The document discusses microbiological risks associated with compounding pharmacies. It summarizes issues that arose from a 2012 fungal meningitis outbreak linked to a compounding pharmacy. While compounding pharmacies fill important niches, they are not subject to the same regulatory oversight as large drug manufacturers. The document advocates applying cGMP standards and microbiological risk analysis to compounding to improve safety. It analyzes potential failure points in sterile compounding and argues current guidelines do not sufficiently ensure product sterility.

1. Microbiological Risk Analysis
And Compounding Pharmacies
Anthony Grilli MS
FOCUS Scientific
November 14, 2013
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2. New England Compounding Center
This time last year …
an adulterated drug, contaminated with a common mold was administered
to 1000’s of patients across the country, killing 64 people and sickening more
than 750 with persistent fungal infections.
And the impact continues to unfold.
How did this happen?
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3. Perfect Storm!
Drug
Company
Mold
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Regulator
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User

4. Debate Over Regulations





Compounding pharmacies are FDA
Registered, but not FDA regulated
They are inspected by State
Departments of Health
Not cGMP
USP <797> Pharmaceutical
Compounding – Sterile
Preparations
Federal oversight may be coming:
Sterile products produced in advance of
or without a prescription and shipped
interstate should be subject to the highest
level of controls, established by FDA and
appropriate to the activity, similar to cGMP
standards applicable to conventional drug
manufacturers.”
 Statement of Margaret A. Hamburg, M.D.,
Commissioner of Food and Drugs, April 16,
2013.
"
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5. National Problem – Distribution of NECC Illness
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6. Compounding Centers Provide Benefits to Patients

Allows medication to be personalized for an individual patient



Can make medications more palatable


Liquid or topical form for patients who can’t swallow pills
Can formulate medications that large pharma manufacturers have
discontinued


Take out unpleasant flavors – important for children, elderly, pets
Can make medications in formulations that may not be available
from mass manufacturers


Can remove allergens from product (lactose, dyes, preservatives, glutens)
Future of medicine will be personalized doses
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 and inspection process, for
patients that have an immediate unique need.
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7. Other Compounding Problems

Product Recalls and
contamination

Med Prep Consulting


Main Street Compounding, TN


Nationwide recall – 5 patients
with eye infections
Compounding Shop, FL


Nationwide recall of products FDA
found product contaminated with
fungus and bacteria
Clinical Specialties, GA


Nationwide recall of all sterile
products after hospital discovered
mold in unopened IV solution.
Recall Budensonide, not sterile
Specialty Compounding, TX

Rhodococcus equi
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8. How big is the problem?


53,000 compounding pharmacies in the US
According to recent estimates, there are about 3,000 compounding
pharmacies practicing sterile compounding in the US : (National Conference of State
Legislatures June 2013 Kara Hinkley)




FDA started auditing these compounding centers last year.
To date, almost 60 US FDA 483 responses posted:
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryO
perationsandPolicy/ORA/ORAElectronicReadingRoom/ucm340853.htm
The response back to the FDA to these 483’s has been predominantly – we
don’t have to follow GMP’s and you have no authority over us.
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9. Let’s do a thought experiment …..
Mega Compounding Corp
manufactures sterile
methylprednisilone for
intrathecal injection to treat
back pain. Components are
received as non-sterile
ingredients, they are
compounded, sterilized and
filled to vials with elastomeric
closures.
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10. Reducing Microbial Risk of Contaminated Product
Hurdles to Microbial Contamination and Illness
Formulation
Water Activity
Kill steps
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pH
Preservatives
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11. Microbial Risk Analysis of the Product
Score
Delivery
Route
Water
Activity
Kill Step in
Process
Inherently
antimicrobial
Preserved
Immune
Status
1
Oral
Low
Yes
Yes
Yes
Competent
3
Topical
Medium
Partial
Moderately
Moderately
Mixed
5
Parenteral
High
No
No
No
Compromised
Cortisone pill =
1
+
1
+
1
+
1
+
1
+
1
=6
Cortisone cream = 3
+
1
+
3
+
1
+
5
+
3
= 16
Cortisone inj: =
+
5
+
5
+
5
+
5
+
5
= 30
5
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12. Microbiological View of Manufacturing Process
Receive
components
Formulate
Components
Sterilize
Formula
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Sterilize
components
Aseptically
fill
components
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Test Final
Product

13. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• How do we store the
components
• What is shelf life of
components
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14. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• What kill value do
we need
Formulate
Components
• Are we blending in a
clean environment
• Is there a heat step?
• What is the hold
time?
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15. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• What kill value do
we need
Formulate
Components
• Are we blending in a
clean environment
• Is there a heat step?
• What is the hold
time?
Sterilize
Formula
• Have we validated
the process
• What are the critical
limits for the
process?
• Time
• Temperature
• Bioburden from
first step
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16. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• What kill value
do we need
Formulate
Components
• Are we blending
in a clean
environment
• Is there a heat
step?
• What is the hold
time?
Sterilize
Formula
Sterilize
components
• Have we
• Validate process
validated the
• Confirm package
process
sterility
• Bioburden from
components
informs how
we sterilize
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17. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• What kill value
do we need
Formulate
Components
• Are we blending
in a clean
environment
• Is there a heat
step?
• What is the hold
time?
Sterilize
Formula
Sterilize
components
• Have we
• Validate process
validated the
• Confirm package
process
sterility
• Bioburden from
components
informs how
we sterilize
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Aseptically
fill
components
• Controlled
Environment
• Controlled
gowning
• Controlled
cleaning and
disinfection
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18. Microbiological View of Manufacturing Process
Receive
components
• What is the
bioburden?
• What kill value
do we need
Formulate
Components
Sterilize
Formula
• Are we blending • Have we
in a clean
validated the
environment
process
• Is there a heat
• Bioburden
step?
from
components
• What is the hold
informs how
time?
we sterilize
Sterilize
components
Aseptically
fill
components
• Validate process • Controlled
• Confirm package Environment
sterility
• Controlled
gowning
• Controlled
cleaning and
disinfection
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Test Final
Product
• Proper testing
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19. Environmental Monitoring
Risk Analysis:
 Microflora changes with seasons



HVAC is in constant state of flux



More mold in fall
More bacteria from skin in dryer months
Filters fail or become saturated
Room pressures changes with doors
opening and closing
People and materials change over time
Control Point:
 Perform EM every day you manufacture
USP <797>:
 Perform EM twice a year
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20. Gowning

Risk Analysis:






Control point


People are the greatest contributor to
contamination
Each person brings 100,000,000,000,000
germs in the clean room with them.
People shed 100,000 particles per
minute
A simple nod contributes 50,000
particles
Technicians must lean into hoods to fill
product
Full sterile gown with no skin or street
clothes showing.
USP <797>

Lab coat, gloves, hair net.
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21. Gowning Validation


Microbial samples of gowns are taken
to verify outside of gowns and gloves
are still clean
USP <797>




Only gloves are sampled
Only sampled immediately after garbing
Only sampling gloves
Microbiologists know:



Other body parts become contaminated
and can contaminate inner core
Glove contamination occurs DURING
manufacturing (touching head, etc)
Should be run as a check every day
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22. Sanitizers/Disinfectants/Sterilants:
Right product for the right application
Antimicrobial Target
Resistance Organis
Examples
Category
Examples
Herpes, HIV,
Hanta, Flu
Antisceptics and
up
Alcohol
Chlorhexidine
Povidone-iodine
E.coli
Salmonella
Sanitizers
Disinfectants
Phenolics
Quats
S. aureus
A. niger
C. albicans
Fungicides
Phenolics
Iodophors
Quats
M. pneumoniae
Disinfectants
Above
B. subtilis
B. anthrasis
Sporicides/
Sterilants
Peracetic acid
Gluteraldehyde
C. botulinum
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Corrosivity

23. Disinfection

Risk Analysis






Control Point:


Sterile processing means no organisms
Spore forming bacillus common air
contaminant
Mold spores common air contaminant
Manufacturing surfaces differ in their
ability to protect microbes from
disinfection.
Microbes differ in their ability to resist
disinfection.
Validate sporicide efficacy on
manufacturing materials using
environmental isolates.
USP <797>:


Not specific about sporicide usage
No mention of validation
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24. Finished Product Testing


Even more critical in an
environment of loose control.
USP <797> does not require
Sterility Testing on all aseptically
produced products that



Only required on products that are
“high risk” which means they were
not sterile on receipt or
experienced a processing
deviation.
Not needed on products that are
“aseptically processed” in a
controlled environment and are
stored for 48 hours at CRT.
USP <797> allows for release
prior to test results.
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25. What happened at Mega Compounding Corp?


“They did what they were told, they followed the
compendia”
But unfortunately,




Inadequate gowning
Incomplete monitoring of environmental microbes
Inadequate disinfection
Insufficient testing
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27. Conclusion



cGMP or not – hazard analysis, critical control point
identification, and critical limit setting will ensure a safe
product.
No regulation can cover every situation.
The compounding pharmacy debacle shows:


Importance of cGMP to ensuring drug quality
Importance of applying sound quality and scientific evaluation
to ensure drug quality.
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28. Questions?
Anthony Grilli MS
Principal Consultant
FOCUS Scientific Services LLC
agrilli@focus-sci.com
(973)216 6039
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