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Lesson 1- don’t ignore the FDA• Schering Plough was audited by the FDA on several occasions and 483s were issued• Every time the FDA returned none of the issues identified in the 483s had been addressed.
The FDA and Schering-Plough• FDA indicated that they are serious about GMP by the record $500 million “disgorgement”.• The FDA took action against the company after inspectors found serious violations of CGMP regulations during 13 inspections at four New Jersey and Puerto Rico facilities since 1998.
Reactionary?• Dr. Lester M. Crawford, the FDA deputy commissioner, said the FDAs action against Schering-Plough sends a message to the manufacturers of pharmaceuticals that violations of federal regulations will not be tolerated.
The Law• Under the Federal Food, Drug and Cosmetic Act (the "Act"), a drug is adulterated if "the methods used in, or the facilities or controls used for, its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess." 21 U.S.C. § 351(a)(2)(B)
FDA Inpection• FDA investigators conducted a general inspection of Barrs Northvale facility during August and September 1989 as well as separate general inspections of Barrs Northvale and Pomona facilities from May to September 1991. After each inspection, the investigators issued Forms 483.• The 1989 Form 483, which contained six general observations, cited Barr for unvalidated manufacturing and cleaning processes, the lack of failure investigations, incomplete annual reviews and failure to explain retesting.
The Offense• Barr Laboratories was accused of having breached GMP guidelines by routinely retesting, resampling and reprocessing, had effectively persuaded all pharmaceutical industry laboratories to standardize their protocols for dealing with out-of-specification results (OSRs).• The court did not accept the FDA submission that an OSR necessarily meant a batch failure.
FDA humorless warden?• District Judge Alfred M. Wolin described the Barr case as a “confrontation be- tween a humorless warden and its uncooperative prisoner”• a product of “an industry mired in uncertainty and conflict, guided by vague regulations which produce tugs-of-war of varying intensity.”
Barr Decision (1993)• cGMP regulations are vague about exactly how to handle OOS• 1993 Barr Laboratories, Inc – United States District Court for the District of New Jersey• Jurdge Wolin made it clear – what is acceptable and – what is not acceptable in handling OOS
Out of Specification (OOS)• Judge Wolin preferred to use the term "out-of-specification" (OOS) laboratory results rather than the term "product failure" which is more common to FDAs investigators.• He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test, or overcome by retesting is not a product failure.
Key Points: Essence of BarrLabs Decision• Release of batch – Testing must show satisfactory conformance to specifications, including ID/Strength of each active ingredient• Context and history of product and batches inform the final conclusion
Averaging• Assay results should never be averaged because averaging hides individual variability:• Individual content uniformity tests should not be averaged to obtain passing value• Microbiology averaging is acceptable due to biological variability
Avoid“Testing into Compliance”• Retesting: Additional test should be for the same sample, only after a failure investigation is underway – “Testing into compliance” is not acceptable• Retest only by predetermined written SOP
FDA Out of Specifications Guidance OOS Draft issued in September 1998
CASE STUDY # 3• Chiron and the flu vaccine- 2004
The Chiron Case: Good ManufacturingPractice Gone Bad?• When British regulators suspended the license of Chirons manufacturing plant in Liverpool, England, in October 2004, the move caught the US Food and Drug Administration by surprise and triggered an international vaccine crisis. The FDA had inspected the plant in the past, and Chiron was slated to provide nearly half of the US vaccine supply for 2004–2005: 48 million doses of Fluvirin. Instead, the United States scrambled to find enough vaccine to protect against influenza, which kills 36,000 Americans each year. The Emeryville, Calif.- based companys stock plunged, and it reported a $22.9 million net loss in the fourth quarter of 2004
Lesson 3- A Sponsor is responsible• When a sponsor outsources manufacturing of ingredients they are obligated to ensure the company meets the regulatory guidelines for manufacturing of that product.
• On January 16, 2008 Baxter Healthcare Corporation issued an urgent product recall for multi-dose vials of the blood-thinner heparin following reports of hundreds of patients experiencing severe allergic reactions.• The Baxter Heparin supply accounts for about half of the U.S. supply and may result in a public health crisis resulting from heparin shortages.
• Both the FDA and Baxter are researching scientifically the cause of this contamination with capillary electrophoresis and magnetic resonance spectroscopy to detect the contaminant (Reinberg 2008).• The FDA has published that there are at least 62 reports of deaths of patients who experienced one or more allergic reactions and who were infused with heparin from Jan. 1, 2007 through the end of last March (Harris 2008).
• Heparin is made from pig intestines and other animal tissues. The suspected ingredient originated at a Changzhou, China in a plant owned by Scientific Protein Laboratories.• There are 566 plants in China that export drugs to the United States, but the FDA inspected just 13 of them last year (Harris 2008).
So who is to blame?• Clearly, Baxter, as the producer of this product, must have ultimate responsibility, as must its Wisconsin based partner, Scientific Protein Labroratories, based in Waunakee, WI, who had the joint venture with the Chinese company that imported the toxic product
You are responsible…• The agency finally conducted an inspection of the facility in February and found so many problems that the F.D.A. blocked the plant from exporting to the United States.• Baxter International, which bought heparin ingredients from Changzhou SPL from 2004 through 2008 but did not inspect the facility until September 2007.• The company sent one person who spent one day in the plant, Mr. Nelson said. Five months later, the F.D.A. discovered many problems.• How can so much go wrong in 5 months?
Baxter is responsible• The Good Manufacturing Procedures GMP were violated in the Chinese manufacturing plant who provided inexpensive product to Baxter.• Unfortunately for Baxter when you outsource you are still responsible for qualifying your vendors [21 CFR 211.84].
http://www.fda.gov/ora/fiars/ora_import_ia5502.html• In October 2006, a number of illnesses and deaths in Panama were linked to cough syrup that was found to be contaminated with diethylene glycol (DEG). Laboratory analysis performed by the U.S. Centers for Disease Control (CDC), subsequently confirmed by FDAs Forensic Chemistry Center, detected DEG, an ingredient in anti- freeze products, in two samples of acetaminophen elixir products, "Afebril" and "Valodon." The source of the contamination was determined to be glycerin that had been adulterated with less expensive but highly toxic DEG; shipping records indicated the source of the glycerin may have been China.
http://www.fda.gov/ora/fiars/ora_import_ia5502.html• *** In 2007, *** toothpaste manufactured in China was removed from stores in Panama, the Dominican Republic, and Australia after the products were determined to contain DEG. Multiple other incidents involving pharmaceutical products made with DEG contaminated glycerin have occurred, including an incident in 1996 involving acetaminophen syrup that was linked to the deaths of 80 children in Haiti. In 1937, over 100 people in the United States died of renal failure after consuming a DEG contaminated elixir marketed to treat infections.
http://www.fda.gov/ora/fiars/ora_import_ia5502.html• *** In 2008, teething relief products were removed from the market in Nigeria after the deaths of over 40 children in that country. The product of concern, a combination of an analgesic and an antihistamine, was determined to have been contaminated with DEG. The DEG contamination is believed to have come from contaminated propylene glycol. ***
• Thousands of doses of the meningitis C vaccine have been withdrawn by the manufacturer Novartis following fears of contamination.• It is understood that the move was taken after samples from two batches were found to contain a bacterium.