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Frequent Advisor
Posts: 26
Registered: ‎05-18-2012

BUD justification

Beyond use dates are based on the premise that a contaminated solution will support a logrithmic growth of microogranisms and that after a limited time such a solution, if infused, would produce a high risk of infection. Experiments measuring growth in purposefully contaminated plain and drug solutions actually demonstrate no growth (EJHP Science • Volume 13 • 2007 • Issue 2 • P. 27-32, J Clin Pharm Ther. 1989 Oct;14(5):393-401). The simple explanation for this is that these solutions lack the necessary macro and/or micronutrients to support growth. Yet, the guidelines are different for a product mixed in bacteriostatic water vs SWI when, based on the evidence, there is no difference. In this era of drug shortages and skyrocketing healthcare expenditures, should we be re-evaluating USP guidelines?

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Expert
Posts: 1,168
Registered: ‎02-23-2010

Re: BUD justification

Ray,

 

Thanks for starting this discussion.  You are correct that one of the principles behind the BUDs in USP 797 is the concern for the exponential growth of microorganisms if the drug or CSP becomes contaminated.  The EJHP article you referenced shows that many drugs do not possess antimicrobial activity meaning that if contamination was introduced into the drug solution during handling or compounding, that the microorganisms will neither grow nor die, however the authors did mention that microorganisms can survive in both concentrated and diluted solutions of antineoplastic drugs and once transferred to a nutrient solution like D5W, growth could occur. We must realize the concept that "chemo kills everything" is not true. The CDC reported on a contamination event in 2002 involving methylprednisolone and the fungus, exophilia where it took several weeks and up to 152 days post injection for the fungus to manifest itself into clinical symptoms in five patients. One patient died from that microbial exposure.   http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5149a1.htm.   Based on this article, I am not sure what changes you would suggest regarding the USP standards.  The chapter is under a revision as we speak and any suggestions are greatly appreciated.   Is there an acceptable level of contamination that we should establish for our CSPs based on the nutrient value of the drugs we handle and their ability to support exponential growth if contaminated?    We want and need to have ZERO microorganisms in our CSPs that we give to our patients because it is not acceptable that we subject them to any extrinsic contamination (introduced by us and that can be controlled by us).  

 

Authors in the EJHP state in their conclusion that “In pharmacy departments, solutions for parenteral administration are to be prepared under strict aseptic conditions and appropriate quality assurance programmes are to be established in order to guarantee the sterility of drug preparations.”  Although you cannot guarantee the sterility of drug preparations prepared by humans, it is important to have a robust quality schema that works to eliminate the principle sources of contamination and risks associated with sterile compounding practice.   In Europe, they adhere to a robust set of compounding practices much like USP 797 that is followed with vim and vigor.  There is strong oversight of these programs from regulators.  Last year, the national USP 797 survey conducted by CriticalPoint showed that the average level of compliance was only 72.4%!   http://www.pppmag.com/article/985/October_2011_Cleanrooms_Compounding/The_2011_USP_797_Compliance_St... . Why isn't it at 90-95%?  72.4% illustrates to me that we are not following strict aseptic conditions and appropriate quality assurance programs as called for in the paper.

 

Much of the focus in revised (2008) USP Chapter <797> has been to minimize the impact that compounding personnel have on the final compounded sterile preparation from a sterility perspective.  Accuracy is also critical but not the focus of the 2008 revision.   We need to make sure that our biggest asset, our employees don't become are greatest liability.  It is critical that managers and supervisors show leadership in both promoting and encouraging good aseptic technique practices like hand washing, proper use of gowns and the use of sterile gloves, and proper disinfection of vial septa so that microorganisms don't get into vials and CSPs.  We must work in environments that achieve a state of control so that the environment does not negatively impact the quality of the components we use and the CSPs we prepare. 

 

The chapter is written as a mosaic of processes and procedures designed to create a safe and effective way to handle, compound and store compounded sterile preparations.  The problem is that people want to "cherry pick" what from the chapter processes and procedures that are considered too expensive, inconvenient or difficult.  It’s like a jigsaw puzzle with every piece being needed to complete the picture.  I have heard many people tell me that they don't believe in USP 797!  What don't they believe?  That washing your hands is good or wearing sterile gloves or using sterile alcohol isn't necessary?  Yes, those elements can be expensive but what is the cost of noncompliance?  We don't really know because we don't measure it but we know that hospital acquired infections continues to be a problem and that pharmacy can have either a positive or negative role in minimize them.   Instead of cost-cutting, we need to focus on eliminating the waste that is inherent in pharmacy practices with wasted drugs and unnecessary waste of motion and duplication (such as missing doses) so we have the fiscal and human resources to do it right.  We need to use good growth media when we do media fills and environment sampling so we don't get false negatives. 

 

Safe and effective aseptic practices require employee vigilance and accountability, discipline to robust work practices and supportive leadership.  Without the core fundamentals in place, the drug shortages cannot be safely minimized by arbitrarily extending the BUDs.  The problem to me is that we are not willing to do what it takes to prevent the contamination of the components that we work with, and until we do, we can't look at extending the storage of SDVs to lessen the impact of the drug shortage.   

 

Eric S. Kastango, MBA, RPh, FASHP

It's all about the patient.
Frequent Advisor
Posts: 26
Registered: ‎05-18-2012

Re: BUD justification

I agree that ZERO contamination should be our goal. However, in my opinion the risk of infection has been greatly exaggerated. You described D5W as a "nutrient solution" but the article documents that even D5W doesn't support growth. Again, there is no growth unless BOTH macro AND micronutrients are present such as in TPN or PPN. The risk of infection is a function of bioburden and virulence. With very low bioburden, there is very low risk. The problem from a clinical trial design standpoint is that you are trying to measure the endpoint of clinical infection using a false surrogate marker (growth after transfer of an aliquot of CSP to a growth medium). The correlation is dubious at best. We should always strive to do what's best for our patients. We don't serve our patients best by shorting drugs and inflating drug costs in the name of phantom safety concerns.  

Expert
Posts: 1,168
Registered: ‎02-23-2010
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Re: BUD justification

These are not phantom safety concerns but real issues.  You are not correct about needing both macronutrients and micronutrients for growth to harm patients. Microorganisms can survive in nutrient poor environments well enough to kill patients.  With that being said, what would you propose as an alternative to the current system since you believe we are wasting drug?   

Eric S. Kastango, MBA, RPh, FASHP

It's all about the patient.
Frequent Advisor
Posts: 26
Registered: ‎05-18-2012

Re: BUD justification

The evidence shows that microorganisms survive but they do not grow. Certainly, if there is enough gross contamination you will put the patient at risk. This is why we need to be diligent about sterility. However, since the degree of contamination appears to be a function of the number of breaches of the sterile environment and NOT a function of time from the initial breach, we should limit vial utility based on the number punctures and stability data.

Expert
Posts: 1,168
Registered: ‎02-23-2010

Re: BUD justification

Ray,

 

I appreciate the dialogue.  A septum on a multi-dose vial needs to demonstrate sealability after 10 punctures with a 21g needle per USP <381>.  Most of the medications we use are considered single-dose vials (SDVs) which technicially means a single puncture/single use and the stopper membrane may not be capable of self-sealing, especially if we are using an 18g needle.  USP 797 looked to extend the use of SDVs to 6 hours, which is not consistent with the definition in the General Notices of the USP/NF.  The problem as you know is that many times there is a lot of drug left over in SDVs and we don't want to waste it.  If we put a dispensing pin on the vial, we have an open system that requires aseptic connections and not punctures.  Proper and viligant disinfection of the vial septum is one of the keys to sterility. 

 

So, building on your thoughts re: punctures and stability, any specific language would be greatly appreciated.  I am chairman of the USP 797 subcommittee and this topic is being critically discussed and debated in light of the drug shortages by the committee.  I am attaching another article that describes how the manufacturer assign the sterility storage times in the PI.   Thanks.  

Eric S. Kastango, MBA, RPh, FASHP

It's all about the patient.
Frequent Advisor
Posts: 26
Registered: ‎05-18-2012
0

Re: BUD justification

Random thoughts:  We could significantly reduce waste by enabling BUD to just 3-4 punctures (no need for 10 punctures). Manufacturers should be mandated to produce stoppers with proper sealability. Another strategy to insure patient safety would be to filter the product with a 0.22 micron filter either at the point of compounding or at the terminal end of the IV tubing. Maybe the terminolgy of "single-dose vial" should be changed to something like "limited-dose vial".

 

Thank you for allowing me to express my point of view. 

 

Ray Vella, PharmD

Expert
Posts: 1,168
Registered: ‎02-23-2010
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Re: BUD justification

Ray,

 

I appreciate your thoughts and suggestions. It is a difficult task in trying to develop a standard that will be used across the varying continuum of compounding practices. I would interested in knowing your thoughts and interpretation of the two articles that have been published re: drug vial optimization and the use of a CSTD to extend the use of SDVs. 

Eric S. Kastango, MBA, RPh, FASHP

It's all about the patient.
Frequent Advisor
Posts: 26
Registered: ‎05-18-2012
0

Re: BUD justification

We have been using a CSTD for years now.  There are several compelling reasons for using a CSTD: 1) minimizing use of needles & possible needle sticks 2) ergonomics (minimizing repetitive stress issues) 3) minimizing chemo contamination 4) possibly minimizing microbial contamination. The articles you refer to (Utility of the PhaSeal Closed System Drug Transfer Device Microbiological challenge of four protective devices for the reconstitution of cytotoxic agents) did not include an arm using good old fashioned needle & syringe technique for comparison. The first article claims 98.2% sterility at 168 hrs using Phaseal. However, using good technique you can achieve about 99% sterility the old fashioned way (American Journal of Health-System Pharmacy. 2007;64(8):837-841). The question remains: how much would repeated entries into the vial using a needle reduce results? 

Expert
Posts: 1,168
Registered: ‎02-23-2010
0

Re: BUD justification

Ray,

 

I agree with you re: CSTDs and the studies missing the arm using good old fashioned needle and syringe technique.  Aseptic vigilance and vial stopper disinfection are critical steps to preventing vial contamination. The problem is that many people ignore those critical activities and still want to apply extended BUD.   The second article you cited showed that repeated punctures increased the risk of contamination.  Thanks for your response. 

Eric S. Kastango, MBA, RPh, FASHP

It's all about the patient.