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!