1. No category

Why is does it matter?
Sterile compounding and the
New England Compounding Center:
What went wrong and how do we prevent it
from happening again?
Melissa Hogan, Pharm.D.
Associate Professor in Clinical Sciences
Roosevelt University
Lillian Cary
July 1945-September 30, 2012
George Cary,
diagnosed with fungal meningitis
after his wife died
Summary
Objectives
• Summarize the role of the NECC in the 2012 outbreak of
fungal meningitis
• Review applicable laws that should have prevented this
crisis
• Understand the timeline of events including FDA and
public health efforts to control the outbreak
• Discuss the multiple failures that led to the outbreak
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Sterile compounding and manufacturing
Illegal dispensing
Purchasing
Regulations/enforcement
• Describe state and federal
efforts to prevent further outbreaks
Summary
• Compounding pharmacy governed by state boards of
pharmacy
o M ust provide medications for a specific patient pursuant to a
prescription
o In M assachusetts, pharmacies conducting sterile compounding must
“observe the standards of the current USP.”
• NECC asked some customers to generate lists of patient
names for order; did not require patient names for many
orders
• NECC cited with multiple violations of USP <797>
•
The New England Compounding Center opened in 1999 in
Massachusetts. The business grew and sold compounded
medications nationally
•
NECC conducted high risk compounding starting with nonsterile
ingredients and autoclaving to provide for final sterilization
•
Over 700 of patients became infected with fungal meningitis and
other infections after contaminated lots of NECC-produced
preservative free methylprednisolone were administered to
patients in 20 states
•
Crisis revealed gaps in legislation and enforcement of
compounding pharmacy practice
CDC Multistate meningitis outbreak current case count. Updated Aug 5, 2013. Accessed at
http://w w w .cdc.gov /hai/outbreaks/meningitis-map-large.html on 8/9/2013.
Overview of USP <797>
• USP NF is official compendium of drug standards
• Chapters <1000 are official (legally enforceable)
monographs and required by FFD&C
• Chapter <797> focuses on all
aspects of sterile preparations
2012 NABP survey of Pharmacy Law: Does Board of Pharmacy Require Compliance with USP Chapter 797,
Pharmaceutical Compounding – Sterile Preparations?
The committee on Energy and Commerce Majority Memorandum regarding Hearing on “the Fungal Meningitis
Outbreak: Could It have been prevented?” November 12 2012.
60 Minuters: Lethal Medicine Linked to Meningitis Outbreak. Originally aired 10 March, 2013.. Accessed online at
http://www.cbsnews.com/video/watch/?id=50152765n on 8/5/2013.
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What is sterile compounding?
• Compounded sterile preparation (CSP):
o Free of biological contamination
• Bacteria, viruses, fungi
o Free of pyrogens
o Free of particles
o Contain intended (labeled) concentration of ingredients
• CSP is prepared when a ingredients are
combined and handled to render the final
preparation sterile
USP <797>
• Applies to all personnel who work with sterile
products and preparations
o Pharmacists, pharmacy technicians, nursing staff,
therapists, radiology technicians, etc.
• Applies to all sterile preparations
o Injectables, ophthalmics, otics, irrigations, implants
USP <797>
• Applies to all locations where sterile products are
prepared, store, and dispensed
• Pharmacies
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Hospital
Community
Compounding
Home infusion
Nuclear
• Physician practices
• Allergy clinics
• Outpatient oncology clinics
USP <797>
• Compounding personnel responsibilities and
training
• Hand cleaning and garbing procedures
• Cleaning and disinfecting methods and frequency
• Sterile prep environments including facility design
and HVAC specifications
• Quality control testing
o Air sampling, surface sampling, media fill tests
• May be enforced by Boards of Pharmacy if required
by state practice act
• Beyond use dating
o Low risk, medium risk, high risk compounding
o Storage conditions
• Is included in Joint Commission survey
Methods to ensure sterility
• Aseptic technique
o How the pharmacist puts the medications together without
causing touch contamination
• Primary engineering control
o The “hood”, a sterile environment
where the pharmacist makes the IV
(ISO Class 5)
Methods to ensure sterility
• Secondary engineering control
o The cleanroom, where the hood is located (ISO Class 7)
o The anteroom, adjacent to the cleanroom (ISO Class 8)
• Quality Control standards
o Surface sampling, air sampling, air pressure monitoring
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High risk compounding
• Medications compounded under the following
conditions are considered at high risk for
contamination:
o Nonsterile ingredients OR a nonsterile device is employed
in compounding
o Ingredients or devices used in compounding are exposed
to air quality worse than ISO Class 5 for more than 1 hour
o Compounding personnel are improperly gloved and
garbed
o Nonsterile water –containing preparations are stored for
more than 6 hours before being sterilized
High risk compounding
• If no sterility testing is done, beyond use dating cannot
exceed 24 hours at room temperature, 3 days at cold
temperature and 45 days in a solid frozen state
• All high risk preparations undergo prefiltration through a 1.2
micron filter. Final sterilization is conducted through at 0.2 or
0.22 micron filter within an ISO class 5 environment
• All personnel involved in high risk compounding must undergo
high risk level media fill testing every 6 months which includes
compounding with nonsterile ingredients and final sterilization
United States Pharmacopeial Convention. <797> Pharmaceutical
Compounding—Sterile Preparations. 2007
Timeline
• September 18, 2012
o Vanderbilt infectious disease specialist
diagnosed fungal meningitis in patient who had
received intraspinal injection. Notified Tennessee
Department of Health (TDPH)
• September 21, 2012
o TDPH notified the CDC. Patient later died.
Timeline
• September 25, 2012
o CDC informed FDA of the situation and that 3 lots of
methylprednisolone from NECC were suspected.
o MDPH convened a teleconference with CDC, FDA, TDPH,
and Cadden and Conigliaro (NECC principal owners)
• September 26, 2012
o NECC issues voluntary recall of 3 lots of preservative-free
methylprednisolone acetate for epidural injection
Bell BP and Khabbaz RF. Responding to the outbreak of invasive fungal
infections. The value of public health to Americans. JAMA 2013;309(9):883-4.
Timeline
• October 1 2012
o FDA begins inspection of NECC
• October 3, 2012
o NECC voluntarily shut down operations and recalled all
preservative free methylprednisolone acetate
Timeline
• October 6, 2012
o NECC recalled all medications produced in its facility
• October 10, 2012
o Exserohilum identified in 10 cases of spinal meningitis
o Aspergillus identified in 1 case of spinal meningitis
• October 11, 2012
• October 4, 2012
o 35 cases of fungal meningitis, 5 deaths
o First personal injury lawsuit filed against NECC
• October 14, 2012
205 cases, 15 deaths
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Timeline
Timeline
• November 1, 2012
• October 18
o Exserorhilum rostratum identified in unopened vials of NECC
preservative free methylprednisolone acetate
• October 19, 2012
o CDC announces voriconazole is the drug of choice for exserohilum
fungal meningitis
• 281 cases, 23 deaths
o FDA finds preservative free betamethasone and
cardioplegia solution contaminated with bacteria
o 377 cases of fungal infections
• December 11, 2012
o NECC files for bankruptcy
• June 3, 2013
• October 31, 2012
o 745 cases, 58 deaths
o Ameridose, the sister company of NECC, recalled all of its products
after the FDA found it could not assure sterility of its products
o 368 cases of fungal infections, 28 deaths
The Committee on Energy and Commerce. Majority Memorandum for the Nov ember 14, 2012
Ov ersight and I nv estigations Subcommittee Hearing on the Fungal Meningitis Outbreak: Could it
hav e been prev ented?” Nov ember 12, 2012. Accessed 8/15/2013
CDC Multistate Fungal Meningitis Outbreak Investigation Meningitis Case Counts. Accessed
8/5 at http://www.cdc.gov/hai/outbreaks/meningitis-map-history.html
Timeline
• August 5, 2013
o Over 180 civil suits filed against NECC and its principals
o Criminal charges also pending
o 749 cases of fungal infections, 63 deaths
CDC Multistate meningitis outbreak current case count. Updated Aug 5, 2013. Accessed at
http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html on 8/9/2013
What did the FDA find?
• Multiple records of surface samples positive for bacteria
and mold in clean room (ISO 6 Class 1000 room and ISO
7 room where final sterilization was conducted)
• Use of nonsterile ingredients without adequate
procedures for final sterilization
• 83 of 351 vials of methylprednisolone acetate ready for
shipment contained visible greenish black foreign matter
• 50/50 vials tested positive for
microbial growth
.
What did the FDA find?
• Multiple records of discoloration and/or residue on room
surfaces and compounding and sterilization equipment
• HVAC system intake manifold directly adjacent to
recycling station
• White filamentous and dark particulate matter were
observed covering louvers of HVAC return
• Boiler adjacent to prep room (ISO 8) leaked, resulting in
puddles. Puddles contained thick white and thick black
granular material
• Tacky mat at entrance to Prep Room was brown and
soiled
Department of Health and Human Serv ices FDA Form 483. I nspection of New England Compounding
Pharmacy, I nc., d/b/a New England Compounding Center. I nspection dates 10/1-2, 10/4-5, 10/15 and
10/26 2012. Accessed at
ttp://w w w .fda.gov /downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPoli
cy/ORA/ORAElectronicReadingRoom/UCM325980.pdf on 8/2/2013
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Who purchased from NECC?
• Customers included hospitals, MD offices, outpatient
centers nationwide
o Sold directly to facilities, not through distributor
• Customers of Ameridose, also owned by the Caddens
and Conigliaros, were referred to NECC
o Ameridose functioned as manufacturer
o NECC represented as manufacturer as well
• Many large hospitals in Illinois purchased from NECC
o Not equipped to conduct high risk compounding
• NECC provided products not available through other
sources
How did NECC do it?
• Produced medications that were not available from
manufacturers
o Shortages and/or products not in production
o High risk compounding not routinely conducted by most
facility pharmacies
• High demand led to projected doubling of sales in 2
years
o Increased from 20 million in 2010 to 32 million through
September 2012.
o Barry and Lisa Cadden earned $6 million in year preceding
meningitis outbreak
NECC Customer List since 5/21/2012 Accessed at
http://www.fda.gov/downloads/Drugs/DrugSafety/FungalMeningitis/UCM325467.pdf
How did NECC do it?
• Multiple citations by Massachusetts Board of
Pharmacy and FDA
o Insisted they were compounding pharmacy and not under
the jurisdiction of FDA
o Responded to repeated complaints with assurance and
evidence of remediation
Who is responsible?
• Federal Food Drug and Cosmetic Act dictates that
pharmacies comply with USP NF, including USP
<797> when sterile compounding is done
• FDA does not enforce regulations in compounding
pharmacies; it is responsible to ensure compliance
in manufacturers
o State Boards of Pharmacy are charged with inspecting
pharmacies operating in their states
o 25 states currently require compliance with USP <797>
o Massachusetts requires compliance
o Illinois does NOT, but it is included in proposed changes to the
Pharmacy Practice Act
What is being done?
• Federal Efforts
o FDA Hearings November 14, 2012
o Legislation
o NABP
• Illinois Efforts
Federal efforts
• Aug 2, 2013: HR 3019 Amendment to the
Federal Food Drug and Cosmetic Act
“Supporting Access to Formulate an Effective
Compounded Drugs Act of 2013”
(S.A.F.E Compounded Drugs Act of 2013)
H.R. 3019--113th Congress: S.A.F.E. Compounded Drugs Act of 2013. (2013). In
www.GovTrack.us. Retrieved August 15, 2013, from
http://www.govtrack.us/congress/bills/113/hr3019
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SAFE Compounded Drug Acts
NABP efforts
• Resolution 109-1-13, passed June 5, 2013
• Key provisions:
• Provisions:
o Limit compounding to exclude specific drugs
o Physician and pharmacist informs patient that medication
prescribed will be compounded
o Labeling: “Non-FDA approved compounded drug product”
o Pharmacies will register as compounding pharmacies and
provide information to the Secretary of Health and Human Serives
regarding the compounding methods, quantity of product
compounded to determine if pharmacy is manufacturing
o Cannot register as manufacturer and compounding pharmacy
o Training to be provided to state agencies that regulate
compounding pharmacies
o There is a need for compounded sterile preparations and many
states require compliance with USP <797> standards
o Pharmacies engaging in high risk sterile compounding require
additional oversight
o All states should require compliance with USP <797> standards
o States should inspect compounding pharmacies or recognized
inspections by nationally a recognized organization
o NABP will review and consider amendments to the Model State
Pharmacy Act and the Model Rules of the National Association of
Boards of Pharmacy
http://www.nabp.net/news/pharmacy-compounding-of-sterile-products-resolution-109-1-13.
Accessed 8/15/2013
Illinois efforts
• Proposed Pharmacy Practice Act includes
requirement for adherence to USP-NF for sterile and
non-sterile compounding:
“Section 1330.640 Pharmaceutical Compounding Standards
The minimum standards and technical equipment considered
adequate for compounding drugs shall include:
All pharmaceutical compounding standards, both sterile and nonsterile, shall be governed by the USP-NF, as set forth in the USP
Compounding- Guidelines for the Compounding Practitioner (2013
ed.),”
Pharmacy Practice act draft 7/2013. Accessed at
http://www.ichpnet.org/news/display_news.php?article=idfpr_releases_draft_practice_
act_rules on 8/12/12.
Summary
Summary
• Death toll continues to rise; patients continue to
suffer from fungal infections
• New awareness of gaps in laws and enforcement of
sterile compounding
o Federal laws not enforced
o States lack consistent legislation
o Agencies lack funding
• Efforts to get new federal law passed that includes
explicit language allowing FDA enforcement and
patient awareness
Questions?
• NABP encouraging states to require compliance
with USP <797> and enforce laws
• Illinois seeking to include language in practice act
that requires compliance with USP <797>
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