quality failures new england compounding center

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Entropy and New England Compounding Center: How Things Can Disastrously Fall Apart

Anthony Grilli MSFOCUS 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 partiesNECC 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 MSPrincipal Consultant

FOCUS Scientific Services [email protected]

(973)216 6039

mailto:[email protected]

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