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Preparing for an FDA Pre-Approval Inspection (PAI) – “Begin with the End in Mind.”

CMC Maturity Model

Preparing for an FDA Pre-Approval Inspection (PAI) – “Begin with the End in Mind.”

Presented by: Teresa Gorecki, Practice Lead, Compliance Architects

What is it Steven Covey said in “The 7 Habits of Highly Effective People?”

“Begin with the End in Mind.”

This is the first in a four-part series of articles on Preparation for a Pre-Approval Inspection. This first article will focus on one of three objectives FDA has during the Pre-Approval Inspection:  conformance of the production process and in-process controls, QC test methods, and specifications to the information provided by the NDA/BLA applicant to the CMC Section of the NDA/BLA.

I am often asked as a Consultant and Practice Lead working in Quality and Compliance with extensive experience in Pharmaceuticals, Biopharmaceuticals and Combination Products…

When should a company begin preparation for an FDA Pre-Approval Inspection?

It begins as you move through the development phase and create the documentation that will be part of the CMC Section of the NDA/BLA Submission to FDA for a new product.

Why?

The CMC Section of the NDA/BLA Submission is prepared months, if not a year or more, prior to an FDA Pre-Approval Inspection. Key Sections of the Development Report submitted in the CMC Section of the NDA/BLA, along with the documentation supporting the tech transfer and validation of the process and QC testing methods, are extensively reviewed during a Pre-Approval Inspection.

The “FDA Compliance Program Manual1. for Pre-Approval Inspections” provides a framework for the FDA Pre-Approval Inspection Program, the overall process for the program, and instructions on how the Program is executed by FDA.

There are three primary objectives for an FDA Pre-Approval Inspection, each of which consider the potential risks identified during the review of the NDA/BLA Submission and the risk posed by the manufacturing facility(ies) based upon prior Inspection outcomes. These objectives include:

  • Adherence of the Production Process, Test Methods etc., to the information provided in the CMC Section of the NDA/BLA Submission
  • Facility Readiness for Commercial Manufacturing
  • Data Integrity Audit
  1. The FDA Compliance Manual may be found at: compliance program (fda.gov) .

The FDA Investigator(s) conducting the Pre-Approval Inspection are tasked with assessing the adherence of the Production Process, Test Methods etc., to the information provided in the CMC Section of the NDA/BLA Submission. This then means that the data generated to create the CMC Section of the Submission is subject to FDA review during the Pre-Approval Inspection.

The quality of the final stage of the development documentation, technical transfer documentation, and validation documentation needs to be created in a manner that it can withstand rigorous review by FDA during the Pre-Approval Inspection.

This is why I believe that a firm must begin Process Development “with the end in mind.”. 

In the “FDA Compliance Program Manual. for Pre-Approval Inspections,” FDA summarizes what their expectations with respect to product and process design and how it impacts the risk to product quality, safety, and efficacy in the commercial manufacturing environment.

“Drug product design helps to determine whether the product can meet patients’ needs and maintain its intended performance through its proposed shelf life.”

In preparation for the Inspection, the FDA Investigators are instructed to review the CMC Section of the Submission prior to initiating the Inspection. Per the “FDA Compliance Program Manual. for Pre-Approval Inspections,” FDA Investigators are instructed to:

  • “Become familiar with the chemistry, manufacturing, and controls (CMC) section of the application and related drug master files (DMFs) for the establishment to be inspected. If possible, review the pharmaceutical development section before initiating the inspection.”
  • “Participate as appropriate in internal FDA Integrated Quality Assurance (IQA) Team meetings to provide or seek feedback on the application. Also, as necessary, discuss questions/concerns related to data reliability (e.g., test methods, 17 See MAPP 5014. Determine if other FDA IQA team members need data audit coverage of specific areas during the inspection.”

A key objective during the Pre-Approval Inspection is to verify that the formulation, manufacturing, and processing methods; QC methods; and master production batch records are consistent with information contained in the CMC section of the Submission. This will likely include a review of tech transfer and/or process validation batch records and documentation including the QC testing, microbiology/sterility testing and stability testing completed to date.  In addition to these documents, segments of the Development Report may be reviewed during the Pre-Approval Inspection. In particular, the segments on In-Process Controls, Bulk and Finished Product Specifications and Stability will likely be referenced or reviewed by the FDA Investigator.  Ultimately the FDA Investigators conducting the Pre-Approval Inspection are tasked with assuring the accuracy and reliability of the information provided in the NDA/BLA Application.

Where do I see firms go wrong?

There are a few areas where I often see firms struggle:

  • The protocols and reports which capture the development of the process, test method and stability data generated during product development are often not stored in a manner that is easily retrievable. I often see these reports stored in file cabinets, on the hard drives of individual pcs throughout the firm, or on unsecured “shared sites” on the firm’s network.
  • The history of the changes to the formula, production process, in-process controls, specifications and/or QC testing methods is not adequately documented.
  • The documentation to support the development of seed stocks or viral vectors is not well organized and does not link to the clinical trial lots manufactured. This is also true for Reference Standards developed by the firm which are critical to the biological and/or analytical test methods which quantitate identity, purity, and potency/efficacy.
  • The history of change in production sites for the API and/or drug products is not adequately documented.
  • The link between which site(s) clinical trial material was produced at and the clinical trial outcomes is not adequately documented. In turn this is not linked to the overall history of change through the development process.
  • The Development Report itself is not well structured and is an unorganized “composite” of numerous studies required to support the CMC section of the NDA/BLA. It does not “tell the story” of the development of the product.
  • The protocols and reports supporting the tech transfer of the process and QC test methods are not often seen as a critical document package FDA will review during the Pre-Approval Inspection.

All of the documentation described above is part of the information that creates the foundation needed to support the product through its lifecycle.  Regulatory Affairs creates the CMC section of the NDA/BLA, working from documents provided to them from many diverse sources; there is, in some extreme cases, no way to assure that the documents provided were indeed the correct documents because the documentation supporting the development of the product is in disparate places and is not well organized.

That is a strong statement, but I have seen many situations where this IS the reality.

How does a firm know if they are well positioned to achieve a favorable Pre-Approval Inspection outcome for the first objective in the Inspection?

… that first objective of FDA being:

  • Adherence of the Production Process, Test Methods etc., to the information provided in the CMC Section of the NDA/BLA Submission.

The firm should self-assess to understand how mature their Development Process is supporting the development and submission of the CMC Section of the NDA/BLA.

Many organizations see the creating of the CMC Section of the NDA/BLA as a paper exercise driven by Regulatory Affairs. It is indeed much more than that. I agree with FDA’s statement:

“Drug product design helps to determine whether the product can meet patients’ needs and maintain its intended performance through its proposed shelf life.” 

The critical activities and documentation of those activities during development and tech transfer and validation at the commercial manufacturing site are key to being able to reliably supply a finished drug/biological/combination product from launch through retirement that is safe and effective throughout its life in the marketplace.

So where is your firm?

Did you begin Development with “the End in Mind?”  The end being a successful Pre-Approval Inspection as one of the criteria for a successful end?

I have created a CMC Maturity Model based upon what I have seen through my career in Industry and as a Consultant. It is presented in Figure 1., below

Figure 1.

At Level 1 the firm will struggle to adequately support the documentation requests and discussions with an FDA Investigator(s) during a Pre-Approval Inspection.  The outcome of this Pre-Approval Inspection could potentially result in numerous 483 observations or even a withhold approval inspection rating by the FDA.

The firms which are able to successfully navigate the Pre-Approval Inspection smoothly are those at Level 3.  Barring any significant GMP issues cited for the plant site GMP Quality Systems, a firm at Level 3 will be able to conclude the Pre-Approval Inspection with an approval of the site for commercial manufacturing of the new product.

Those firms at Levels 4 and 5 are not only able to easily support the intensive document review from development through tech transfer to and validation at the commercial manufacturing site with FDA, but they will also able to support the changes needed post-commercialization which will support future FDA Inspections post approval of the NDA/BLA.  They will have no difficulty receiving an approval rating for the commercial site by the FDA at the conclusion of the Pre-Approval Inspection.

With that in mind…  I will go back to my initial question…

When should a company begin preparation for an FDA Pre-Approval Inspection?

During the development of the product, process, and test methods.

The Development Organization must understand that each and every experiment, test, protocol, and/or report may potentially be inspected by FDA months to years after the work was done.

Organization of that data and documentation is important; ensuring the correct information is submitted to the CHC Section of the NDA/BLA is critical. The link between the clinical trial product and what will be launched commercially and the history of changes throughout clinical and product development is important. The Development Report should provide a well-organized summary of the history of the development and evolution/changes to the formula, process, test methods, primary container/closure, site(s) of manufacturing, primary production equipment, and etc., for the product.

What should the Commercial Site Team have available for the Pre-Approval Inspection to fulfill FDA’s first objective for the Pre-Approval Inspection?

(Adherence of the Production Process, Test Methods etc., to the information provided in the CMC Section of the NDA/BLA Submission.)

The site team should have the information needed to support the final commercial manufacturing package including the master batch record and in-process controls, QA test methods, specifications, and product expiry dating.  This includes tech transfer and validation of the production process and QA test methods at the site. It also includes the stability data submitted in the NDA/BLA as well as the proposed marketed product stability protocol.

How should the firm prepare for the first segment of the Pre-Approval Inspection which will assess the firm’s adherence of the production process, test methods etc., to the information provided in the CMC Section of the NDA/BLA Submission?

To prepare for this segment of the Pre-Approval Inspection I would recommend the following:

  • Determine your CMC maturity level. The level that your firm is at will inform how early your firm needs to begin to prepare for the up-coming Pre-Approval Inspection. The higher the maturity level, the less time will be required to prepare.
  • Assemble a “PAI Readiness Team” comprised of key subject matter experts from Development, Analytical Development, Tech Transfer/Tech Ops, Manufacturing, Plant QA, QC, and QA Compliance. If the product is produced at a third party or QC/Micro testing is conducted by a third party, create a cross-site team to ensure adequate support at the third-party location for the Pro-Approval Inspection; present a united front to FDA.
  • Review the CMC Section of the NDA/BLA as a team along with the Development Report and key Reports that will likely be requested by FDA during the Inspection.
  • Invite an independent third party (from with the company or outside of the company) to conduct a “mock PAI” with the PAI Readiness Team. Optimally this should be done twice. Once, early in the readiness process, so that any critical gaps found during the mock PAI can be addressed prior to the FDA Pre-Approval Inspection. The second mock PAI should be a dress rehearsal with the subject matter experts who will present to FDA. This will provide an opportunity to coach the subject matter experts on how to manage their interactions with FDA during the Pre-Approval Inspection.
  • Invite the company Compliance organization to conduct a data integrity audit of the data and documentation that will likely be requested by FDA during the Inspection.
  • Organize all the documentation prior to the Inspection so it is readily available in electronic and hard copy format.
  • Develop an overview in PowerPoint of the development history including the history of changes to the process, test methods, specifications, and etc., to be presented to FDA during the opening of the Pre-Approval Inspection.

What is the most important thing your firm can do to be “really ready” for an FDA Pre-Approval Inspection?

“Begin with the End in Mind”…

  • Understand how mature the CMC process is within your firm. Request a third-party assessment from one of the Q&C Consulting Firms with Consultants who understand the Development/CMC process. Compliance Architects may be able to assist you with this assessment. compliancearchitects.com
  • Utilize one of the newest IT solutions available to organize all of the develop documentation needed to support the CMC Section of the NDA/BLA, understanding that this critical information is the foundation upon which the quality of the product will be managed through its life cycle. One product which I personally recommend is QbDVision from Cherry Circle Software. qbdvision.com
  • Develop a culture withing the Development Organization within your firm that deeply understands the importance of the documentation created during the development process and how it forms the foundation upon which the product will be managed throughout its lifecycle.

 

 

 

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