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Let Patient Safety Frame Our Definitions of 'Sterile'

James Agalloco, President, Agalloco & Associates
Monday, February 25, 2013 00:02 EST

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Mudassir
Mudassir  
1/10/2014 7:22:46 AM
User Rank Dealmaker (Master)
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Re: How clean is clean enough?
The sterilization is vital for drug manufacturing and we all give importance to maintain sterility in healthcare facilities as well.

Alison Diana
Alison Diana  
3/6/2013 9:23:51 AM
User Rank Survivor (White Belt)
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Re: How clean is clean enough?
Between the compounding pharmacies and frequent stories about less-than-sterile conditions in our nation's hospitals leading to untreatable superbugs, it does seem we need to do more than we are to ensure strict adherence to both commonsense and standards -- whichever standards are most stringent -- to keep our medications, drug manufacturers, and healthcare facilities sterile. Losing patients because of these 'oversights,' 'mistakes,' or dueling standards is terrible to see in a country as developed as the U.S.

James Agalloco
James Agalloco  
2/27/2013 2:36:36 PM
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Re: Why are we seeing so many contamination cases?
Several Reasons,

First. because we have squeezed generic injectable margins to the point where maintaining compliance at the same levels possible where there's price protection simply isn't possible.  When market share goes to the firm with the lowest COGS then something has to be cut to make that happen.

Second, the facilities and systems currenly used for most generics are among the oldest in the industry.  It isn't universally true, but there are few new plants with the latest technologies. 

Third, FDA's review process for ANDA's perpetuates the use of older practices and techologies. I just 'validated' my process, I can't change it for the better.

Fourth, expectations for performance have exceeded our ability to meet them.  Rejecting a lot because there were 2 CFU's on the operators sleeve is FDA thinking.  It's called aseptic processing for a reason, it's not now and never has been 'sterile' processing. So a excellent facility can be put in regulatory crisis because it's not perfect!

There's more, but these are the biggest factors.

James Agalloco
James Agalloco  
2/27/2013 2:35:34 PM
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Re: Why are we seeing so many contamination cases?
Several Reasons,

First. because we have squeezed generic injectable margins to the point where maintaining compliance at the same levels possible where there's price protection simply isn't possible.  When market share goes to the firm with the lowest COGS then something has to be cut to make that happen.

Second, the facilities and systems currenly used for most generics are among the in the industry.  It isn't universally true, but there are few new plants with the latest technologies. 

Third, FDA's review process for ANDA's perpetuates the use of older practices and techologies. I just 'validated' my process, I can't change it for the better.

Fourth, expectations for performance have exceeded our ability to meet them.  Rejecting a lot because there were 2 CFU's on the operators sleeve is FDA thinking.  It's called aseptic processing for a reason, it's not now and never has been 'sterile' processing. So a excellent facility can be put in regulatory crisis because it's not perfect!

There's more, but these are the biggest factors.

Agnes Shanley
Agnes Shanley  
2/26/2013 11:26:53 AM
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Why are we seeing so many contamination cases?
Thanks for a great post.  There's a world of difference between cutting corners and taking a rational, patient-focused approach to regulation.  But Rodney asks a great question...looking at recent FDA 483's and recalls, endotoxin and microbial contamination are very often at the root of noncompliance.  Given all the newer technology (such as rapid microbial measurement) and approaches that are now available, why should this be the case? Is there a mindset issue at work, too? Is it all a sign of "do more with less" syndrome? 

James Agalloco
James Agalloco  
2/25/2013 10:46:49 PM
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Re: How clean is clean enough?
You only need to kill what is there.  The bioburden is there every lot, and requires a lot less process time-temperature than the biological indicator that is only present during validation.  Raising the minimum criteria above what is necessary results in collateral damag to the product.  You can kill a fly with a fly swatter or a hand grenade.  One takes care of the fly an nothing else.  The other takes care of the fly and does damage to everything around it.  There's simply no value in escalating the process conditions to extremes,  Taken too far, and the product ends up being made aseptically which is certainly less safe.

What I'd like to see is a process that uses enough post-fill lethality to make the product safer than straight aseptic processing.  Assuming the bioburden is always highly resitant means more aseptic processing and less terminal sterilization will be used.  That's not in the patients best interest. 

James Agalloco
James Agalloco  
2/25/2013 10:37:44 PM
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Re: If not this or that... then what?
There's a clear middle ground.  Aseptic (or near aseptic) fill to control the bioburden well, and then sufficient lethality afterwards to make it confidently sterile. Any possible bioburden after aseptic filling is likely low in number and resistance thus allowing for the use of a modest post-fill treatment to make the product safe for administration.  Mandating an F0 for the purposes of killing a 'worst case' BI that is overly resistance, may sound right, but doesn't make the product any safer if the BI is 1,000's of times more resistant than the bioburden we're really trying to deal with.

Plus consider the other benefits of this. 

Fewer investigations into the inevitable microbial excursions that occur in aseptic processing.

The potential for parametric release. as the product will be certainly sterile after the follow-up process.

Puhing for high F0 processes sounds safe except when it results in the use of a less capbale aseptic one.  Combining them should be in wider usage.  Everyone wins.

Rodney Brown
Rodney Brown  
2/25/2013 12:45:49 PM
User Rank Survivor (White Belt)
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How clean is clean enough?
The problem is that once you start talking about something that, to a layman, sounds like accepting a "less than perfect" level of sterility, you start conjuring up images of the tainted steroids from the New England Compounding Center that killed more than 40 people via fungal meningitis. How is it possible to convince people that patient safety can be met with less than the EMA's strict guidelines?

Terry Sweeney
Terry Sweeney  
2/25/2013 12:09:13 PM
User Rank Survivor (White Belt)
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If not this or that... then what?
Really intriguing post, James... you don't seem to like either aseptic processing or terminal sterilization. Is there a third possibility? Or some half-way point that splits the difference? Or do you just want to see the EMA's guidelines revised?

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