OOS failures

Go and read the January 2021 FDA warning letter to Allay Pharmaceuticals and then go and read the 1993 decision in United States vs Barr Laboratories.

The Barr decision, issued 28 years ago, explains how to deal with OOS results. The FDA followed up with a guidance in 2006 “Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.” Companies have no excuse for continued failure here, and yet as we see with Allay (and so many others) failures in investigation of out-of-specifications continues to be a major concern. Yet nothing we see is not covered in the Barr decision.

If you a pharmaceutical GMP professional these three documents should be ones you are more than ready to explain against your quality system.

Warning Letter for Aurolife demonstrates failures in process validation

The FDA commented in a Warning Letter to Aurolife Pharma that the manufacturer lacked data showing that the process was in “state of control” before batch release. The 483 pointed to the FDA’s guidance document Process Validation: General Principles and Practices, and found the company lacks a state of control of the process, which comes back to change control.

They also found major deficiencies in their OOS and cleaning programs.

System failures are rarely due to the employee

Between January 2016 and May 2019, you recorded approximately 397 customer complaints related to container closure issues (e.g., approximately 60%), product separation, lack of effect and adverse events. Your quality unit failed to adequately review these complaints, identify trends, and implement effective CAPAs. During the inspection you explained that these lapses in quality system performance were due to underperforming staff, who had since been dismissed. In your response, you attributed these and other quality related issues to under staffing of the quality unit as your business expanded.

Your response is inadequate because you failed to appropriately address your quality unit not performing their required duties. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities to consistently ensure drug quality.

FDA Warning Letter to Teligent Pharma, Inc. dated 26-November-2019

Continuing the trend of making me petrified about generics, this warning letter is a roller coaster read. One big set of failures to actually investigate and apply appropriate resources to the quality unit. And then the management had the gall to blame the employees.

80+ years of quality principles ignored. I personally thought the FDA was being overly nice.

There are basically three questions to answer:

  • Do you have a properly established, staffed, and managed Quality Unit?
  • Does your Quality Unit have appropriate responsibilities and authority?
  • Does your Quality Unit have access to the data it needs to make informed decisions?

FDA enforcement actions decline

Investigative report on FDA enforcement under Trump from Science’s news department shows a steep decline in enforcement actions.

I’ve noticed this, but it is good to see actual data behind it.

I’ll be frank, it would take a lot of data that does not exist to make me feel the companies under the FDA’s oversight have gotten better as a whole. Anecdotally, well there are a lot of less than sterling players out there.

I have mostly questions:

  1. Have we seen this trend in previous Republican administrations, and is it more pronounced here?
  2. Is there any evidence that the increase under Obama was a reaction to the previous Republican administration? Are we in a cycle of lax and then tougher enforcement that maybe evens out? That sort of variance is not healthy.
  3. What, if any data, will we be able to see about impact? There are certainly concerns that the FDA has not done enough. Will this be exacerbated?
  4. What will it take for this to start affecting the mutual recognition agreements with the EU and other major bodies?

An Analysis Of FDA FY2018 Drug GMP Warning Letters

BioProcess Online has a nice summary of the drug GMP warning letters issued in FY2018, as well as a comparison of trends since fiscal year 2013.
— Read on www.bioprocessonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003

Data Integrity definitely continues to be a theme, and I agree that we are seeing a growing trend around process validation. I also think root cause investigations was a theme of 2018 that we are going to be seeing a lot more of.