FDA has halted most in-person manufacturing facility inspections during the COVID-19 pandemic, but some physical inspections are still being performed—for example, for-cause inspections where the public health could be at risk or pre-approval inspections for important new therapies. FDA can also perform virtual inspections or those based on records review.

How is the agency deciding which firms to inspect? What is the chance that your firm will be inspected?

In mid-June, the law firm Arnold & Porter sponsored a webinar, “FDA Inspection Alternatives During the COVID-19 Pandemic: Requesting, Preparing for and Responding to FDA Virtual Inspections,” featuring two speakers formerly with FDA, Howard Sklamberg and Ricki A. Chase.

Sklamberg is a partner at Arnold & Porter who spent seven years at FDA, most recently as Deputy Commissioner for Global Regulatory Operations and Policy when he left the agency for private practice three years ago. Ricki A. Chase is Executive Director, Compliance at Lachman Consultant Services, and spent 16 years with FDA, most recently as Director, Investigations Branch in Chicago before joining Lachman four years ago.

Sklamberg spoke about the current FDA inspection landscape and Chase addressed how firms can prepare for virtual inspections.

This article will be published in four parts:

Part 1: Sklamberg’s review of the current inspection landscape and what may trigger an inspection

Part 2: A review of a state-of-the-art virtual inspection platform using mixed reality technology developed by Thermo Fisher Scientific discussed at the ISPE Biopharmaceutical Manufacturing conference held virtually in early June

Part 3: Chase’s advice on how to prepare for a virtual inspection

Part 4: Chase’s advice on how to host a virtual inspection

In his portion of the webinar, Sklamberg specifically addressed:

  • FDA inspection status
  • Preapproval inspections
  • For cause, surveillance, and warning letter close out inspections
  • Inspection alternatives
  • Putting yourself in FDA’s shoes
  • When physical inspections might resume

During the Q&A at the end, he answered questions regarding virtual inspections and warning letter issuance from a virtual inspection.

[RELATED: How does your inspection rate compare to that of your peers? If you want to find out, get your Free Benchmark Report.]

FDA Inspection Status

Sklamberg explained that most of FDA’s physical inspections have been suspended, but that “mission-critical” inspections will proceed. According to FDA, for cause inspections and preapproval inspections for important therapies or to address shortages will take place. “Anecdotally, some of those are occurring,” he said. “I know that a client of ours has gotten a surprise for cause inspection in the pharmaceutical area.”

There are also some preapproval inspections taking place. “Now that we know the pandemic will be around for a while, FDA is ramping up virtual inspections,” Sklamberg said. “FDA has said that it is working with the Center for Disease Control and Prevention (CDC) to develop a phased approach to resuming inspections, and that would be largely domestic.”

States and localities are at different stages in the process of reopening. FDA will send investigators in when the states’ and localities’ rules and laws permit it. That is going to vary geographically. If your company has a site in a state when it completely opens up, FDA will be able to perform an inspection there.

During the COVID-19 crisis FDA has talked about some inspection alternatives, “but they are really of limited benefit to the agency,” Sklamberg maintained. “They have talked about sampling, use of mutual recognition agreements, records review, virtual inspections, and import alerts.”

The limited benefit is that, for example, sampling as FDA has said, is not a substitute for an inspection. Mutual recognition agreements work. FDA has used its mutual recognition agreement with Europe, but Europe has limits on its inspections as well. “Records review and virtual inspections are areas that we all think FDA will ramp up in the coming months,” Sklamberg said.

Preapproval Inspections

In terms of preapproval inspections, FDA has broad discretion on when to inspect and how to inspect. It must find a manufacturing facility suitable. Compliance Program Guidance Manual (CPGM) 7346.832 lists the criteria for priority pre-approval inspections (Figure 1).

Figure 1: FDA Pre-Approval Inspections Criteria

Figure 1: FDA Pre-Approval Inspections Criteria

Priority pre-approval inspections are based on risk, Sklamberg maintained. Risk increases when applicants have less experience, drugs are more difficult to manufacture, or have an Official Action Indicated (OAI) status, for example.

FDA has some more general criteria aside from priority preapproval inspections, “but they kind of mirror the criteria we just talked about. Again, risk for the product, risk for the facility, risk related to the compliance record of the company itself.”

Sklamberg pointed to the supply chain risk at the bottom of the list and noted that FDA has increasingly emphasized this at top levels in the agency, especially in the last year or so. And with the Covid-19 crisis, it is concerned about risks created by extended supply chains and supply chains that have problematic compliance records, particularly global supply chains, he pointed out.

For Cause, Surveillance, and Warning Letter Close Out Inspections

Surveillance inspections are the ones that are “the least mission-critical from FDA’s perspective, as they are not tied to cause,” Sklamberg maintained. “But they are nevertheless relevant because the CDER Manual of Policies and Procedures (MAPP) 5014.1 on this topic gives you a particularly good idea as to what FDA thinks is going to cause it to really want to inspect” (Figure 2).

Figure 2: For Cause, Surveillance, & Warning Letter Close Out Inspections Criteria

Figure 2: For Cause, Surveillance, & Warning Letter Close Out Inspections Criteria

“When looking at those criteria, you can apply them to FDA thoughts about the need for a preapproval inspection and when it can waive inspection. If you look at these criteria, they are just like the CPGM ones that we talked about. They focus on risk from the facility, risk from the compliance history, risk related to the product, risk related to the company, and then specific instances of risk like patient exposure and hazard signals.”

“These would cause FDA to want to inspect or at least do a virtual inspection for an application rather than just waive the inspection. And there are also for cause inspections, which, as I indicated, FDA is doing domestically.”

According to Sklamberg, FDA has the extremely broad authority in the international realm to issue an import alert without an inspection. Oftentimes, when FDA gets a signal, it will quickly do an inspection and then issue an import alert afterwards. However, if there is a troublesome enough issue FDA might reach out to a company and ask for a recall. They also could just issue an import alert. The statutory standard is the appearance of a violation, which does not require an inspection to meet.

Regarding warning letter closeouts, “if you are thinking of instances where a firm wants an inspection, it would be to get their application approved or to close out a warning letter after remediation. The overwhelming majority of times the agency requires a physical inspection to close out a warning letter. But that is not required by statute. The whole warning letter process is something that is within FDA’s control. If FDA wanted to, it could rely on virtual inspections to close out warning letters.”

Inspection Alternatives

One alternative to performing an inspection is to waive the inspection. And for some particularly simple or less risky products, waiving inspection might be something FDA would do more frequently now than it would in the past, the Arnold & Porter partner said.

Figure 3: Inspection Alternatives

Figure 3: Inspection Alternatives

It is also important to understand that FDA is very aware of its user fee goals and user fee negotiations heading toward reauthorization of user fees a couple of years from now. “And they do not want to be missing a lot of goals. They are also probably aware that it would be hard for them to do physical inspections for all the products that are out there.”

As indicated, Europe has not been doing much inspecting outside of small areas. That is changing a bit as Europe is opening up. So, we may have increasing situations where European regulatory bodies can access European sites and that inspection report can be used by FDA for approvals.

The mutual recognition agreement with Europe only covers facilities in Europe and the US. There is an open question about if FDA wants to whether it could rely on European inspections outside of Europe—for example, if a European agency inspected a facility in India. “I think if this crisis goes on for a longer period, there will be more of an incentive for FDA to use that” he said.

FDASIA section 706 applies to pharmaceuticals and gives FDA the authority to get records in lieu of or advance of an inspection. The utility for a records inspection depends on what FDA is inspecting, Sklamberg pointed out.

“If they are looking at, for example, a follow up regarding investigation reports or out-of-specification (OOS) investigations, a lot of that work can be on paper. If it is something more physical where FDA is looking at an issue regarding equipment, obviously paper would not cut it nearly as much. And that is where a virtual inspection would be much more appropriate, where you can use live video interviews of personnel and look at some of the physical aspects of inspections.”

Sklamberg shared that FDA has reached out and informally told associations and some of his firm’s clients and others that “if you think your situation is one where it is appropriate to have a virtual inspection, make a proposal and make it specific. For example, if you have a warning letter close out and you think FDA can verify that without physically being there, tell them specifically how they could do it and how that would meet their needs. It would be the same thing for an application. How can FDA be satisfied that the company can make this product from this facility?”

Put Yourself in FDA’s Shoes

“As a former regulator,” Sklamberg said, “I would say to put yourself in FDA’s shoes.

  • What does FDA want from that inspection?
  • Why is FDA physically there normally?
  • What are they looking at?
  • And what can you provide them?

If there is an issue with equipment, then you would propose something visual. And I would be proactive with the agency in how specifically they can accomplish their goals. There are some concerns FDA would have, for example, if there is a big data integrity concern. FDA has said that would be extremely difficult to address remotely.”

“Spontaneous interviews, as you know, are an important part of an FDA inspection. From their perspective it is harder to do when it is not visual. When you have a video inspection, there can be other people in the room that FDA might not see, just like there will be other people in the room at FDA that you might not see. And that affects the spontaneity.”

He noted that some of his company’s clients have thought that a virtual inspection would be easier because the investigator is not there. “And I think it is just the opposite,” the former regulator said. “FDA is going to want to be sure that it is getting the information to satisfy itself. It knows it is being scrutinized. And you have the ability at FDA, instead of just having one or two investigators at a site, have a couple of them appearing on the computer screen but a whole bunch of people in the room.”

When Will Physical Inspections Begin Again?

“You hear lots of rumors from folks at FDA, at various levels of the agency about when they are going to restart their domestic or foreign inspection program,” Sklamberg noted. “But I can pretty much guarantee you that no one in the agency knows because it is an incredibly complex question.”

‘You hear lots of rumors from folks at FDA, at various levels of the agency about when they are going to restart their domestic or foreign inspection program,’ Sklamberg noted. ‘But I can pretty much guarantee you that no one in the agency knows because it is an incredibly complex question.’

It relates to not just what FDA wants to do, but the whole federal government and its policy. It relates to what foreign countries will permit as far as travel by folks from the US. “And even at FDA, it relates to labor issues, as most of FDA’s inspection force is in a union. And if there are going to be dangers to any of the investigators, that becomes a labor issue. FDA is a public health agency that is not looking to endanger its employees.”

“So, there are a lot of intangibles here. But I think one thing is for sure: There are going to be sharp limits on physical inspections for quite a while. And FDA is going to want to be able to approve important therapies and not miss a lot of its goals. So, they are going to be relying on virtual inspections, paper inspections, and other inspection alternatives.”

Q&A Focuses on Virtual Inspections and Warning Letter Issuance

In the Q&A at the end of the webinar, questions addressed to Sklamberg focused on the circumstances under which FDA might perform virtual inspections and on the agency’s ability to issue a warning letter based on a virtual inspection.

Several of the attendees wanted to know if a virtual inspection is possible for a site that has never been inspected by FDA before, and whether a virtual inspection could be used for an OAI site that wants to close out a warning letter.

Sklamberg replied, “the answer to both is yes. There is no legal limitation on FDA that requires it to do an in-person inspection, either for a warning letter close out or for new facility.”

“I think the way to look at it is the fact that a facility is OAI or that it is new makes it a higher inspection priority for FDA. What that means is it is much less likely the FDA is going to want to waive inspection for an application.”

“Whether it can do a virtual inspection or not I think it might depend on some other factors. For example, if it was an OAI site and the OAI issue was related to a big data integrity issue, I think it would be harder for FDA to do a non-physical inspection, as I mentioned earlier.”

“Some other types of warning letters are much more amenable to FDA following up without being there physically. As I mentioned before, if FDA is reviewing data, if they are reviewing a third party consultant evaluation of your OOS investigations, that can be done well with records remotely. There are certain types of issues in inspections that FDA can verify visually through video.”

For a new facility, which is a high risk for FDA, it is unlikely they are going to want to waive inspection, but they could do it virtually. In both those instances, if you are the entity that wants the inspection—maybe for preapproval or to close out a warning letter—be proactive with FDA and try to anticipate what FDA concerns would be and then try to address them.

“For a new facility, which is a high risk for FDA, it is unlikely they are going to want to waive inspection, but they could do it virtually. In both those instances, if you are the entity that wants the inspection—maybe for preapproval or to close out a warning letter—be proactive with FDA and try to anticipate what FDA concerns would be and then try to address them,” Sklamberg advised.

Another question directed to Sklamberg asked whether it will be possible for FDA to issue a warning letter or take other enforcement action because of a virtual inspection.

Sklamberg replied in the affirmative. “One way we know this is FDA issues warning letters based on illegal claims that are on the Internet without ever going to do an actual inspection. It can issue a warning letter based on FAQs on a firm’s website that make disease cure claims without going down to the firm, issuing a 482, and then looking at the computer system.”

“The thing about warning letters is they are quite formal in the way FDA has developed procedures, but the structure and details of a warning letter are not part of FDA’s statute,” he explained. “They are something that FDA came up with to get voluntary compliance. So, FDA has a lot of flexibility. It can issue a warning letter. It can withhold approval of applications. It can do an import alert. The thing that might get tricky is if it were to take judicial action. But judicial action is uncommon.”

Next Up

This wraps up Part 1, Sklamberg’s review of the current inspection landscape and what may trigger an inspection. 

Next time, we’ll dive into Part 2: A review of a state-of-the-art virtual inspection platform using mixed reality technology developed by Thermo Fisher Scientific discussed at the ISPE Biopharmaceutical Manufacturing conference held virtually in early June.

Editor’s Note: On July 10, 2020, FDA announced a plan to resume domestic inspections. Of particular interest is a statement that for the foreseeable future all FDA inspections (except undercover operations for tobacco) will be preannounced.

[RELATED: How does your inspection rate compare to that of your peers? If you want to find out, get your Free Benchmark Report.]

Get your Peer Benchmark Report

Download the Special Report

Quality Week report sidebar

What You Will Learn from This Report:

How a major pharmaceutical company designed a program to train future leaders in quality

An industry-led initiative to advance the state of quality in the pharma industry

A pharma GMP leader’s tips for supporting quality culture within an organization

An update on FDA’s Quality Maturity Model

Redica Systems Enforcement Analytics

Compare two companies of your choice.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Evaluate Your CDMOs

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the inspection history of your CDMO sites.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the enforcement history of your CDMOs.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Monitor compliance at your Clinical Investigator sites.

Enter your email address and someone will contact you shortly to get you started.

Redica Systems Enforcement Analytics

Prepare for inspections of Clinical Investigator sites.

Enter your email address and someone will contact you shortly to provide more Clinical Investigator data about your sites.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore enforcement trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore observations and trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to run your custom report.

Redica Systems Enforcement Analytics

Get help choosing the right CRO.

Enter your email address and someone will contact you shortly to customize your insights.

Download the Special Report

Download your copy of THE FDA INSPECTION LANDSCAPE IN MID-2020 AND A LOOK AT VIRTUAL INSPECTION

In this summary we identify:

  • Trend analysis of FDA inspections through mid-2020
  • Strategies for preparing and hosting virtual inspections
  • New technologies to support remote inspections
Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need to prepare for your next inspection.

Download the Special Report

CDMO Comparison opt-in

In this summary we identify:

FY2018-FY2020 GMP data for Lonza & Catalent

Top GMP primary citations

Top FDA 483 observations

Panel Discussion – Remote Audits

Panel Discussion opt in image

Featuring Panelists:
—Barbara W. Unger, Unger Consulting, Inc.
—Jerry Chapman, Redica Systems
—Stephanie Gaulding, Pharmatech Associates

Who Will Benefit?
This session will be valuable to GMP quality, regulatory, compliance, and management personnel in FDA-regulated industries who want to have a conversation on remote audits and get to know what is going on in the industry.

Turning Failure into Success

Presented on Tuesday, April 27, 2021 by Steve Greer, Executive Coach, Genesis Assist, and former Quality Leader, Procter and Gamble

What you will learn:

  • How to use the Leadership SOS Model to transform quality culture
  • How to strengthen quality systems to eliminate human error
  • How to generate ideas on how to set your organization up for success for shareholders, FDA, and staff
Redica Systems Enforcement Analytics

Get Full Access to Redica Enforcement Analytics

Enter your email address and someone will contact you shortly to answer all of your questions and get you started.

Quality Management Systems for Small Pharma and Biotech Firms

Webinar: QMS for Small Pharma and Biotech Firms

Presented by Fenton Fong, Founder, Managing Director, & Principal at xCellarate

Get instant access to the webinar video and slides.

What you will learn:

  • Common challenges small pharma firms face when developing a QMS
    Recent enforcement trends involving the Quality Unit
    Impact of the COVID-19 pandemic

Download the Special Report

APAC ad

In this summary we identify:

GMP data from FY2017 to FY2020 for the Asia-Pacific region

Top 3 GMP primary and secondary citations

Top 3 483 observations

Download the Special Report

An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

In this summary we identify:

  • Data from 2019 UK MHRA Inspections
  • Trends from 2015, 2016, 2018, and 2019 inspections
  • Conclusions drawn from an analysis of drug inspection data

Experience the Power of Redica Systems

Redica_Vert_Periwinkle_RGB_Large

SEARCH Find the inspection records you want by inspector’s name, company name, site, city, country, etc.

WARNING LETTERS Easily search the largest database of FDA Warning Letters by date, company, FDA office, or subject

SITES Quickly assess inspection records including dates and inspectors across all of your sites

INSPECTIONS Complete list of FDA inspections by date, company, category, and country

Get Complete Access to the Redica Systems Platform

Please submit your email address and one of our team members will contact you shortly to answer all of your questions and get you started with the new Enforcement Analytics platform.

Experience the Power of Redica Systems

Complete the form and one of our experts will reach out to you to schedule a demo and answer questions about our subscription options.

INDEX INFORMATION  Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

STRENGTHEN DATASETS Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

ANALYZE & INTERPRET PATTERNS Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Webinar: Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Presented by Paul Smith, Agilent Technologies on Aug. 26, 2020

What you will learn:

  • Examples of essential laboratory actions to remain compliant during the pandemic
  • Recent data integrity non-compliance findings and trends
  • Essential strategies to find, understand, and leverage regulatory non-compliance data

Get the scoop on recent data integrity 483 observations!

  • FY 2020 Data Integrity 483 Observations
  • Data Integrity Observations for Human Drugs
  • Observations Falling Under GMP
  •  

Past, Present, and Future of Quality Culture

Presented by Regulatory Compliance Associates Distinguished Fellow Susan Schniepp

What you will learn:

  • How the 2014 FDA quality metrics initiative led to greater focus on quality culture
  • New quality culture tools and standards under development by PDA and other organizations
  • Best practices for quality culture, including case studies with lessons learned

Changing Medical Device Regulations

Presented by Redica Systems 

What you will learn:

  • The latest developments regarding the EU MDR
  • Quality Systems requirements for medical devices
  • Regulatory updates affecting medical devices

Download the Special Report

Combination Product Report

What You Will Learn from This Report:

The latest U.S. and European regulatory developments

The impact of smart combination products

How the EU MDR impacts drug-device combination products

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

In-depth analysis of the findings

Lessons learned

How companies can avoid similar shortcomings.

Experience the Power of Redica Systems

Redica Systems Expert Jerry Chapman to Present at SQA Annual Meeting

Index Information Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

Strengthen Datasets Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

Analyze & Interpret Patterns Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Download the 510(k) Sample

What You Will Learn from This Sample:

See how a 510(k) submission is structured

Find out what information to include

Review correspondence between sponsor and FDA

Redica Systems Enforcement Analytics

Unlimited Access to Reports and Data

Enter your email address and someone will contact you shortly.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

The first countrywide import alert issued by FDA

An inadequate deviation investigation

An inadequate product specifications and a product recall

Process validation issues at a CMO

A different perspective on process validation and the culpability of the quality unit

 

A.I. for Quality and Compliance Teams

August 3 webinar

Presented by Redica Systems Senior GMP Quality Expert Jerry Chapman

What you will learn:

  • A basic understanding of data sources, machine learning, NLP, and A.I. tools
  • Building and applying Expert Models
  • Two case studies, one on sterile manufacturing/503B and one on data integrity

Human Factors – Compliance and Applications

June webinar

Presented by Alison Sathe, Founder, Regulatory Mark & Valerie Fenster, Director of Insights and  Human Factors, Kaleidoscope Innovation 

What you will learn:

  • Human factors strategies from simple drug products to complex surgical devices
  • Primary and secondary labeling development and evaluation for usability
  • Human factors activities from product development to post-market
  • International strategies: expectations for human factors in regulatory submissions in international markets

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Sign up for your FREE account today and get instant access to Enforcement Analytics.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Let us know who you are and we’ll be in touch to answer all of your questions and get you started.

Redica Systems Enforcement Analytics

Keep up with the latest Regulatory Developments on Clinical Trials

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save your team valuable time when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save time and Resources when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Get immediate access to the news that matters to your sites.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

See how we can help you eliminate yet another spreadsheet.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Stay ahead of changing regulations.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO monitoring strategy.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO management strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Discover the power of the most comprehensive database of 483s in existence.

Our database of over 20,000 483s is retyped and tagged, making it easy to create an Observation Report in seconds.

Eliminate days of work and get your FREE personalized 483 Observation Report.