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

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.

Pfizer plant in Kansas repeatedly hit with form 483 infractions

In the last 6 years, Pfizer’s Hospira plant in Kansas has received eight FDA Form 483 citations, as well as other observations for regulatory bodies, such as this summer’s  from the MHRA.

The latest FDA 483 was in August 2018.

Comparing these observations with this year’s from Mylan certainly brings to mind a lot of thoughts about cleaning validation and contamination control.

All eight observations are repeat, some from multiple years. I find this troubling given the June 2018 Close Out letter to the 2017 Warning Letter.

Mylan Warning Letter

Mylan’s West Virginia plant received a Warning Letter this month and US FDA Commission Scott Gottlieb tweeted on it, and Mylan recently issued a press release.

I’ve made a few posts on their 483:

Mylan’s issues really need to be viewed as a lens of current regulatory body thinking and not as an issue of a company behind the times. In short, this could be you and if your company is not pouring through these and evaluating your own systems you should be.

The Warning Letter has a few trends we see in this sort of document:

  1. Requiring an independent review. If your system is broke than the agency doesn’t trust you to say its okay. Get an independent consultant.
  2. Lack of quality unit authority. One of the best things my site head of quality ever said (and if he is reading this, take this as a serious compliment) was to a group of high school interns when he said the quality unit is the only part of the Pharma manufacturing organization with duties required by law. That we have a legal duty to our companies and to the patients.
  3. Go to the ICH guidance documents
  4. This is happening at more than one site. Clean it up corporate wide.

The last one is worth further thought:

These repeated failures at multiple sites demonstrate that Mylan’s management oversight and control over the manufacture of drugs is inadequate.Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the products you manufacture, consistently conform to FDA requirements.

It is a critical part of your inspection program to be evaluating issues at each and every one of your sites for all your sites. The CAPA program needs to have the ability to assess CAPAs for similar root cause at all sites, that’s part of the preventive, and without it you are truly not addressing all the potential risks in your organization.

In past decades Mylan was a golden-child of cGMPs, and a lot of thought has gone into why the massive backslide. Cases like this, and Toyota, really reaffirm how a quality culture is something that must be constantly maintained and grown, and how easy it is to go backwards.