If you have worked in this industry for at least a few years you have probably heard the phrase “PAI” thrown about.  What is a PAI? Why is it important? And how can I best position my company and our product?

Have a Game Plan

We always say that the worst thing you can do is to let an inspection happen to you.  An inspection is not just time taken out of your day, or a speed bump on the way to regulatory approval.  An inspection is your firm’s opportunity to put your best foot forward and clearly demonstrate to the US FDA  that you know what you are doing, your application is accurate, and you are ready for commercial manufacturing.  This is the opportunity to demonstrate that you (as a firm) have a clear understanding of your process and the associated risks.  You want the inspectors leaving your site with their questions answered AND a high degree of confidence in your product/process. If there are any questions regarding safety, efficacy, purity, identity, or reproducibility of your drug product you will have a difficult road to approval.  

Avoid the Silo

Inspectors do not work in a silo, and neither should you.  The FDA field investigators, reviewers, and center liaisons (CDER, CBER, CDHR, etc) all share information and work together.  FDA Reviewers will send their questions to the FDA Field Inspectors to address with the firm. Similarly, the field inspectors will be verifying the information submitted in the firm’s filing and subsequent correspondence. One question we often receive is, “Should a firm re-evaluate its submission documents in light of a pending inspection.”  The answer to this question is a resounding YES! It is strange how many companies still sequester this information and dole it out sparingly to only a few people. Employees should be aware of the submission information for their technical operation or area of expertise. For example, the purification team should be aware of relevant submission documents for purification, the process control strategy, purification specifications, process flow diagrams, etc.  Subject Matter Experts (SMEs) can’t explain and defend information that is not shared. Limiting this information within your company is like waiting to step into a pothole; it will lie there beneath the surface and eventually someone will step in it.  

What is a PAI (Pre-Approval Inspection)

Pre-approval Inspection Compliance Program 7346.832

“Pre-Approval Inspection Compliance Program 7346.832, Rev. 4, eff. 5/12/2010 The Food, Drug, and Cosmetic Act provides that FDA may approve an NDA or ANDA only if the methods used in, and the facilities and controls used for, the manufacture, processing, packing, and testing of the drug are found adequate to ensure and preserve its identity, strength, quality, and purity.” §§ 505(d) and 505(j)(4)(A) (21 U.S.C. §§ 355(d)(3) and 355(j)(4)(A))

In Layman’s terms, you must be able to demonstrate to the US FDA in order to approve an NDA (New Drug Application, used for new drugs) or an ANDA (Abbreviate New Drug Application, used for generics) the drug will have adequate processes and controls in place to ensure the drug’s identity, strength, quality, and purity.  The way that the FDA ensures adequate controls are in place is to evaluate the methods, facilities and controls that the firm has implemented.  

You will notice that the FDA chose its words very carefully.  

  1. The FDA takes a holistic approach.  They are looking at not only the facilities (buildings & utilities) and physical structure but also the controls that are in place (process controls, facility controls, material controls, etc.) and the methods being used in the product including test methods, sampling methods, etc.  This is actually a very broad range of data to evaluate.  
  2. They are not just evaluating the manufacturing process. In practical terms the FDA will evaluate all parts of the manufacturing of the product, processing, packing, and testing.  This may include the selection and testing of raw materials, components, packing materials, final products, vendors, and outside laboratories. The firm should also be prepared to demonstrate the evolution of their product showing that they have adequate process understanding to begin commercial manufacturing.  
  3. The small words make a difference.  The FDA carefully states that the process must be adequate to ensure and preserve its identity, strength, quality, and purity.  This means that the product is capable of meeting all specifications over the life of the product, not just at the time of release.  This is where stability testing, shipping studies, and other testing come into play. It is important to have a carefully planned stability program, shelf-life, and distribution chain.  

Site Evaluation 

Before approval, FDA evaluates the establishments by on-site inspections and/or by establishment file review when the firm is named in the Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologic License Application (BLA)

Which sites generally trigger a facility evaluation for a pre-approval inspection?  Facility evaluations are conducted for: Finished dosage manufacturers, API manufacturers, Finished dosage and API testing sites, Primary packaging and labeling sites, and when using  animal derived APIs they may review the facility that performs the crude extraction. (Ref https://www.fda.gov/media/94064/download).  PAIs may also be conducted for excipient manufacturers (for novel or critical excipients) or intermediate manufacturers if they are critical to the quality of the drug product.

When Does The US FDA Perform PAIs? 

How does the FDA evaluate if a site requires a Pre-Approval Inspection? The FDA uses risk based priority inspection criteria to make the decision to inspect a firm based on their potential Facility Risk, Product Risk, and Process Risk.  The U.S. FDA uses the following criteria to determine which site to inspect for a PAI:

Facility Risk

  • CGMP issues relevant to application product 
  • Recent FARs relevant to application product 
  • Recent recalls relevant to application product 
  • Numerous applications filed at once

Product Risk

  • New molecular entity 
  • First application filed by applicant 
  • First ANDA filed for an approved drug 
  • RLD has complaints, ADEs, stability issues 
  • Patient population or for serious condition 
  • Breakthrough therapy, shortage situation

Process Risk

  • Narrow therapeutic range (95%-105%) 
  • API derivation is high risk (derived from animal tissue) 
  • PAT, NIR, QbD 
  • Development data is incomplete 
  • Batch records non-specific 
  • Complicated process 
  • Substantially different process than previously covered at facility

If the FDA determines that an inspection is needed, they will assign investigators as well as specialists such as microbiologists, chemistry experts, process development experts, formulation experts, sterility experts, etc.  

Two Important Things to Remember!

A pre-approval inspection (PAI) is performed to contribute to FDA’s assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. Pre-Approval Inspection Program (7346.832).   

How is a Pre-Approval Inspection Different from Other Inspections?

  • PAI is product specific
  • Limited or no commercial manufacturing
  • More focus on development data 
  • More emphasis on authenticity of data and application commitments
  • Process validation is commonly not completed 
  • Application actions are administrative; typical enforcement actions that are used for marketed products do not apply here
  • Trend toward more FDA experts and scientists involved in the inspection and review process.

PAI Coverage: Objectives (Per the US FDA)

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 the 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.

Remember The PAI Is Only One Step Towards Approval

The inspection is one part of the approval process. The FDA’s lead investigator will make a formal recommendation at the end of the inspection of either Recommend Approval or Recommend Withholding of Approval.  

Recommend Approval indicates that the inspection found no significant issues and that the onsite inspectors have completed their review of (1) readiness to perform commercial manufacturing (2) Conformance to the application and (3) Data integrity review.  The firm’s responses to any FDA observations or follow up inquiries is important.  

Recommend Withholding of Approval indicates that the investigators observed that the site is not GMP compliant, information in CMC is not consistent with site records, or information submitted is not accurate and complete. The firm’s response to observations is absolutely critical.

It is important to remember that CDER’s Office of New Drugs or Office of Generic Drugs makes the ultimate decision on whether to approve or withhold approval of the application or licensure. A successful onsite inspection (PAI) is just one step towards product approval.  

Conclusion

To ensure a successful PAI inspection it is important to understand the intended purpose of the Pre-Approval Inspection (PAI) and what documentation will be requested.  Manufacturers should remember to “Have a Game Plan” and “Avoid the Silo.” The recommendation from the onsite FDA investigator will confirm the site’s readiness to perform commercial manufacturing, their conformance to the application filed with the US FDA, and the integrity of the data the application relies on.  For more information on US FDA Inspection Readiness contact Exemplar Compliance. www.ExemplarCompliance.com or email to  Info@ExemplarCompliance.com  

References:

FDA’s Pre-Approval Inspection (PAI) Program and How to prepare for a successful outcome CDR Denise DiGIulio Facility Reviewer Office of Process and Facilities CDER/Office of Pharmaceutical Quality. https://www.fda.gov/media/94064/download

FOOD AND DRUG ADMINISTRATION COMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM 7346.832, PRE-APPROVAL INSPECTIONS.  https://www.fda.gov/media/71498/download

www.FDA.gov

Author:

Rebecca Waterbury ChE, JD.  Rebecca is a Senior Quality Consultant with Exemplar Compliance, LLC and has worked in the life science space for over 18 years.  She has experience in medical devices, drug products, combination products, IVDs and biologics. She specializes in leading quality organizations and in preparing for product approval and commercialization.  www.ExemplarCompliance.com