In July, acting FDA commissioner Janet Woodcock announced that the FDA would be resuming non-mission-critical facility inspections, effective immediately. In this article, we’re going to discuss what that means for pharmaceutical companies, and how they can prepare for a successful audit.   

First, some context. This announcement came as a follow-up to a May 2021 FDA report that detailed how inspections were handled in the period from March 2020 to May 2021. Due to COVID-19, in March 2020 the agency suspended normal operations to focus only on “mission-critical” inspections, including those related to developing COVID-19 treatments. Routine surveillance inspections, as well as some inspections in response to complaints and adverse events, were not classified as mission-critical and were postponed. 

In the May report, the FDA outlined three possible scenarios for a return to normal inspections. These included a base-case scenario where routine inspections would resume in July 2021, a best-case where they could resume immediately, and a worst-case in the advent of a resurgence in COVID-19 cases in which the FDA would maintain their current limited operations. In a July Senate testimony, Woodcock reported that the FDA had initiated the base-case plan. 

So the bottom line is that routine surveillance and pre-approval inspections are returning now. A tier system will be used to prioritize inspections as the FDA works through its backlog in the rest of 2021, which we’ll talk more about in the next section. 

For pharmaceutical companies, this is a good time to make sure you’re prepared for an audit. This means preparing your site, as well as making sure you have a plan for how to handle the mechanics of the audit when inspectors are on-site and after they leave. An FDA audit requires significant preparation, since inspectors will be going through your quality systems thoroughly to make sure you’re following federal GMP regulations. Problems with an audit can lead to costly corrective actions, plant shutdowns, or even more severe consequences. 

In this article, we’ll discuss the types of companies that should expect to be audited earlier, what to expect during an audit, and provide a list of items you should include on a GMP facility audit checklist. When an audit is announced, you can use this checklist to remain organized and thorough with your preparations. 

Who Should Expect an Auditor’s Visit

The FDA conducts three types of on-site audits:

• Pre-approval / pre-market / pre-license inspections are conducted as part of the application process when new products are developed and released to the public. 
• For-cause inspections are done to investigate adverse events, serious manufacturing problems, or consumer complaints.
• Surveillance inspections are routine, ongoing audits that focus on GMP compliance. (These are the inspections that we’ll be focusing on in this article.)

From March 2020 - May 2021, the FDA conducted mission-critical pre-approval inspections and some for-cause inspections, selected on a case-by-case basis. Surveillance inspections were not considered mission-critical and were postponed, which led to a backlog of about 967 surveillance inspections of sites that manufacture human drugs and biologics, most of which are in the US. 

Going forward, the FDA will prioritize inspections on a tier-based system. The 3 tiers are classified based on the types of applications and inspections:

• Tier 1, Mission Critical: COVID-19 treatments, products used to treat serious conditions for which there is no substitute, mission-critical violation follow-ups, and a handful of other critical cases. 
• Tier 2: Higher Priority: For-cause and application approval inspections that aren’t considered mission critical. The FDA is likely to face increased pressure to clear the backlog of these, since there are drug approvals which are delayed due to these postponed inspections. 
• Tier 3: Lower Priority: Almost all post-approval and routine surveillance inspections fall into this category. 

Going forward, Tier 1 and 2 sites will continue to be prioritized. With the base-case approach the FDA appears to be taking, about 26% of the backlog of Tier 3 surveillance inspections will be completed this year on sites that make human and animal medical products. Although not explicitly stated, the philosophy of the FDA to prioritize for-cause and non-critical pre-approvals suggests that a higher proportion of those types of inspections will be completed. 

Inspections will also resume for human and animal foods, but only about 10% of that backlog is expected to be completed in 2021. 

What to Expect During an auditor’s visit

First, to address a common question: are FDA inspections pre-announced? The answer is: usually, but not always. For routine surveillance inspections, the FDA is likely to contact you ahead of time to notify you an inspection is coming, and to schedule dates for the site visit. However, it is more typical that for-cause inspections are unannounced. 

Either way, you can prepare for any type of visit by maintaining a GMP facility audit checklist that you can work through when you’ve been notified of an inspection. 

The audit process itself is fairly straightforward and well-established. You can expect it to play out in four stages:

1. Introduction and opening conference

When the inspector (or multiple inspectors, depending on scope) arrives at the facility, they’ll present their credentials and an FDA form 482 Notice of Inspection that describes what they are there to inspect.

The opening conference is important for a number of reasons. First, it can clarify and define the scope of the inspection. One basic question to answer first is what type of inspection is being conducted: routine surveillance, post-approval, for-cause, or pre-approval. If it is a surveillance audit, the inspector should specify whether it is a full or abbreviated version (we’ll have more about that distinction in the next section).

Second, it will set the tone and the agenda for the visit. It’s important to demonstrate a well-organized, responsive, and collaborative approach from the start. This is a good time to set up a daily schedule for the inspector’s visit that includes some time set aside every day to discuss, clarify, or correct any findings.

2. Facility tour/inspection and document review

Initially, the inspector may want to conduct a walk-through of your facility. During the tour, the inspector will look for housekeeping issues and make note of items to follow up on. Expect the inspector to record things like equipment ID’s and names of personnel. Later on, this will be the basis for document requests, for calibration or validation records, training information, or other GMP-related documentation.

The document review part of the audit will be thorough, with the inspector looking for a number of specific types of documents related to your quality systems. A complete, accurate set of these documents is the key to demonstrating compliance with federal GMP regulations for most organizations. As we suggested above, having a GMP facility audit checklist ahead of time is an excellent preparation tool. This checklist should include an exhaustive list of documents that the inspector could ask to see, including:

High-level quality documents:

• • • Quality policy and quality plan. These documents should describe your organization’s overall approach to quality, how it applies to manufacturing operations, and systems for ensuring ongoing product quality
    • Listing of management representatives for quality
    • Records of regular management reviews of the quality system

Documents generated as part of new process startup:

• • • Risk analysis. In the view of the FDA, an important part of pharmaceutical process validation is a risk analysis, which helps to guide areas of focus for validation activities
    • Process validation reports. These are documents generated as part of the IQ OQ PQ process

Documents showing internal processes for responding to quality excursions:

• • • Standardized system for deviation reports
    • Records of any product recalls, rejections, or consumer complaints
    • Records of internal investigations into the root causes of the two items above
    • Systems for implementing corrective and preventive actions (CAPA systems) after internal investigations

Documents showing systems for ongoing quality and continuous improvement:

• • • Personnel training records and qualifications. Inspectors will expect thorough training records for anyone involved in processes covered by GMP. 
    • Reports from internal audits
    • Shipping records
    • Supply chain audits. The FDA expects pharmaceutical manufacturers to verify GMP compliance throughout the supply chain, which means having a system to audit vendors and service providers
    • Evidence of statistical process control
    • Facility monitoring and control records. One of the requirements for GMP is ensuring an appropriate manufacturing environment
    • Equipment/instrument calibration and maintenance records
    • Process change control system
    • Product and process performance review

3. Closing conference

In this meeting, the inspector will review their findings, which could include minor deficiencies, or more major problems that are recorded on Form 483. This meeting is an opportunity to have a discussion to clarify any deficiencies, and even to proactively address any issues before the inspector issues a final written report. 

4. Post-inspection follow-ups

The findings of the inspection will be documented in an Establishment Inspection Report (EIR) sent within 30 days. 

If any major issues needing correction are found, those will be described in a Form 483. At this stage, you’ll have an opportunity to take corrective actions. If an organization doesn’t reply to a Form 483 within 15 days, or if the response is insufficient, a warning letter could be issued, which is the first step in more serious actions like product seizures or recalls. 

How to Prepare Your Facilities For an Auditor’s visit

The FDA publishes several detailed documents that will give you a picture of the issues that auditors will be looking for. Two primary documents are:

• The Investigations Operations Manual (IOM), a detailed guide that all FDA inspectors follow for production facility audits and other site visits
• Compliance Program Guidance Manual (CPGM) 7356.002, which describes the specific inspection program for GMP in pharmaceutical manufacturing operations

In this section, we’ll distill these documents down to the most critical information you’ll need to be prepared for an audit. 

The first thing to understand is that, for GMP reviews, the FDA breaks pharmaceutical operations into six sub-systems. These systems, as given in CPGM 7356.002, are listed below. 

Since each pharmaceutical organization is complex and different, it is impossible to give an exhaustive list of items to prepare that will apply to everyone. However, below each area, we’ve listed some primary examples of what an FDA auditor will check for, which can be used as a starting point for a GMP facility audit checklist. 

• Quality, the most important system during an audit. It includes systems for overall compliance, quality control, change control, validation, overseeing root cause investigations of excursions, and developing CAPA plans in response. 
• Reviews of representative batches to identify trends over time
• Investigations/reviews and CAPA for complaints, discrepancies and other quality failures 
• Validation 
• Change control
• Plans for continuous process improvement
• Systems for evaluating, dispositioning, or quarantining reworked/returned/rejected batches

• Facilities and Equipment, which includes the building and environment where production takes place, utilities, and process equipment. 
• Facility layout, and specifically measures to prevent cross-contamination
• General cleaning and sanitation of the facility 
• Environmental monitoring (temperature and humidity, differential pressure where used)
• IQ OQ PQ of process equipment
• Systematic equipment identification

• Materials, which includes control of finished products, raw materials/ingredients, containers, as well as the systems used for inventory and distribution. 
• Inventory control for raw materials/ingredients and packaging components, including systems for storage, quarantine, or rejection
• Sampling/testing program for raw materials, including at least one specific identity test on each component, and validation of suppliers’ test results 
• Verification that containers and closures do not react with or absorb the product
• Visual ID of every lot of containers/closures
• Qualification of computerized inventory control 
• FIFO (first in-first out) stocking method
• Shipping records for finished products

• Production, which includes process development, validation, control, and documenting process performance. 
• Process validation, including justifications for setting in-process limits based on final product quality
• Contemporaneous individual batch records, including control data and yield calculations
• Master batch records
• Validation or verification of container preparation
• Monitoring of key manufacturing process parameters (temperature, pressure pH, tank level, hold time, etc)
• In-process control systems and records (statistical process control, for example)
• Equipment logs for cleaning, use, and calibration

• Packaging and Labeling, which includes label accuracy and validation of packaging operations. 
• Retention of label specimens; destruction of unused labels
• System for evaluating labeled product before shipping
• Use of lot numbers
• Separation of packaging/labeling operations for different products
• Expiration dating
• Verification of tamper-resistance 

• Laboratory Control, which includes testing and development of analytical methods. 
• Adequacy of equipment and staffing given the types of materials you’re analyzing
• Equipment calibration and use of reference standards to ensure accuracy
• Raw data retention
• Validation of analysis techniques
• Thorough records of all materials tested
• Response procedure for out-of-spec materials
• Verification of the capability and stability of test methods

There are also items that are likely to be checked in multiple areas, including:

• Process excursion root cause investigations and CAPA
• Process control change systems
• Training and qualification records for employees involved in the given area

We mentioned in the previous section that an important distinction is whether the inspector will be conducting a full or abbreviated inspection. In a full inspection, the inspector will cover at least four of these sub-systems; in an abbreviated version, the inspector will cover at least two. A full inspection is more likely if this is the first time your facility has been audited, if you’ve had compliance issues in the past, or if the FDA judges your operation to involve particularly high risk to consumer safety. 

We’ll take a moment here to point out that using automated IoT devices, like electronic data loggers that continuously upload to cloud storage, is the best way to meet the FDA audit requirements for monitoring and recording process and environmental conditions. These include temperature, pressure, humidity, and any other parameters that could affect final product quality. Automated IoT monitoring devices generate a time-stamped, organized record of the data consistent with FDA ALCOA guidelines (attributable, legible, contemporaneously recorded, original or a true copy, and accurate). 

Furthermore, large networks of IoT data loggers can be integrated into a single data collection/processing/storage system using software tools, streamlining the monitoring process. The benefits of using a modern system of IoT data loggers goes beyond just collecting and organizing data. They have the added potential of keeping calibration records for sensors, and sending out customized alarms, which can be part of a comprehensive approach to proactively prevent excursions in the interest of continuous process improvement. 

Manually recording process or environmental monitoring data is likely going to lead to an issue for auditors, since manual processes are prone to human error, aren’t generally able to continuously monitor critical processes, and require the attention of staff that would be better spent on higher level tasks. Manual data recording approaches also tend to be inefficient and do not scale with dynamic business conditions. 

Tips on How To Successfully Pass an FDA audit

The best way to make sure you have a successful, issue-free audit is to know the basics of GMP, and to make sure that you follow them, and you have all the required documentation in place. In other words: run your production facility as if the FDA could conduct an audit at any time. 

Beyond that, there are a few procedural tips that can help the audit process go smoothly:

• Prepare a written SOP for an FDA audit. The SOP should include preparing the site for the audit, how to conduct the facility tour, where the auditor will be based while they’re on site, any safety protocols or training the inspector should be aware of, what information to clarify from the auditor, the key personnel who will be involved, and a GMP facility audit checklist that includes a list of key quality documents. When you get notification that an audit is happening, you can simply set the plan in motion. 

Identifying the personnel who will be involved in the audit is critical. That includes the point person who will have the most interaction with the inspector, as well as subject matter experts who can be called in to discuss specific topics as needed. Subject matter experts should be chosen based on specific knowledge, experience, and communication skills. 

Some organizations also identify a single person to be responsible for retrieving requested documents, and one person to act as a scribe, recording anything discussed with the auditor. 

• Make sure all of the documentation you’ll need is organized, and you can access it quickly. We’ve talked a lot about documentation in this article, because a heavy focus of the auditor will be to make sure you have documented quality systems in place.
  
  
• Conduct mock audits or internal audits in preparation.
  
  
• Make the most of the introduction meeting:
• Take this opportunity to give a brief presentation on your company, the relevant production processes, and the quality systems you have in place. 
• Make sure to clarify what the auditor plans to focus on, and what type of audit is going to be conducted. 
• Propose an agenda that sets aside time at the end of each day to review the auditor’s findings and answer any questions that may have come up. 
  
  
• Likewise, use the closing meeting as a forum to discuss and clarify any findings before a written report is issued. 
  
  
• Be as proactive as possible when it comes to addressing issues that the inspector finds.  Keep in mind that the auditor’s mission is to ensure that you’re manufacturing safe, effective products, not to issue citations. 

Address issues that the auditor finds immediately, if possible. If the auditor finds an issue that you are already addressing, take the time to completely describe what you’re doing already. 

Conclusions

The resumption of non-mission-critical FDA inspections is a sign of a return to normalcy and is welcome news for the industry. In the second half of 2021, the FDA plans to work through its backlog of inspections, prioritizing mission critical, then for-cause and pre-approval inspections, followed by routine surveillance inspections. 

This is a good opportunity to make sure you’re prepared for an audit, by re-checking, organizing, and updating your internal quality systems and documents. In this article, we’ve described the key documents and facility sub-systems that an FDA auditor is likely to review. Having a GMP facility audit checklist that includes these documents is helpful to prepare for a smooth audit.

Using automated IoT devices like networked digital data loggers is the best way to simplify and ensure compliance in areas where monitoring of process and environmental conditions is required. 

Anyone with additional questions about how automated IoT devices can help your FDA audits go more smoothly is encouraged to contact the experts at Dickson.