Category: Uncategorized

Novartis Slow To Correct Quality Problems

FDA issued (and released) Form 483 reports to three separate Novartis production facilities in 2011, including the Lincoln, Nebraska manufacturing plant. The Lincoln facility produces Excedrin, Bufferin, NoDoz and Gas-X Prevention – recalled last weekend due to potential product mix-ups –  in addition to manufacturing certain prescription drugs on behalf of Endo Pharmaceuticals.

The 483 report is issued at the close of a FDA inspection ONLY when inspectors have observed significant deviations from FDA regulations and/or Current Good Manufacturing Practices. Satisfactory inspections do not result in Form 483 reports.

The other two Novartis plants that received Form 483 reports in 2011 were the Sandoz manufacturing plant in Broomfield, Colorado (report issued 5/6/2011) and the Sandoz plant in Wilson, North Carolina (report issued 6/22/2011). Sandoz is a member of the Novartis family of companies.

All three FDA reports reveal significant lapses in attention to Quality Control and product safety. For example:

From the Sandoz Inc. (Wilson, NC) report

“Your Quality system is deficient and lacks an overall oversight of drug products manufactured at your site to ensure they have validated processes before release for commercial distribution.”

“Your firm released finished drug products for commercial distribution without a validated process.”

“Examination and testing of samples is not done to assure: that in-process materials conform to specifications.”

“Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.”

“There is a failure to supply potable water under continuous positive pressure.”

“There is no qualification performed for the … disinfection unit … installed in the water purification system. Your firm has never validated this unit after installed to ensure that it is effectively killing potential microorganisms.”

From the Sandoz, Incorporated (Broomfield, CO) report:

“Investigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.”

“The purified water in the laboratory failed specification for microbiology testing on 02/07/2011 … on 02/14/2011 … on 02/22/20 11 … and on 03/07/201 … The laboratory investigation stated that “the assignable cause is biological contamination due to stagnation of water in a non-circulating branch of the water system.” “Laboratory water is not a product ingredient and does not affect product quality.” Each time the problem was fixed with flushing of the system and retesting. Investigations were not performed on any impact the purified water might have had on the laboratory tests performed between the previous check and the one that was out of specification.”

“The quality control unit lacks authority to fully investigate errors that have occurred.” 

“Equipment was observed not clean and in sanitary condition.”

“An NDA-Field Alert Report was not submitted within three working days of receipt of information concerning significant chemical, physical, or other change or deterioration in a distributed drug product. Specifically, on 12/29/2010, your firm received a complaint from a pharmacist who reported finding a Methazolamide 50 mg tablet (batch number 191103) that appeared to look “twice as large as the others.” Your investigation found the tablet weighed {REDACTED} heavier than the targeted tablet weight of {REDACTED}. This exceeded your upper specification limit of {REDACTED} grams. The FDA Denver District was not notified of this out of specification.” 

“Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information.”

And from the Novartis Consumer Health, Inc. (Lincoln, NE) report:

“Your Quality Unit has failed in the responsibility and authority to monitor Quality Systems designed to assure the quality of drug products manufactured and packaged at your firm. This failure is evidenced in the Observations below (2-13), as well as continued NDA Field Alerts and recalls for similar problems over the last several years.”

How long has this been going on? While FDA has not released the results of prior inspections at these three facilities, we can deduce the time frame from information contained in the reports resulting from the 2011 inspections.

Sandoz (Broomfield, CO): FDA inspectors noted four “repeat observations” from prior inspections; notably,

  1. Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (repeat observation from the 5/28/2010 FDA inspection),
  2. Investigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy (repeat observation from the 5/28/2012 FDA inspection),
  3. Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information (repeat observation from the 10/08/2008 FDA inspection), and
  4. Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facility operations for its cleaning and maintenance (repeat observation from the 5/28/2010 FDA inspection).

Novartis Consumer Health (Lincoln, NE): FDA inspectors noted one repeat observation:

Investigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy (repeat observation from the 4/5-16/10 FDA inspection).

Although the Novartis report contained “only” one repeat observation, the details contained in the report make it very clear that the problems at the Lincoln facility are long-standing. For example:

You have failed to adequately investigate 166 complaint instances of foreign tablets in your drug products since 2009.

You have failed to identify the root cause of customer complaints for solid dosage form foreign tablets of products manufactured at your firm since at least 2009.

This cavalier attitude towards quality control, customer complaints, and reporting requirements on the part of a major pharmaceutical corporation is unconscionable. And the delays in implementing corrections and improvements are inexcusable.

We wouldn’t hesitate to condemn this behavior by a manufacturing company that was based in China, India or some other “emerging” nation. Why should a North American plant get away with ignoring standard Good Manufacturing Practices?

Novartis – it’s time to clean up your act!

Remembering

In Flanders Fields
By: Lieutenant Colonel John McCrae, MD (1872-1918)
Canadian Army

In Flanders Fields the poppies blow
Between the crosses row on row,
That mark our place; and in the sky
The larks, still bravely singing, fly
Scarce heard amid the guns

We are the Dead. Short days ago
We lived, felt dawn, saw sunset glow,
Loved and were loved, and now we lie
In Flanders fields.

Take up our quarrel with the foe:
To you from failing hands we throw
The torch; be yours to hold it high.
If ye break faith with us who die
We shall not sleep, though poppies grow
In Flanders fields.

Dedicated with love to the memory of:

  • My Dad Louis, who drove Canadian Army trucks through Italy and the Netherlands in WW II;
  • My courageous Uncle Moe, who lost both feet when his tank was shot out from under him during the liberation of Europe, but who never let his disability become disabling;
  • My Uncle Joe, who also served in the Canadian Army in WW II; and
  • My Great Uncle Reuben – too young for the Great War and too old for WWII – who enlisted and served in both World Wars.

Lab Error Triggers Product Recall

There’s a third-party contract lab located somewhere in Canada that needs to review its Good Laboratory Practices and lab sanitation protocols.

On October 5, 2011, the Canadian Food Inspection Agency (CFIA), in conjunction with Foodfest International 2000 Inc., warned the Ontario public that Strubs ready-to-eat Danish Style Smoked Grav-Lox Atlantic Salmon (Lot code 09262011) should not be consumed.

The Grav-Lox, according to CFIA, might be contaminated with Salmonella. Foodfest International 2000 Inc. (the distributor) recalled the offending product.

That was one month ago.

Today, CFIA rescinded its Health Hazard Alert, and advised the public that the Strubs Grav-Lox did NOT present a health risk from Salmonella.

Why the reversal? Because, according to CFIA, the lab responsible for reporting the initial Salmonella-positive result found that “...the Salmonella positive result was in fact a false positive, attributed to laboratory cross contamination.”

Now, I’ve worked in – and managed – several microbiology labs in my professional life. And I’m here to tell you that the LAST thing that should happen in a professionally run lab – whether government, in-house company, or third-party lab – is laboratory cross contamination.

Aseptic technique and assiduous attention to proper lab sanitation procedures are fundamental to the production of dependable lab results. So is the routine use of positive control and negative control sample analysis.

The company for whom the third-party lab did its analyses should have three questions for the lab’s management:

  • How did the lab cross-contamination happen?
  • Why did it take a full month for the cross-contamination to be discovered?
  • How will the lab change its procedures to ensure that the same thing doesn’t happen again?

I don’t know who hired the third-party lab; it could have been either Strubs or Foodfest (CFIA maintains its own labs). But, if I was the one who hired that hapless excuse for a professional lab, I’d be looking for a replacement, ASAP.