1. Case Studies
What went wrong?

2. Case Study # 1
FDA v Schering Plough

3. 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.

4. 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.

5. Reactionary?
• Dr. Lester M. Crawford, the FDA deputy
commissioner, said the FDA's action
against Schering-Plough sends a message
to the manufacturers of pharmaceuticals
that violations of federal regulations will
not be tolerated.

6. Case Study #2
US v Barr

7. Lesson 2- Have a plan for OOS
• Don’t test into compliance
• Have a policy and follow it…
• Avoid repeat testing

8. The US vs. Barr Pharmaceuticals

9. 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)

10. FDA Inpection
• FDA investigators conducted a general
inspection of Barr's Northvale facility during
August and September 1989 as well as separate
general inspections of Barr's 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.

11. 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.

12. 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.”

13. 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

14. 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 FDA's
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.

15. Key Points: Essence of Barr
Labs 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

16. 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

17. 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

18. FDA Out of Specifications
Guidance
OOS
Draft issued in September
1998

19. CASE STUDY # 3
• Chiron and the flu vaccine- 2004

20. The Chiron Case: Good Manufacturing
Practice Gone Bad?
• When British regulators suspended the license of
Chiron's 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 company's stock plunged, and it reported a $22.9
million net loss in the fourth quarter of 2004

21. Case Study # 4
Baxter and Heparin…

22. Baxter and Heparin…

23. 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.

24. • 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.

25. • 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).

26. • 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).

27. 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

28. 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?

29. 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].

30. • More examples of poor practices from
China…

31. http://www.fda.gov/ora/fiars/or
a_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 FDA's 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.

32. http://www.fda.gov/ora/fiars/or
a_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.

33. http://www.fda.gov/ora/fiars/or
a_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. ***

34. Case Study #7 Novartis
2009

35. • 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.

36. Questions…