by Barbara Unger, FDAzilla GMP Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence
A consent decree agreement is an agreement filed in the US courts formalizing a voluntary agreement between two parties.
Here we will address consent decree agreements between FDA and several pharmaceutical companies based on repeated failures to adequately address CGMP deficiencies.
It is not an action taken on the basis of a single form 483, or a single warning letter. Generally, a series of events play out over time when critical inspection observations are not addressed and are identified in subsequent inspections. Frequently one or more warning letters are involved.
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Consent decree agreements often include fines, with the option for additional financial penalties if conditions to which the firm agrees are not met. Often these firms are required to use a 3rd party consultants to perform lot release.
Firms operating under a consent decree agreement have largely lost their independence in GMP activities. Unlike Corporate Integrity Agreement which have a defined duration, firms must petition to have the consent decree agreement condition rescinded.
Here we will address three firms that operate under consent decree agreements:
- Ranbaxy Laboratories Limited
- McNeil Consumer Healthcare, a member of the J&J family of companies
Ranbaxy Laboratories Ltd.
Ranbaxy Laboratories has the distinction of having their own page on the FDA website where FDA identifies the enforcement actions that have been taken against the firm including forms 483, import alerts, warning letters and the specifics of legal actions including a consent decree agreement. It does not include a tally of product recalled by the firm as a result of these actions. The page provides links to three forms 483 issued to the company beginning in 2002. The FDAzilla store has eight forms 483 for Ranbaxy, and eleven forms 483 for Ohm Laboratories available for purchase. Ohm is their US subsidiary with sites in New Jersey, New York and Texas.
Although the forms 483 for Ranbaxy and Ohm sites had ‘routine’ CGMP observations, their most problematic and highly publicized problems were in the area of data integrity for both the GMP and GCP areas. Fortune Magazine’s Katherine Eban wrote in detail about the underlying story, HERE and HERE including the essential role of Dinesh Thakur as a whistleblower.
Enforcement actions of this magnitude are not without financial consequences. Daiichi Sankyo acquired a controlling interest in the company in 2008, and then after failing to make headway in the remediation efforts, sold their stake in the company to Sun Pharmaceuticals. Before the sale however, Ranbaxy and Daiichi paid the US government $500 million to settle various litigation associated with the CGMP deficiencies. The new parent company, Sun Pharmaceuticals, has its own GMP problems with FDA, again in the areas of data integrity and other CGMP deficiencies. The FDAzilla store has thirteen of their forms 483 available for purchase.
Currently four of the Ranbaxy sites, and one site that belongs to Sun Pharmaceuticals are under import alert and cannot import product into the US. The consent decree agreement remains in place.
In May 2010 Genzyme entered into a consent decree agreement. Two warning letters to Genzyme are posted on the FDA website, one from 2007 and one from 2009. For Genzyme, the deficiencies leading to the consent decree agreement were repeatedly identified in inspections and not corrected. They included one data integrity deficiency regarding failure to maintain a computer system in a validated state. Most were associated with deficiencies in the aseptic manufacture of drug products and the presence of foreign particulates in parenteral product.
Here is an abbreviated timeline of the activities from 2007 through issuance of the consent decree agreement in 2010. The FDAzilla STORE has twelve forms-483 available for purchase. Note that the timeline here is much tighter than the one above for Ranbaxy.
|June, 2007||FDA inspection of facility in Lyon, France|
|September, 2007||FDA issues warning letter for the practices at the Lyon France facility|
|October 10, 2008||FDA inspection of facility in Allston Landing, MA|
|February, 2009||FDA issues warning letter for the practices at the Allston Landing, MA facility based on a form 483 that was 6 pages long and identified 16 deficiencies including:· Procedures were not adequate to assure sterility· Buffers were not monitored for bioburden upon hold
· Equipment was not maintained
· Computer systems were not maintained in a validated state.
|June, 2009||Genzyme identifies Vesivirus contamination event at the Allston Landing, MA facility which the firm stated was not associated with the warning letter items from February, 2009. This shut down resulted in:· Destruction of potentially contaminated product in inventory· Severe shortages of important drugs including Cerezyme and Fabrazyme for which there were no equivalent substitutes
· FDA grants fast track status to experimental treatments manufactured by their competitors, Shire and Protalix BioTherapeutics, to help alleviate the shortages
· Carl Icahn, an activist investor, states intent to nominate four new board members
|November, 2009||FDA inspects the Allston Landing, MA facility and issues a 22-page form 483 with 49 observations. Thomas Arista was one of the investigators. Among the observations:· The presence of foreign particulates in parenteral drug product· Failures in aseptic processing practices
· Inadequate media simulations
· Facility and equipment was not maintained in a state of adequate repair
|May, 2010||Genzyme enters into a consent decree agreement, pays $175 million penalty, moves aseptic filling and packaging out of the Allston Landing, MA facility and manufacturing operations are placed under the review of a 3rd party.|
Again, it’s clear that the consent decree agreement was not prompted by a single inspection but rather represented a pattern of behavior over time where the firm did not effectively remediate problems identified by FDA during inspections. FDA’s accelerated approvals of two of their competitor products was very costly and the third party oversight of manufacturing resulted in a serious loss of control over the business. The consent decree agreement remains effective today.
McNeil Consumer Healthcare:
McNeil Consumer Healthcare manufactures OTC products and is a subsidiary of Johnson & Johnson. They entered into a consent decree agreement with FDA in March 2011. No mention is made of J&J in the agreement. The manufacturing site in Puerto Rico conducted a ‘phantom recall’ of Motrin OTC product in 2009. The firm received a warning letter in 2010. The FDAzilla STORE includes twelve forms 483 issued to McNeil between 2008 through 2011, and a total of twenty-four forms 483 including those issued outside that time frame. In my opinion, the issue here was not the kind of immediate serious public health concerns evident at Genzyme, but rather that the OTC drugs in question were taken by millions and millions of individuals. And in addition, the firms involved failed to resolve recurring issues.
Following is a short timeline of the activities associated with this consent decree agreement:
|Nov, 2008||McNeil Consumer Healthcare identifies failing dissolution results in two lots of Motrin|
|Early 2009||A McNeil contractor ‘buys’ the Motrin product from stores and does not mention that the product is actually being recalled by McNeil. This is known as the ‘phantom recall’ event.|
|July, 2009||McNeil begins formal recall of Motrin product after being contacted by FDA|
|January 2010||McNeil receives a warning letter. This warning letter identifies failure to adequately investigate consumer complaints of a ‘musty’ odor. Eventually this was traced to TBA, “which has a musty, mildew-type odor, is a known degradant of 2,4,6, Tribromophenol (TBP). TBP is a pesticide and flame retardant used to treat wooden pallets for transporting packaging materials and finished product.” This warning letter was based on an inspection that ended January 8, 2010 which indicates the warning letter was being written and approved as the inspection was ongoing.This event had implications for all pharma companies. Firms immediately worked to ensure that all wooden pallets in the warehouse were removed, and that vendors and suppliers confirmed they used only specially heat treated wood to store and ship components such as bottles.|
|April, 2010||McNeil shuts down the Ft. Washington PA plant for remediation and recalls product. The site remained shuttered for more than a year.|
|Sept., 2010||Joshua Sharfstein statement to Congress about the McNeil events, identifying that FDA felt that McNeil was not responding appropriately so they went to their corporate parent.|
|March 2011||McNeil enters into a consent decree agreement that does not mention their corporate parent.|
Remediation costs here were severe, particularly for the Fort Washington PA plant.
Finally, Johnson & Johnson was the subject of actions from multiple parties on these issues including congressional investigations by both the House and Senate, State Attorneys General, shareholder lawsuits, including at least five complaints that sought class action status. This seemed to be a good example of FDA holding the parent company responsible for CGMP failures of their subsidiaries.
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