GMP Failures: Ignorance or Arrogance?

A U D I T O R TA L E S .
E XPERIENCES FROM THE PHARMA FIELD
GMP Failures:
Ignorance or Arrogance?
BACKGROUND: MARTIN POOLE/GETTY IMAGES
Michael H. Anisfeld
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INTRODUCTION
The litany of major multi-national pharmaceutical companies failing to follow US Food and Drug Administration regulations for good manufacturing
practice (GMP) keeps going on and on. In 1999, Abbott Laboratories was
fined US$100 million. In 2002, Wyeth-Ayerst was fined US$30 million,
and Schering-Plough was fined US$ 500 million. And in October of 2010,
GlaxoSmithKline (GSK) was fined US$750 million for failing to manufacture drugs in accordance with GMPs at its Cidra, Puerto Rico facility.
GMP problems are not limited to the US pharmaceutical industry.
During 1999-2010, serious GMP failings occurred at Chiron in the UK
and Pan Pharmaceuticals in Australia, to say nothing of the legion of
other companies in other countries with GMP problems that never hit the
headlines. It would be easy to assume that because GMP regulations have
been around for approximately 50 years, the pharmaceutical industry
would know what is expected.
The situation that led to GSK losing a US$750-million lawsuit was
multi-layered and involved personnel in all levels of the company. In taking a look at GSK’s story and their relationship with FDA, what can the
rest of us learn from their experiences?
THE GSK STORY
In March 2005, FDA seized shipments of Paxil CR and Avandamet tablets
from distribution and manufacturing facilities operated by SB Pharmco, a
subsidiary of GSK located in Cidra, Puerto Rico and Knoxville, Tennessee
(1-5). “In a response to ongoing concerns about manufacturing quality, FDA
and the Department of Justice initiated seizures of Paxil CR and Avandamet
tablets manufactured by GlaxoSmithKline, Inc. (GSK). Manufacturing
practices for the two drugs, approved to treat depression and panic disorder
24 Journal of GXP Compliance
Michael H. Anisfeld
(Paxil CR) and Type II Diabetes (Avandamet), failed to
meet the standards laid out by FDA that ensure product safety, strength, quality, and purity,” FDA stated (1).
FDA had found that Paxil CR tablets could be split
apart, potentially leading to the absence of the active
ingredient or controlled-release factor, while some
Avandamet tablets had the incorrect dose of one active ingredient. As a result of inspections in 2003 and
2004, GSK agreed to recall certain batches of these
products. FDA wanted to extend the recall to other
batches of Paxil CR and Avandamet. GSK did not
agree to do so, which led to the March 2005 publicly
announced seizures by the Federal Marshal Service at
FDA’s request.
GSK signed a consent decree with FDA in May
2005 (2), posting a US$650-million bond to guarantee
destruction or rework of existing defective product,
and leaving the company open to fines in addition to
the estimated US$300 million lost in interrupted sales.
In October 2010, the US Justice Department stated in a
press release (3) “British pharmaceutical giant GlaxoSmithKline has agreed to plead guilty in a tainted
drug scandal and to pay a 750-million-dollar US fine.
Pharmco Puerto Rico, a subsidiary of GSK, admitted it
was guilty of the charges relating to the manufacture
and distribution of certain adulterated drugs made at
a now-closed Puerto Rico facility, the department said.
The resolution includes a criminal fine of 150 million
dollars and a civil settlement of 600 million dollars to
the federal government and states.”
What Happened?
A deeper probe reveals a story behind the story, and
one that becomes a salutary lesson to the entire pharmaceutical industry. GSK’s problems occurred at its SB
Pharmco Puerto Rico Inc. facility (to use the facility’s proper legal name, referring back to the facility’s
company name in ‘pre-merger with SmithKline’ days).
An inspection performed by FDA between February
and April 2002 revealed significant shortcomings that
ended in a July 2002 warning letter (6) over issues
including bacterial contamination of ointments; failure
to have validated processes for tablet manufacture and
failure to assure batch uniformity and integrity of drug
products; failure to conduct out-of-specification (OOS)
and deviation investigations in a timely manner and
to take corrective actions to prevent recurrence; and
media fill vials not being incubated for the required
time that would assure bacterial growth for both slow
and fast-growth microorganisms.
In an FDA inspection performed between October
and December 2003, a nine-page FDA-483 list of
observations was given to the company. This FDA-483
(7) begins:
“Your firm’s quality assurance unit lacks sufficient responsibility and authority to exercise the
controls necessary to assure that consistent and
reproducible manufacturing processes and laboratory controls are established and followed and
that scientifically sound and appropriate actions
are taken when process deviations or failures of
product to meet established specifications occur
for drug products manufactured at your firm. The
quality control unit also failed to assure that adequate and complete records are maintained and
that accurate and complete reports and information are submitted to the FDA when appropriate.”
The report delves into 18 areas of failures to meet
GMP observations, each illustrated with examples of
the observation, elaborating on the above introduction. The key issue addressed, and the focus of about
three quarters of the list of observations, involves
process controls. The section on failures in process
controls states:
“Your firm fails to have appropriate procedures
and controls in place to prevent mix-ups and/or
adverse effects to product from occurring during
manufacturing/packaging process. Furthermore,
batches are released by your quality unit for
distribution although you are aware of findings of
mix-ups prior to these batches being released to
the market…”
The section ends with the statement:
“…Note: Product mix-up incidents have
been repeatedly occurred (sic.) since year 2001
through 2003. Products mentioned in the
above examples were approved and released for
distribution. Furthermore, complaints related
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to the mix-ups have been received from FARs
[Field Alert Reports; a company’s notification to
FDA that there might be problems with product
already in the marketplace] and previous and
the current inspection (sic) that all incidents are
isolated and not related to your manufacturing
operation.”
The section cites the company for various failings
including the following:
•Observation two—“the current manufacturing
process for Avandamet tablets is different and
inconsistent to the manufacturing process that
was validated during year 2002.”
•Observation three—“investigations related to
OOS (assay/content uniformity and/or dissolution) obtained for Avandamet have not been
questioned in terms of the adequacy of the process validation for Avandamet.”
•Observation four—“failure to take appropriate
actions against all lots that may be affected by
a conclusion as the assignable cause of the failing result although your conclusion assigns the
most probable cause of the use of a common
Roglitazone concentrate, not all lots using this
same granulation concentration were rejected
… furthermore no action has been taken
against any batch that may have been released
to the market for distribution.”
•Observation five—“your 2003 OOS manufacturing investigations related to assay, content
uniformity, and/or dissolution OOS, obtained
for batches of Avandamet 2/500 and 1/500 are
inadequate in that none of these investigations
have questioned the adequacy of the process
validation used to determine that your manufacturing process is robust and reproducible.”
•Observation six—“investigations [have been
performed] with the wrong raw data.”
•Observation seven—“written records of investigations into the failure of a batch or any of its
components to meet any of its specifications do
not include conclusions or follow-up. Specifically your firm failed to implement effectively
preventive and/or corrective actions to reduce
26 Journal of GXP Compliance
the number of investigations attributed to analyst error.”
The FDA-483 goes on, page after page, covering
inadequate standard operating procedures (SOPs),
inadequate sampling, inadequate analyst training,
and not extending OOS investigations to other
potentially impacted batches of product. The report
digresses to criticize failures in the validated water
system and poor complaint handling.
Inadequate Response
FDA told the company in 2002, 2003, and again
in 2004 that it had significant problems. It would
have made sense if the company had sent a task
group down to the site, reviewed every system top
to bottom, and systematically fixed all the issues.
But when FDA performed another inspection from
September–November 2004, they issued another
FDA-483 (7) citing the following:
•“Procedures for the cleaning and maintenance
of equipment are deficient regarding the
inspection of the equipment for cleanliness
immediately before use. Specifically, line clearance procedures and controls are not appropriate to prevent mix-ups during the manufacturing/packaging process.”
•“There is a failure to thoroughly review any
unexplained discrepancy and the failure of a
batch or any of its components to meet any of
its specifications whether or not the batch had
been thoroughly distributed. Specifically, your
firm failed to take adequate corrective and preventive action to prevent the split tablet defect,
classified by your firm as a critical defect, in
distributed Paxil CR product. Although your
process controls include an inspection after
the coating process to detect the defect, the
defect has been found during the packaging
operation of Paxil CR 12.5 tablets and Paxil CR
36.5mg tablets, in approximately 2% and 25%
of the batches manufactured/packaged during
2004.”
•“ Your firm failed to adequately investigate
and take corrective actions to address the root
Michael H. Anisfeld
cause of burnt induction seals in Avandamet
bottles reported in complaints.”
•“Control procedures are not established which
monitor those manufacturing processes that
may be responsible for causing variability in the
characteristics of in-process material and drug
products.”
•“Employees are not given training in the particular operations they perform as part of their function and written procedures required by current
good manufacturing practices regulations.”
•“Investigations of an unexplained discrepancy
and a failure of a batch or any of its components
to meet any of its specifications did not extend to
other batches of the same drug product.”
The 2004 FDA-483 often repeated comments of
previous inspections and brought into the discussion examples of GMP deficient operations impacting
other creams, tablets, and oral suspensions manufactured by the company at the Cidra facility.
LESSONS TO BE LEARNED
There are obvious lessons to be learned from SB
Pharmco, and from all the worldwide companies
failing GMP inspections over the years. The lessons
learned at a minimum are as follows:
•Design your manufacturing and laboratory system well, and keep in mind that our products
are taken on trust and that our potent products
will be ingested by our grandparents and by
our children–the most vulnerable in society.
•The regulatory authorities do not want to be
a company’s quality assurance (QA) group.
Design your system well, train your staff to follow the system, and frequently repeat the training. Make sure you have an effective QA audit
program to ensure that you catch the issues
before they become “issues.”
•If the authorities do find problems with your
systems, immediately adopt a global approach
to the corrective actions. Do not just address
the symptoms discovered by the inspectors,
but get to the root cause and tackle the issue
system-wide and company-wide.
•Hire QA staff with the intestinal fortitude to
refuse to release batches of product that are not
manufactured according to GMPs.
•Speed is of the essence–make the fix, make
sure it is fixed, and do it quickly. Woe betide
your company if the issues are still outstanding when the authorities come again; and ‘woe
betides’ get exceedingly expensive in money
and corporate reputation.
IGNORANCE OR ARROGANCE?
John Scharmann, an ex-FDA Denver District Director, asked if such egregious GMP failures are due
to company ignorance or company arrogance in an
article in Dickinson’s FDA Review (8). Obviously with
two to three years’ worth of FDA-483s at hand and
four warning letters issued by registered mail to the
GSK CEO prior to the seizure, ignorance cannot
be claimed a factor in this case. Can it be company
arrogance? As Scharmann states, “as long as company CEOs and company presidents see these fines
as a cost of doing business, arrogance will continue.
Make it personal and it will stop.” Which leaves
the question–when will FDA and the European
Medicines Agency start holding senior management
personally accountable for GMP failures within their
company?
RESPONSIBILITIES OF
QUALITY ASSURANCE PERSONNEL
In reviewing SB Pharmco’s case, it would be easy
to assume that the company’s management at all
levels in the organization was only concerned with
corporate profits and their own careers, and was
not willing to think of the patient when faced with
typical corporate bottom line pressures. However,
former quality assurance manager Cheryl Eckard
took a stand.
Cheryl Eckard noticed a number of US GMP violations at GSK’s Cidra facility after she was sent there
to lead a team of 100 scientists and quality experts in
2002. She discovered bad practices such as mixed-up
products, diabetes drugs that were too weak or too
strong, and that an area of the factory used to make
injectable drugs was not sterile. Ms. Eckard exSpring 2011 Volume 15 Number 2
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pressed her concerns to senior management, but she
said her concerns were ignored. She was eventually
removed from her job during a company merger. In
2004, she filed a lawsuit. According to that lawsuit,
she had told her boss that “she would not participate
in a cover-up of the quality assurance and compliance problems” at the company (9). In October 2010,
GSK pled guilty and agreed to pay US$750 million
in fines, penalties, and settlements. Ms. Eckard was
awarded US$96 million “for her role in helping the
government secure a criminal guilty plea” from GSK
(9). It was Ms. Eckard’s willingness to do the right
thing that helped ensure patient safety.
If only the pharmaceutical industry had more
people like Cheryl Eckard and if only more US QA
departments or European qualified persons (QPs) did
what they were supposed to do, then global patient
safety would be dramatically enhanced.
According to all GMP regulations, codes, directives, and guidelines in existence worldwide, it is
the job and responsibility of the QA department to
release product to market when it is manufactured
and tested according to GMPs. But equally, directly
inferred if not explicitly stated, it is the job and
responsibility of QA and QP personnel not to release
product to market when it is not manufactured and
tested according to GMPs. As an industry, we need
QA directors and QPs to have the intestinal fortitude
to stand up and do the right thing.
3. US Department of Justice, “GlaxoSmithKline to Plead Guilty
& Pay $750 Million to Resolve Manufacturing Deficiencies at
Puerto Rico Plant,” Press Release, October 26, 2010.
4. FDA, “GlaxoSmithKline Will Plead Guilty and Pay $750
Million to Resolve Manufacturing Deficiencies at Puerto Rico
Plant,” Press Release, October 26, 2010.
5. Connor, Michael, “GSK to Pay $750 Million Fine; Whistleblower to Get $96 Million,” Business Ethics, October 26, 2010.
6. FDA, Warning Letter issued to Smithkline Beecham Pharmaceuticals Co., July 1, 2002, http://www.fda.gov/ICECI/
EnforcementActions/WarningLetters/2002/ucm144993.htm
7. Both FDA-483s referred to in this article can be obtained by
making a request under Freedom of Information directly to
FDA (they are currently not available on FDA’s website).
8. Scharmann, John, “Ignorance or Arrogance? How Firms Get
into Big FDA Trouble,” Dickinson’s FDA Review, March 15,
2005.
9. Loftus, Peter, “Whistleblower’s Long Journey,” Wall Street
Journal, October 28, 2010. http://online.wsj.com/article/SB
10001424052702303443904575578713255698500.html.
GXP
ARTICLE ACRONYM LISTING
FDA
US Food and Drug Administration
GMP
Good Manufacturing Practice
GSKGlaxoSmithKline
OOS
Out of Specification
QA
Quality Assurance
QP
Qualified Person
REFERENCES
1. FDA, “U.S. Marshals Seize Lots of GlaxoSmithKline’s Paxil
CR and Avandamet Tablets Because of Continuing Good
Manufacturing Practice Violations, FDA News,” FDA.gov,
March 4, 2005.
2. FDA, “GlaxoSmithKline Signs Consent Decree with FDA;
Agrees to Correct Manufacturing Deficiencies,” FDA News,
FDA.gov, April 28, 2005, http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/2005/ucm108432.htm.
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ABOUT THE AUTHOR
Michael H. Anisfeld is a senior consultant for Globepharm
Consulting specializing in GMP and quality activities for the
healthcare manufacturing industries. His clients include United
Nations agencies (WHO, UNFPA, UNIDO), national regulatory
agencies, and more than 260 pharmaceutical, medical device,
biotechnology, and bulk pharmaceutical companies in the
Americas, Africa, Europe, and Asia. Mr. Anisfeld can be reached
by e-mail at manisfeld@globepharm.org.