Risk analysis of a compounding pharmacy

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Microbiological Risk Analysis And Compounding Pharmacies

Anthony Grilli MSFOCUS Scientific

November 14, 2013

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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?


Perfect Storm!

Drug Company Mold Regulator User

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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.


National Problem – Distribution of NECC Illness


Compounding Centers Provide Benefits to Patients 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 and inspection process, for

patients that have an immediate unique need.


Other Compounding Problems Product Recalls and

contamination Med Prep Consulting

Nationwide recall of all sterile products after hospital discovered mold in unopened IV solution.

Main Street Compounding, TN Nationwide recall of products FDA

found product contaminated with fungus and bacteria

Clinical Specialties, GA Nationwide recall – 5 patients with

eye infections Compounding Shop, FL

Recall Budensonide, not sterile Specialty Compounding, TX

Rhodococcus equi


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/OfficeofGlobalRegulatoryOperationsandPolicy/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.

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/ucm340853.htm




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.


Reducing Microbial Risk of Contaminated Product

Hurdles to Microbial Contamination and Illness

Formulation Water Activity Kill steps pH Preservatives


Microbial Risk Analysis of the Product

Score Delivery Route

Water Activity

Kill Step in Process

Inherently antimicrobial

Preserved ImmuneStatus

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 + 5 = 30


Microbiological View of Manufacturing Process

Receive components

Formulate Components Sterilize

FormulaSterilize

components

Aseptically fill

components

Test Final Product



Receive components

• What is the bioburden?

• How do we store the components

• What is shelf life of components



Receive components


• 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?



Receive components





• 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



Receive components





• Is there a heat step?

• What is the hold time?

Sterilize Formula

• Have we validated the process• Bioburden from

components informs how we sterilize

Sterilize components

• Validate process• Confirm package

sterility



Receive components







Sterilize Formula

• Have we validated the process• Bioburden

from components informs how we sterilize



sterility

Aseptically fill

components

• Controlled Environment

• Controlled gowning

• Controlled cleaning and disinfection



Receive components







Sterilize Formula

• Have we validated the process• Bioburden

from components informs how we sterilize



sterility

Aseptically fill

components

• Controlled Environment

• Controlled gowning

• Controlled cleaning and disinfection

Test Final Product

• Proper testing


Environmental MonitoringRisk Analysis: Microflora changes with seasons

More mold in fall More bacteria from skin in dryer months

HVAC is in constant state of flux 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


Gowning Risk Analysis:

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 Control point

Full sterile gown with no skin or street clothes showing.

USP <797> Lab coat, gloves, hair net.


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


Sanitizers/Disinfectants/Sterilants:Right product for the right application

Antimicrobial Target OrganisResistance

AlcoholChlorhexidinePovidone-iodine

E.coli Sanitizers PhenolicsSalmonella Disinfectants Quats

S. aureusA. niger PhenolicsC. albicans Iodophors

Quats

M. pneumoniae Disinfectants Above

B. subtilis Sporicides/ Peracetic acidB. anthrasis Sterilants Gluteraldehyde

C. botulinum

Fungicides

Corrosivity

Herpes, HIV, Hanta, Flu

Antisceptics and up

Examples Category Examples


Disinfection Risk Analysis

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.

Control Point: Validate sporicide efficacy on

manufacturing materials using environmental isolates.

USP <797>: Not specific about sporicide usage No mention of validation


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.


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


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.


Questions?

Anthony Grilli MSPrincipal Consultant

FOCUS Scientific Services [email protected]

(973)216 6039

mailto:[email protected]

Risk analysis of a compounding pharmacy

Health & Medicine

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