Pre-Approval Inspection (PAI): An Expert Guide to Preparation

Pre-Approval Inspections (PAIs) are one of several significant milestones with an outsized impact on product approval and market entrance in FDA-regulated industries.

While organizations that have successfully navigated product development before often ingrain PAI readiness into their processes, companies of all sizes routinely need to devote time and energy to diligent preparation. That often means augmenting their limited internal resources by utilizing external reviewers and auditors to conduct mock audits and remediate as needed before the PAI.

However a mock assessment is just one step in preparing for a PAI. Preparation should be a cross-functional project incorporating training, compliance, organization, and validation.

Here, we offer a clear and concise explanation of what a PAI is, what companies should expect, and how they can prepare accordingly.

We gathered many of these insights from former FDA investigator Christopher Smith. Chris has over 40 years of experience having held senior positions at the FDA, large and small pharmaceutical companies, and contract research organizations.

In October of 2020, he sat down to discuss PAIs in an episode of The FDA Group's podcast, The Life Science Rundown. Watch the full episode below and read on for a clear and simple deep dive into PAIs.

Inside FDA's Pre-Approval Inspections with Former FDA Investigator, Christopher Smith

Listen and subscribe to The Life Science Rundown on Anchor.fm →

What is a Pre-Approval Inspection?

The FDA conducts PAIs to assure that a manufacturing site named in a drug application can manufacture the product and that the data submitted in the application is complete and accurate.

Any manufacturing site named for the first time in an NDA, ANDA, BLA, or PMA is subject to a PAI. These inspections are carried out at all kinds of facilities listed in applications, including API manufacturers, testing labs, and packagers, among others.

During a PAI, regulators will be looking to confirm the following:

• The site conforms to the application
• The site demonstrates manufacturing reliability
• The site can scale its operations
• The site uses suitable and adequate analytical methodologies
• The site is producing authentic and accurate data
• The site is in full CGMP compliance

The FDA has broad discretion on when to inspect and how to inspect. Compliance Program Guidance Manual (CPGM) 7346.832 lists the criteria for priority Pre-Approval Inspections.

Teams should carefully review this document and use it to craft their preparation activities as it offers a wealth of knowledge via guidance to investigators that can be "reverse engineered" to serve as the basis for a preparation plan.

Priority PAI criteria include:

• A facility being named for the first time in an application
• An applicant's first application
• The first ANDA for an approved drug
• New molecular entities
• Narrow therapeutic range drugs
• High-risk APIs
• Multiple changes to a site, process, and/or product
• OAI status or no recent inspection

General PAI criteria include:

• Sites producing difficult-to-manufacture drugs
• Site compliance record considerations
• Corporate compliance record compliance
• Recent inspections
• Supply chain risk

A Useful Background of the PAI Program

Former FDA investigator, Christopher Smith, says the PAI program was born out of an effort to turn what was an ad hoc approach to inspections preceding approval into a well-defined program that carried out consistent and thorough assessments.

Around 1999, the FDA changed their approach to inspections to fix what was then a disconnect between field operations and headquarters.

They started sending reviewers from headquarters out into the field to accompany people on inspections to see what investigators did. They also established the Pre-Approval Inspection program, which is different than FDA walking in the door and saying, "we're here to look at anything and everything."

Before then, one inspection team might have wanted to look at the water system. Another time, they'd look at manufacturing operations. Then the next time it might have been labs. You didn't know what you were going to get. The Pre-Approval Inspection program had some very specific objectives.

— Christopher Smith, Former FDA Investigator

According to a publicly available 2015 REdl Conference Slide Deck (PDF), FDA Small Business and Industry Assistance - FDA's Pre-Approval Inspection (PAI) and How to prepare for a successful outcome, the PAI has three stated objectives:

• Objective 1: Readiness for Commercial Manufacturing: Determine whether the establishment(s) has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.
• Objective 2: Conformance to Application: Verify that the formulation, manufacturing or processing methods, and analytical (or examination) methods are consistent with descriptions contained in the CMC section of the application for the biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s).
• Objective 3: Data Integrity Audit: Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC section of the application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC section such that CDER product reviewers can rely on the submitted data as complete and accurate.

Smith echoed the stated objectives, adding some additional context:

With the PAI program, the FDA wants to see whether what a company included in its application is in fact what they have documented on-site. If, for example, a company said in its application that it made ten batches, and presented that batch data for approval, regulators want to see it for themselves.

The investigators are supposed to examine the raw data that supports the claims in the application. Stabilities are a great example of this—looking at raw stability data supporting what was claimed in an application.

In general, regulators want to be assured that, whether you're actually ready commercially or not, that if FDA was to approve you tomorrow, you would be ready to go to market. It doesn't mean you don't have some time to then scale up your product. Rather, is the plant truly ready to make a commercial product or not?

— Christopher Smith, Former FDA Investigator

Advice for PAI Preparation

For most companies, PAI preparation begins by designating a team responsible for inspection readiness. This team should identify subject matter experts that may need to be involved in the inspection.

Like other types of inspections, physical preparation for an in-person inspection should include setting up a front and back room. The main room serves as the main audit room for investigators and company representatives. The back room is the "war room" where SMEs, document reviewers, and other impacted personnel prepare materials.

It's important to note that at the time of writing this guide, reports of the FDA potentially moving to remote or virtual inspections had only recently emerged. Read our write-up here.

Conduct a Mock PAI

In terms of timing, companies should strongly consider holding a Mock PAI roughly one year before FDA's inspection to allow time for any necessary remediation.

Need help with a mock inspection? We routinely help organizations plan and execute Mock PAIs with the help of former FDA investigators and industry experts. Learn more or get in touch with us.

A thorough and effective Mock PAI should:

• determine any processes, procedures, practices, or any other assets or activities that need to be remediated or improved prior to an official PAI; and
• produce a report that clearly communicates and prioritizes the findings of the mock inspection.

In general, an effective Mock PAI starts by designating a Project Manager who, sometimes with the help of a team, defines the scope of assessment, develops an audit plan and timeline, identifies resources, and executes the project.

Like any mock inspection, a Mock PAI should be conducted by or with the assistance of an expert third party who can bring objectivity and a wealth of knowledge to the project. Firms offering access to former FDA investigators can be particularly partners toward this end.

In addition to having firsthand experience conducting Mock PAIs, an independent consultant with requirements for other regulatory agencies can be tapped to carry out preparation for multiple markets. Need expert assistance with PAI preparedness? Let us know.

Perform Any Necessary Pre-Inspection Remediation

After the mock inspection report is finalized, teams should prioritize remediation activities according to risk and use the necessary mechanisms to carry out those activities (such as CAPA).

Here again, a third-party resourcing firm can help manage or augment the workload with third-party contractors and consultants.

Read our step-by-step guide to quality system remediation or learn more about our remediation support services.

Use the FDA's Compliance Program Guides

The FDA has program guides (such as the one we linked to earlier) for educating their field and headquarters staff about different program requirements. These guidelines include, for example, steps FDA investigators and other FDA staff involved in inspections should take when conducting routine manufacturing inspections.

These guides also include instructions on:

• what investigators should cover during an inspection;
• what investigators should include in their reports; and
• where those reports should go when they're completed.

But that's not all. These compliance guides also include instructions for the FDA compliance officer who reviews these reports on the kinds of recommendations to make to headquarters regarding problems based on the findings and if samples should be collected.

The program guide we referenced earlier specifically addresses PAIs. We've linked to this central PAI program guide below

• FDA Compliance Program Guidance Manual for Pre-Approval Inspections (PDF) (2019 Revision)
  

Consider Guidance and Other Regulations

In addition to FDA resources, many guidance documents and regulatory initiatives can be useful to incorporate into a PAI preparation project despite not having the full force of regulation. 

The FDA has adopted many of the ICH guidelines. These aren't law or regulation, so if you're preparing for an FDA inspection, you should know that the FDA is there to inspect against your application and GxP—things like that. Guidance documents and other initiatives do not have the force of regulation, so those observations shouldn't find their way into any write-ups.

However, the FDA may link to these tertiary documents, which might be referenced as a current regulatory "standard" of some kind. And of course, today, a lot of other guidance documents exist from other regulatory agencies. I think it's very useful to watch and see what the EMA is doing in Europe, or what Health Canada is doing, for example.

— Christopher Smith, Former FDA Investigator

Keep the FDA's Role in Mind

I think companies sometimes forget what the FDA's job is as they put preparation plans in place. If an investigator, in his or her opinion, finds something wrong, they say, "we don't think this is meeting the regulation." Too often, the next question from the firm is, "well, what should I do? How should I do it? What would you do?"

Investigators are told not to go down the road of recommending things to people. It's not the Agency's job. I tell people all the time, they're policemen. They're cops on the beat.

These days, however, companies are typically way more transparent and cooperative with the Agency, and oftentimes, that good faith is returned by regulators.

— Christopher Smith, Former FDA Investigator

Focus on Conducting and Writing Excellent Investigations

One big weakness I find in the industry is doing investigations. Not just doing them, but writing them. Companies are always going to have deviations and problems. The FDA knows that. Machines break. People make mistakes. Equipment in the lab goes down. An experiment goes wrong. These things happen and they're understandable. Don't hide it!

Instead, clearly and diligently document what happened and make sure you have the procedures in place to resolve and prevent what happened. The FDA expects an investigation. And then they expect corrective actions be put in place to prevent it from happening again. Sometimes they're unavoidable. Machines just break. Other times, however, a machine breaking down is the result of improper servicing and maintenance. When that's the case, a complete investigation and robust CAPA program can convey diligence and attention to what's important.

Keep in mind that an FDA investigator doesn't know your system. They don't know your people. They don't know your equipment. They've got limited time to come in and make some judgments.

Your investigations should be written up such that when you hand one to the investigator, whether it's one page or 25 pages, they should get to the end of it and say, "I know exactly what happened. You handled this really well."

What you want to avoid are the 50 questions that can come as a result of something being poorly written. Understand the terminology. Understand the procedures you're referring to inside and out. Write it for someone who doesn't work in the company—someone who hasn't been working with a machine for years. If a layperson can't understand it, revise it until they can.

— Christopher Smith, Former FDA Investigator

Keep the Audience in Mind When Crafting Form 483 Responses

It's the same thing I tell people about 483s. You have 15 days to respond, so you need to make some clear commitments. Just like investigations, you need to keep your audience in mind when writing up a 483 response. Don't just write briefly, like you're talking to the inspector in the room. The inspector clearly knows what he's writing up. But that 483 response is going to get read by people at the district office who weren't in your plant. It might get sent to headquarters for review by people who don't know much about your firm at all.

So, again, you have an opportunity to lay out your argument about what happened. Were you missing something? Was there genuinely a misunderstanding? Tell the full story so that somebody reading it gets a really clear picture without any prior knowledge of the situation.

— Christopher Smith, Former FDA Investigator

Summary and Next Steps

Preparing for a PAI is a process that should start at least a year before regulators are expected to walk through the door.

A Mock PAI planned and executed by a knowledgeable and experienced auditing professional is an important assurance activity. Following this assessment, any findings that require attention should be remediated through a diligent remediation project.

As part of any preparation plan, companies should designate a readiness team, identify and work with subject matter experts who will be involved, and ready their facility to receive regulators.

Learn more and schedule a Mock PAI with The FDA Group.

We've helped many life science companies plan and execute Mock PAIs and support subsequent remediation projects. Our large staff of industry experts and former FDA investigators minimize internal disruption and help ensure full confidence in your state of preparedness.

From regulatory observation responses to inspection readiness, our large staff of compliance specialists can tackle virtually any challenge and move your organization forward in a continuous and complete state of regulatory compliance.

Learn more about our Mock PAI services here or contact us and get the conversation started. Download our case study below to see how we helped a large healthcare product company support their PAI preparation project and subsequent quality system remediation efforts on time and 15% under budget.

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International PAI Audit Preparation & Remediation Project