Quality Failures New England Compounding Center

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Entropy and New England Compounding Center:
How Things Can Disastrously Fall Apart
Anthony Grilli MS
FOCUS Scientific
May 21, 2013

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American Pharmaceutical Industry
 The United States is world
leader in biopharmaceutical
research.
 U.S. firms conduct 80 percent
of the world’s research and
development in biotechnology
and hold the intellectual
property rights to most new
medicines.
 We are admired around the
world for our quality
standards, regulations, and
safe drugs
 The US FDA is considered the
gold standard by other
countries

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But …
End of last year, an adulterated drug, contaminated with a
common mold, was administered to 1000’s of patients
across the country, ultimately killing 48 people and
sickening more than 720 with persistent fungal infections.
And the impact continues to unfold.
How did this happen?

What is Entropy?
. The tendency for all matter and energy in the universe to
evolve toward a state of inert uniformity, from order to
disorder.
. Inevitable and steady deterioration of a system or society.

Entropy -- must exert control to keep biology back

Who are the partners in this story working to prevent
entropy?
Safe
Product
Manufacturer
Government
User

Introduce the Characters
Drug Company Mold Regulator User

The Drug
 Methylprednisolone Injection
 A hormone very similar to one
naturally produced by our
adrenal glands.
 A corticosteroid used for it’s
anti-inflammatory effects
 Solid oral dosage form (tablets)
or Parenteral (injection)
 Useful in halting allergic
reactions, reducing
arthritis, lupus, and other
autoimmune irregularities
 Immunosuppressant drug–
individuals with fungal
infections should not take this
drug.
“Corticosteroids may exacerbate systemic fungal
infections and therefore should not be used in
the presence of such infections unless they are
needed to control drug reactions”

The Mold: Exserohilum rostratum

Where is it found?
 Ubiquitous mold
 Found everywhere
 Primary habitat is vegetation
 Has been used as a biocontrol
agent for invasive species of Red
Sprangletop
 Not generally thought of as a
human pathogen

The Company – NECC History
 New England Compounding Center
 A “compounding center”, not a “drug manufacturer”
 Private company in Framingham, MA founded in 1998 by Barry
Cadden, his wife Lisa Cadden and her brother Gregory Conigliaro.
 Such pharmacies are authorized to combine, mix or alter ingredients
to create specific formulations of drugs to meet the specific needs of
individual patients, and only in response to individual prescriptions.
 Compounding centers must register with the FDA but are regulated
by State Departments of Health. FDA does not approve their
prescriptions before marketing, nor automatically receive adverse
events reports.
 Compounding centers support local patients, and therefore
interstate commerce regulations do not apply

The Company – Compounding Centers
 Compounding Centers provide a benefit
 Allows medication to be personalized for an individual patient
 Can remove allergens from product (lactose, dyes, preservatives, glutens)
 Future of medicine will be personalized doses
 Can make medications more palatable
 Take out unpleasant flavors – important for children, elderly, pets
 Can make medications in formulations that may not be available
from mass manufacturers
 Liquid or topical form for patients who can’t swallow pills
 Can formulate medications that large pharma manufacturers have
discontinued
 Product may still be needed by thousands of patients, but not profitable
to make on large scale any longer.
 Can bypass the FDA’s long approval process, for patients that have an
immediate unique need.

The Regulators – FDA History and Oversight
 US FDA
The 20th Century saw a gradual increase in the level of federal oversight
of drug quality, reacting to tragedy:
 Congress passed the Pure Food and Drug Act in 1906,
 For the first time drug labels had to truthful
 No more “snake oil” claims: syrups and tonics containing opium and
morphine were addicting unsuspecting consumers.
 1938 Congress passed the Federal Food, Drug and Cosmetic (FD&C)
Act of 1938.
 Companies were required to prove they were safe before marketing them
 In response to diethylene glycol adulteration of a sulfanilamide drug –
107 people died many of them children.
 Still had adverse events – 300 deaths and injuries from distribution of
sulfathiazole tablets tainted with phenobarbital.

Regulators -- FDA History and Oversight
 US FDA
 Ultimately led to current Good Manufacturing Practices
(cGMP’s)
 21CFR210 and 211: Strictly defines how drugs are to be
made, packaged and tested
 GMP’s are effective, but after implementation there still
followed a trail of reactions to latest tragedies:
 Infant Formula Act
 OTC tamper resistant packaging
 Generic Drug Enforcement Act
 Out of Specification regulations
 Compounding Pharmacies next??????

End User
 Corticosteroid injected right into
epidural space
 To reduce inflammation of nerve root.
 Alleviate swelling for lower back and
sciatica pain

Increasing Market
 The use of steroid injections
to treat back pain has
skyrocketed in the past 15
years The frequency of
steroid injections dispensed
to Medicare patients rose
121 percent from 1997 to
2006.
 Washington State found that
the use of back injections
grew 12.6 percent between
2006 and 2009, at a cost to
the state of $56 million.
Some people received more
than 10 shots a year.

Methylprednisolone
 Manufactured by large pharma
 Pfizer
 Teva Pharma
 Sandoz Pharma

New England Compounding Center
 Decided to enter the market
 Decided to ASEPTICALLY fill product
 Use sterile product
 Fill in sterile environment
 Fill in sterile vials with sterile stoppers
 Aseptic Processing is one of the hardest things to do in
drug manufacturing.
 Clean Ingredients, Clean processes, Clean people….

Aseptic Processing
• Environment where
drug is made must be
closely monitored
• Increasingly clean
areas
• Center is where drug
is manufactured
• <100 particles per
cubic meter
• Monitored daily for
viable and nonviable
particulates

People
• People shed 100,000
particles per minute
• A simple nod can
shed 50,000
particles
• Gowning and
training is very
important
• Must monitor
cleanliness of
gowning

Massachusetts Inspection in 2004

Start to see a problem in September 2012

Fast Forward to 2012
 Sept 24: Mass DPH notified by Tennessee DPH that a
cluster of six rare fungal meningitis cases with onset of
symptoms between July and September had something in
common – NECC methylprednisolone acetate
preservative free
 Sept 25: convened multi-agency investigation with CDC
and US FDA
 Sept 26: Mass DPH and FDA conducted new
investigations – rigorous inspections of NECC begins

Mass DPH Site Inspection Findings After Deaths:
 Massachusetts Department of Health Inspection Findings:
 Products was shipped before sterility test results were received
 Product was not autoclaved properly – systematically failed to
keep product in autoclave for required 20 minute sterilization
period.
 Did not validate autoclaves
 Hoods were dirty
 Tacky mats were dirty
 Boiler leaking next to clean room
 Rooftop HVAC units 100 feet from recycling facility

Rooftop HVAC units 100 feet from recycling facility

Sterility Test Data
 Over-reliance on sterility test results – CANNOT TEST
QUALITY INTO A PRODUCT
 USP requires 20 articles tested out of 1000s
manufactured in a lot – not a meaningful
sampling, especially with mold which may not be
homogenously distributed.
 In fact, 20 samples were not actually tested per lot, not in
compliance with USP <71> requirements
 Not incubated for full 2 weeks
 Takes time for mold to grow out.

FDA Inspection Findings After the Deaths
 Food and Drug Administration:
 Ingredients used in manufacture were not sterile
 Clean room AC shut off nightly
 Bacteria and Mold found in Environmental Monitoring samples taken
from clean room air and surfaces.
 Action and Alert Limits were consistently exceeded in surface and air
samples, no action was taken
 Personnel touch plates consistently showed bacteria and mold, no
investigation taken.
 Dark particulate and white filamentous substances covering the
louvers of an HVAC return
 Dark hair-like discoloration along gasket and crevices located at
bottom edge of pass through to ISO 6 Clean Room where drug is
made

ISO 8 Room

ISO 6 Class Room

ISO 5 Room

National Problem
 NECC had clearly expanded
beyond a local compounding
pharmacy, by shipping
product around the country.
 FDA had issued a Warning
Letter in 2006 to NECC
notifying them they must
cease manufacturing copies
of commercially available
drugs.
 Details of delay, stall and
entropy that followed are
found in Congress’s
Preliminary Majority Staff
Report April 16, 2013.

Risk Analysis – Who did it?
RISK Factor Ibuprofen tablet Methylprednisolone
Injection
Water Content Low – low risk for microbe High – high risk for microbe
Route of Administration Low – GI Tract High – Direct to nervous
tissue
Patient Population Low – generally healthy High – drug suppresses
immune system
Preserved Product Low – no water activity
acts as preservative
High – no preservatives
SUMMARY Low risk HIGH RISK
Risk Analysis is an important tool to decide where to put resources – quality,
regulatory, technical. Here is a risk analysis of a regulated NSAID tablet versus
methylprednisolone injection

Who’s fault? Entropy in all parties
NECC Regulators Physicians
Lack of control of
manufacturing
Difficulty taking action on
Interstate commerce
Opting for low cost
alternative
Did not perform Risk
Analysis
Difficulty taking effective
action on compounder
making existing
formulation
Questions about the
effectiveness of methyl
prednisone injection
therapy?
No culture of continuous
Improvement
Perhaps not properly
financed to do all it needs
to
Was there a visual check
on vials before injecting?
Support Labs releasing
results before results done
Local regulators may not
have been adequately
trained to audit aseptic
processing

Monday Morning Quarterbacks
 From WMUR New Hampshire Radio:
 NECC was supposed to manufacture drugs for individual patients, but a
tech interviewed by media says a month before the first death he
warned his supervisor, “Something's going to happen, something's going
to get missed and we're going to get shut down. We weren't
compounding any more. We were manufacturing.”
 An unidentified salesman told “60 Minutes” that NECC dispensed to
nearly 3,000 hospitals and clinics nationwide -- in many cases issuing
medications based on fake names supplied by clients looking for cheap
drugs.

Quality Professionals Fight Entropy Everyday
• Change Control, Risk Analysis, Continuous Improvement, Root Cause
Analysis, Corrective Actions – all the tools we use are intended to fight
entropy
• Quality is often taken for granted. We work hard to keep drugs safe and
the out come is a given for most people – drugs are not supposed to kill
people
• The struggle against entropy is not easy – KEEP UP THE GOOD FIGHT

Anthony Grilli MS
Principal Consultant
FOCUS Scientific Services LLC
agrilli@focus-sci.com
(973)216 6039

Quality Failures New England Compounding Center

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