrective actions or procedural changes that were accomplished immediately in the presence of the investigator are regarded as positive indications of your concern and desire to voluntarily correct discrepancies.
• If you do not agree with the actions being taken by the FDA or if you have a question about the jurisdiction of the agency in a particular matter, you can contact the FDA's Office to seek a resolution.

What does FDA inspect?

• FDA inspects manufacturers or processors of FDA-regulated products to verify that they comply with relevant regulations. Those inspected include:

1. Vaccine and drug manufacturers
2. Blood banks
3. Food processing facilities
4. Dairy farms
5. Animal feed processors
6. Compounding pharmacies

• FDA also inspects facilities that conduct studies on people (clinical trials) laboratories that conduct studies on animals or microorganisms when these studies are used to apply for FDA approval of a medical product foreign manufacturing and processing sites for FDA-regulated products that are sold in the United States imported regulated products at the border.
• FDA conducts several types of inspections to help protect consumers from unsafe products: pre-approval inspection after a company submits an application to FDA to market a new product routine inspection of a regulated facility “for-cause” inspection to investigate a specific problem that has come to FDA’s attention.
• FDA makes available to the public certain frequently requested records of inspections in an electronic reading room. You would need to file a Freedom of Information request to obtain other records.

ALSO READ: FDA Audit Preparation

What Happens During an FDA Inspection?

• From drugs to medical devices to nutraceuticals and imports, the FDA inspects all manufacturers that produce products to GxP standards for compliance.
• Under the Federal Food, Drug, and Cosmetic Act, the FDA is required to inspect manufacturers at least once every two years—even more for companies just getting started, those with a history of compliance problems, and those who have started producing products significantly different from what they produced before.
• With a stepped effort by the FDA to monitor the growing number of manufacturers entering the market, many new companies struggle to understand what to expect and how to prepare when inspectors show up at their door.
• While the FDA’s Investigations Operations Manual offers the best complete resource for preparing to host an inspector auditor or any other compliance specialist, here are a few basic things to prepare for no matter what manufacturing space you’re in.

1. Arrival and Introduction

• It’s one of the biggest questions new manufacturers ask: “Will we be notified of an upcoming FDA inspection or not?” The short answer: Maybe, maybe not.
• Inspectors aren’t required to give notice of their arrival ahead of time, but if they don’t, they still need to make their presence known when they arrive.
• Once an inspector arrives at your facility, he or she will present official FDA identification along with the FDA form 482 Notice of Inspection which clearly lays out what the inspector may and may not inspect during their visit.

• As a general rule of thumb, it’s best to meet the inspector at arrival and discuss the agenda for the day. Most importantly, be sure to set aside time at the end of each inspection session to review, answer questions and provide clarification on anything the inspector might want to know more about or may have seen as problematic.
• These review periods can go a long way in avoiding additional exploration and can clear up any misunderstandings that pose problems down the road. If the inspector notes a problem you’re currently addressing, take the time to clearly lay out your process improvement with them one-on-one.

2. Facility Inspection and Audit

• After giving official notice of the inspection and running through the agenda, the inspector will get to work.
• When the FDA conducts an inspection, the inspectors will look for several specific components within your Quality Management System (QMS): 

A quality policy: 

• You’ll need to show that you’ve established a quality policy that applies to each on-site operation.

An appointed management representative:

Deviation reports:

Regular management reviews: 

• Inspectors will want to see evidence that your organization conducts management reviews regularly.

Internal audits: 

• Inspectors will want to see that not only are you auditing internally but that you’ve put a standard procedure for doing so in place.

A quality plan: 

• Inspectors will want to see if you’ve established a list of goals for ensuring quality moving forward.

Statistical evaluation of product data

CAPA procedures: 

• Inspectors will want to see you’re making an effort to investigate and correct quality issues to prevent a recurrence.

Risk analysis: 

• Inspectors will want to see that you’ve put any and all appropriate risk monitoring systems in place and that you’re routinely assessing relevant risks within your operations.

Product recall and rejection reports

Equipment and instrumentation calibration and maintenance reports

Training procedures: 

• Training is an important component of any inspection. Inspectors will want to ensure all operations are supported with adequate training systems.

EHS control charts

Internal investigations into failures: 

• If problems have occurred that lead to any kind of failure, inspectors will want to see documentation showing you’ve investigated the root causes of those issues and made the appropriate adjustments.

Manufacturing processes validation reports

Product and process performance reviews: 

• In addition to other internal audits, inspectors will want to see that you’re routinely reviewing the performance of your products as well as the processes that go into producing them.

This is just an abbreviated list of the inspection points common among manufacturers in general. Read the FDA’s Investigations Operations Manual for a complete explanation of the investigation process.

ALSO READ: FDA Inspection Preparation Guide

3. Closeout Meeting

• After completing their audit, the inspector will meet with company management to review the findings and bring to light any issues they found along the way.
• Keep in mind that the closeout meeting isn’t simply a report. It’s meant to start a discussion to better understand the regulatory deficiencies and any steps you’re currently taking to remedy them.

4. Post-Inspection Procedures

• After the inspection is complete, you’ll receive a letter from the FDA documenting the inspector’s findings.
• If regulatory deficiencies were found, they’ll be listed in the FDA form 483. In addition, the inspector will give a timetable or rough timeline by which any corrections should be made.
• Lastly, you’ll be given instructions on how to respond to these observations.
• After your responses are received, the investigator will write and submit an Establishment Inspection Report to the compliance office. If major compliance problems or any other kind of legal violation was identified, the Agency will take further disciplinary actions as needed in the form of warning letters, consent decrees, and/or detentions.

How to Prepare for an FDA Inspection?

• Sooner or later, an FDA investigator will walk through your door, greet the receptionist, and wait patiently for the leadership team to meet them in the lobby. The call goes out that the FDA is in the building and your inspection procedures snap into action.
• After learning an investigator has arrived, one of two feelings will strike you. For the prepared, it’s calm excitement. You can finally put your preparation to work, impressing the inspector with your initiative.
• For the unprepared, it’s panic. You always intended to prepare for this, but never got around to actually doing it. You frantically call down to various offices to relay the news, desperately hoping the I’s are dotted and T’s are crossed.
• This quick guide is designed to prevent this second scenario from becoming a frightening reality. While you may have the luxury of having a few days or weeks to prepare if the FDA decides to announce an inspection ahead of time, this doesn’t always happen.
• Companies need to be prepared for all possibilities. Here are six ways to make sure you are:

1. Make FDA Inspection Procedures Clear and concise

• Don’t obfuscate what should be a clear list of dos and don’ts with complicated, hard-to-follow procedural language.
• Boil it down to the essentials such as:

1. “When asked a question by the investigator, answer only the question asked of you.”
2. "If you don’t know the answer to a question, don’t guess. Inform the investigator that you don’t know, but will find out for them.”
3. “If an issue arises, don’t attempt to quickly resolve it in front of the investigator.”

• Assigning clear responsibilities requires clear communication. To ensure personnel aren't scratching their heads after reading through the procedure, check in with them to learn how they’ve interpreted them.
• If misunderstood responsibilities become a common pattern, chances are the procedures themselves are to blame.

2. Make Key Documents and records Easily Accessible in an Inspection-Ready Binder

• FDA inspections can span days, and in extreme cases, weeks or months depending on a facility's size, the nature of the inspection, and complications that arise if issues are discovered.
• Preparation ahead of time can help move the process along as fast as possible. In particular, make sure all basic information you know inspectors will need is available at all times in a central location or “war room.”
• Typically, an inspection binder is the most convenient way to compile and present information to investigators.
• No matter what type of inspection it is, here’s what you should be prepared to provide when asked:

1. Important procedures are related to document/change controls, complaint handling, CAPA, etc.
2. Quality system overview including a Quality Manual if applicable
3. Organizational charts & tables
4. Job/role descriptions and training protocol/records
5. Device listings
6. Responsibility matrices

• Since it’s very likely the investigator will want to see more than just the materials you've prepared (especially if observations are noted during the inspection), try to copy and catalog quality-related documents and records for quick reference.
• The point here is to avoid making the investigator wait unreasonably long to see a document they request. Delays are more than just annoying—they can suggest you’re either trying to hide something or a more general sense of disorganization.

3. Label Items for Fast Retrieval

• Investigators will most likely inform you of the products, processes and/or clinical programs they plan to evaluate before they begin. Marketing materials will likely be included in their document requests. Organize these materials in such a way that helps you retrieve them when asked to.
• As a particularly hot area of regulatory compliance, be sure those who should know about these items are completely prepared to answer questions.
• Expect investigators to test your staff to ensure they’re knowledgeable about the product and FDA expectations.

4. Compile Product Complaints and CAPAs Since Your Last Inspection

• This is a common request from investigators, so it plays in your favor to be ready for it ahead of time.
• Designate someone who can clearly and completely explain the complaints as well as the process in place to handle them. For those handling complaints electronically, you'll likely be expected to offer electronic information regarding them.
• While you may be asked for more specific information, prepare the basics first: name, product, date of receipt, is it MDR-reportable and a summary of the issue(s) cited.

5. Report All Corrections/Recalls & Keep Documentation Current

• Companies that have reported corrections/recalls will be asked for documentation to support Part 806.10. If any have gone unreported, expect investigators to want documentation in support of Part 806.20 and a compelling reason why it hasn’t been reported.
• Expect investigators to want to examine CAPA and risk management systems as well as your recall processes.
• Remember that every recall requires a CAPA. Make sure these are comprehensive and accessible during the inspection.

6. Run Mock FDA Inspections to Ensure Preparedness

• Mock FDA inspections are one of the best ways to shore up your ability to engage investigators when the time comes. While these are sometimes performed internally, it’s best to bring in an unbiased professional who can accurately replicate the real thing.

ALSO READ: Audit Checklist for the New Drug Approval Process by FDA

Types of FDA Inspections

• If the organization is manufacturing drugs or drug devices or it is the processor of the USFDA product, then the organization is bound to go through FDA inspection.
• There are 4 types of FDA inspection in pharmaceuticals. Each inspection type is intended to help protect the public from unsafe products, but their focuses and expectations are different.
• FDA inspections are conducted to verify compliance with regulations recommended by the regulatory agency.
• A company’s response to an FDA inspection should be tailored to the specific type of event. USFDA conducts four types of FDA inspections at many different types of facilities.

1. Pre-approval Inspection

• If you want to market the product in the US, pre-approval of the product is a must. Once the organization submits the application to the FDA, the FDA is ready to conduct the inspection. It is a pre-approval inspection of the FDA. This FDA inspection is basically conducted to know the facility and capability of the manufacturing site of the drug product that is marketed to the US.
• The outcome of the FDA inspection depends on how the manufacturing site is ready and follows compliance for the product. Either the facility is working according to the FDA inspection checklist. Based on that, it can be a recommendation for the manufacturing of drug products or a recommendation for better performance.

2. Routine Inspection

• In the early days, a routine inspection is conducted after every 2 years. But nowadays inspection can happen at any time.
• In a routine inspection, FDA inspectors visit the site and inspect the manufacturing facility and the compliance. If in routine inspection, any serious violation is observed with respect to a patient's safety or health safety, the inspector may issue an observation on “FORM 483”.
• FDA Auditors may come with an FDA audit checklist to inspect the facility and if found non-compliance FDA may issue the “FDA 483 letter” or “FDA warning letter” for a serious violation to the manufacturing site.
• In order to inspect quality systems, they utilize a technique known as Quality System Inspection Technique (QSIT).
• There are two levels of routine QSIT inspection:

Level 2 Baseline QSIT Inspection:

Baseline QSIT inspections are conducted every six years when a company does not had a level 2 inspection before. The inspection is intended to provide an overall evaluation of the quality system.

Level 1 Abbreviated QSIT Inspection:

Generally, Level 1 Abbreviated QSIT inspections are performed after the firm has gone through a Level 2 inspection, and it has been determined that the quality system is compliant.

• The CAPA subsystem always appears in a Level 1 inspection, and one other major subsystem will appear at each subsequent Level 1 inspection.

3. Follow-up Inspection

• Inspections that track the actions taken by firms and manufacturers in response to earlier inspections that resulted in significant observations or a Warning Letter are considered compliance Follow-Up Inspections.
• Normally, a compliance follow-up entails verifying whether previous violations were adequately corrected, documenting ongoing violations, or supporting future compliance control actions.

4. “For Cause” Inspection

• During a “For Cause” Inspection, the FDA examines a specific problem that has been reported to them, either by the manufacturer, consumers or employees. In an on-demand inspection, the firm is asked to turn over documents, but other non-critical elements of its operations can be examined as well.
• Inspections such as these are usually requested by CDRHs, ORAs, or regional directives. These inspections tend to be much more in-depth than routine ones, and may not follow an FDA QSIT (Quality System Inspection Technique) approach.

FDA Audit Documentation Checklist

ALSO READ: Role of the FDA in the Drug Development Process

FDA Inspection Checklist