Rescuing Product Approvals from Data Integrity Issues

The pharmaceutical industry is inundated with a plethora of communications about data integrity.  Most of those are focused on the downside – operational snags, negative inspection findings, adverse compliance actions by health authorities and aggrieved shareholders are just a few.  

What is less often publicized are cases where applicant holders who face these issues successfully manage the issues and secure approvals and a free hand to commercialize a product.  Let’s have a look at what one of these situations looks like in practice for a change.

A publicly held, global multi-national specialty pharmaceutical company purchased a late stage asset as the intended cornerstone for a new business unit.  The acquisition was done relatively quickly based on personal relationships between senior managers at the two companies and the time for product quality due diligence was limited.  This was a business-critical project and one of the highest priority items for the acquiring company’s new Chief Executive Officer (CEO).

The supply chain that was acquired by the company included only a single supplier for drug substance starting materials.  It was also the same supplier that manufactured the drug substance. Senior management had made an ironclad decision when the company was going to submit the marketing application to the U.S. Food and Drug Administration (FDA) and made that commitment known to shareholders and the equity markets.

There was not enough time to locate and qualify a second supplier before the NDA was submitted. As the date for the submission of the application was fast approaching, the company learned that the FDA had uncovered serious data integrity violations at the supplier during a routine current good manufacturing practices (CGMP) surveillance inspection.

Then just a month prior to NDA submission, the company learned that the FDA had placed that supplier on import alert. All future shipments of starting material and drug substance from the single supplier were being detained.  The supply chain for the product was now at a standstill and potentially riddled with data integrity issues that could require long lead times and significant expense to resolve.

To rescue the application and provide the best opportunity for a first cycle product approval with an intact supply chain free from data integrity snags, a four-step regulatory strategy was implemented to attack and resolve the problems.

• The first step was an analysis of recent consent decrees for data integrity, corporate integrity agreements for manufacturing issues, Warning Letter content for data integrity remediation and the FDA Application Integrity Policy (AIP) to synthesize essential elements for a manufacturing oversight program for the supplier.  The elements of this program were presented to the FDA in both a pre-submission meeting and in the application to gain FDA agreement for continued use of the supplier despite the data integrity observations.
   
• Recently published FDA action packages were reviewed to understand how FDA evaluated and made review decisions for manufacturing facilities in similar situations.  Those recent decisions indicated a very high likelihood that FDA would not include the troubled supplier as part of an approved application.  As a result, a strategy was created to implement and qualify an additional drug substance and starting material supplier using only a limited technology transfer program.  That argument was also presented to the FDA in the pre-submission meeting and the application.
   
• FDA recommendations from policy documents and public presentations for the expected elements of a petition to exempt the starting material from the import alert were identified.  The applicant and the drug substance supplier who manufactured the starting material cooperated in providing information to complete the contents of the petition and satisfy those elements.  The petition was then prepared for submission to FDA.
   
• The applicant gained FDA agreement to schedule a meeting just prior to the close of the product quality review to discuss and resolve these issues since time was of the essence.

During the pre-approval inspection (PAI) of the drug substance and starting material manufacturer, FDA investigators remarked that the elements of the proposed oversight program were rigorous, well recognized and very similar to FDA consent decree conditions.  The FDA initially did not agree with the argument to qualify an additional drug substance and starting material supplier on a limited basis during the application review. 

The applicant was able to persuade the FDA to change its position during the meeting held just prior to the close of the product quality review. The FDA was willing to review the initial comparability data for the additional starting material and drug substance supplier late in the application review timeline without penalizing the company.  The petition to exempt the starting material from the import alert was granted by FDA.

As a result of implementing this robust strategy on short notice, the company was able to receive a first-cycle approval of the application with an expanded and ready to use supply chain for both starting materials and drug substance despite being saddled with unforeseen data integrity issues.

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