05-31-2012 11:58 AM
I have a question about Sodium Citrate 4% 250 mL bags and what BUD can be used when preparing 2.5 mL syringes from this bag. Typically, we batch the entire bag into syringes in one sitting. We are preparing these syringes in a horizontal flow hood in an ISO 7 compounding suite. Would this be considered low risk or medium risk and what BUD can be given to the resulting product? 48 hours? More?
06-04-2012 08:53 AM
This preparation would be medium risk level because multiple individual doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient multiple times. Additionally you are making multiple punctures into one infusion container which also confirms the classification as medium risk. Therefore, barring any stabiltiy concerns, the maximum beyond use date that you could apply to these syringes would be 30 hours at room temperature or 9 days in the refrigerator.
11-14-2012 12:43 PM - edited 11-14-2012 12:44 PM
In full disclosure, I am consulting with Equashield, a company that manufacturers CSTDs and as a member of the USP Compounding Expert Committee, so the following comments are my own professional opinions and do not reflect the opinion of USP. In order to demonstrate and maintain transparency, I am only one member (out of 16) on the committee, and have an actual conflict of interest on this subject. I would not participate on a vote on this, and in fact, USP by-laws prohibit me from voting due to my conflict of interest.
I can tell you that the desire to optimize the use of medications is a goal of the USP committee; however, the patient population associated with this potential practice change is immuno-compromised and least likely to tolerate any level of contamination. The USP Compounding Expert Committee does not validate individual studies, but does consider them when evaluating existing USP standards.
It is important to note that a single-dose container has a specific definition with the General Notices section of the current USP-NF. It says:
10.20.60. Single-Unit Container
A single-unit container is one that is designed to hold a quantity of drug product intended for administration as a single dose or a single finished device intended for use promptly after the container is opened. Preferably, the immediate container and/or the outer container or protective packaging shall be so designed as to show evidence of any tampering with the contents. Each single-unit container shall be labeled to indicate the identity, quantity and/or strength, name of the manufacturer, lot number, and expiration date of the article.
This definition has far reaching implications relative to accreditation standards (The Joint Commission), regulatory compliance, infection control practices, CMS standards, and billing practices. It is my understanding that Carmel Pharma, the manufacturer of the CSTD in the study is distributing it as prima facie evidence that the BUDs of SDVs can be extended. This could be considered a labeling claim and one subject to FDA approval since everything that a drug or medical device manufacturer says or puts in their literature has to go through a formal and scientifically validated approval process.
USP Chapter <797> states the following condition: The use of technologies, techniques, materials, and procedures other than those described in this chapter is not prohibited so long as they have been proven to be equivalent or superior with statistical significance to those described herein. There are some things you may want to consider:
The McMichael study that was published in The American Journal of Pharmacy Benefits, January 2011, Vol 3, No.1, showed a failure (contamination) rate of 1.8% which means that not all of the vials maintained their sterility during the study. There was no control group to evaluate the contamination rate of vials accessed without the CSTD. The last reference in the study, De Prijck, et al., (reference 12) noted that PhaSeal “had the lowest transfer of microorganisms”. The study demonstrated a 2.2% to 2.5% contamination rate with PhaSeal and noted that the level of contamination was dependent on the number of couplings.
De Prijck and his coauthors note that the use of high inoculum used in the study should be considered in context of their results as well as the need for a robust disinfection step. They concluded that the PhaSeal system did not guarantee total sterility of the vial content. In addition, as De Prijck found that more transfers resulted in more contamination. The purpose of a CSTD being used in this manner would be to extend the BUD of the SDV, which would involve increasing the number of transfers and would therefore potentially increase the risk of contamination. I attached a copy of the study article and the reference with this forum post.
I believe that ANY study (regardless of the manufacturer) would have to demonstrate the capability of the CSTD to maintain sterility irrespective of aseptic technique. This is the biggest problem I am having in designing a study that would “prove” that CSTDs are effective in maintaining single-dose vial sterility in light of variability in disinfection practices and operator aseptic technique. There is a belief out there that “nothing” will grow in antineoplastic and hazardous drugs. A review of the published literature shows a different story. I have attached a copy of an article draft for your consideration.
Assuming that a study could demonstrate that a CSTD can maintain SDV sterility, you would have to repeat the study at your own facility to demonstrate that your compounding staff could duplicate the results of study. Since there are several factors that were not described in detailed in the paper, so I’m not sure how you could demonstrate that conditions at the different hospitals would be equivalent to those at your facility. The expectation of any extended storage of single-dose vials would be that all vials maintain their sterility during the storage period as is the expectation of single-dose vials during the initial puncture.
his is one study and the sample size appears to not be statistically significant. Since the probability of contamination is low (less than 3%, based on extrapolation from media fill studies), the number of vials that need to be tested would have to be in the thousands in order to detect any contamination. It is my belief that any study would have show zero contamination (growth in media) based on a statistical sampling size (minimum# of 3,000-4,750 samples).
Currently, most hazardous drugs are packaged and labeled as single-use containers and failing to handle them as such can lead to other regulatory, accreditation or legal ramifications since their use outside of their approved use. There are several confounding factors to this matter and believe me, something everyone is trying to figure out how to best handle in light of the ongoing and crippling drug shortages. As a licensed professional, you can always make a professional decision based on the literature that might differ with the USP standard if you believe that it would be in the best interest of the patient. It is a “benefit vs. risk issue” and something that you should be prepared to defend (legally and professionally) if your decision to extend the dating of SDVs is based on this or any study.
Given the recent 510K- K120384 released by the FDA on September 12, 2012 http://www.accessdata.fda.gov/cdrh_docs/pdf12/K120384.pdf does this change anyone's opinion on using SDVs as MDVs if PhaSeal is used? In the 510K, FDA approved a labeling change to state "The PhaSeal protector also prevents microbial ingress."
If the FDA supports this labeling that PhaSeal prevents microbial ingress, would it not suggest that the 6 hour BUD for SDVs could be extended to the chemical/physical stability of the drug or up to the sterility test limits of the studies (168 hours), whichever is shorter?
In full disclosure, I am a co-author on both of the studies published in AJPB that showed sterility when using PhaSeal.
Ryan Forrey, PharmD, MS
11-15-2012 10:06 AM
Would using a single-dose vial (with a dispensing pin) and drawing up into multiple syringes (3 or more) still be a medium risk? Some feel that since there is only one entry into the original vial due to dispensing pin it should be a low risk, not a medium risk. Thanks in advance for this clarification.
11-16-2012 08:49 AM
You are not beating this subject to death. These vials should be treated as SDVs and according to USP 797 cannot be used outside an ISO Class 5 environment for more than 1 hour. Technically, 1 hours is too long in my opinion.
02-15-2013 02:35 PM
I find it very interesting that Phaseal's labeling has been approved to include language that it "prevents microbial ingress". This could be a game changer. However, I still have the same concerns that I noted in my post on 8/19/2011. Although I can accept that the Phaseal device, AFTER ATTACHMENT TO THE VIAL, is effective in "preventing microbial ingress" during subsequent storage of the vial, I believe the biggest risk is that microbes can gain ingress into the vial at the moment of attaching the Phaseal device to the vial. If the vial stopper is not adequately disinfected, or if the spike of the Phaseal device is contaminated, microbes can be introduced into the vial at the moment of puncture. In the absence of a preservative, those microbes could multiply over the course of seven days of storage and present a risk to patients.
Forsyth Medical Center
02-16-2013 07:15 AM
I couldn't agree with you more. Proper vial septum disinfection and proper aseptic technique are critical aspects using this or any device. Not sure how or why the FDA CDRH (Medical Device side of the FDA) gave this device the indication of "prevent microbial ingress. None of the published studies did a microbial ingress test. They did an in-use test. A challenge test would immerse the system in a bath of microbes and assess how many microbes were able to gain access to the inside of the container. In addition to doing only an in-use test, the paper authors did not even use the system as it is intended to be used in the clinic; they provided extra sterile caps to use during the study. Also, authors did observe a contamination rate of 1.8%.
The De Prijck paper "Microbiological Challenge of Four Protective Devices for the Reconstitution of Cytotoxic Agents, K. De Prijck, et.al., The Society for Applied Microbiology, 543-548 (2008)." (on page 546) summarizes a contamination rate of 2.2% and 2.5% when using the PhaSeal. This paper was not financially supported by the device manufacturer, and it concludes that use of PhaSeal “does not guarantee sterility”.
11-02-2017 04:46 PM
I would like to ask a question about BUD in the hospital setting. My is for the nurses. Say we have an emergent med to be mixed. The nurses make Norepi drip in an area designated for IV compounding, no ISO air. The bag is hung immediately. My question is how long is the compound good? They use a sterile mfr single dose vial and mix with a sterile 250ml bag.
11-05-2017 09:10 AM
As you know from reading other posts on this forum, that once the infusion starts, USP 797 BUDs are no longer in effect. Those dates are associated with the date/time that drug cannot be stored. The hang time will be dictated by organization SOPs and chemical stability of the drug in solution. Hope this helps.
11-06-2017 02:47 PM
We, (along with the rest of the country) are looking at ways to conserve IV fluids and how to be pro-active with the impending lack of available 50mL and 100 mL Baxter IVPBs. I read ASHP's "Small-Volume Parenteral Solutions Shortages Suggestions for Management and Conservation (Compiled by ASHP and the University of Utah Drug Information Service, October 18, 2017)" and had some questions.
I would like to know if we use 1 L bags of commercially available 5% Dextrose in water or 0.9% Sodium Chloride and repackage into burretrols (for the intent of using the buretrol in place of a Mfr available IVPB) using a repeater pump to fill to either 50 mL or 100 mL, then place the batch in refrigerator, give a 9 day BUD, then remove from refrig and add antibioitic or other medication to burritrol solution and dispense, would be be able to assign a 24 hour BUD without sterility testing and meet USP 797 standards? The burretrol would be sent in lieu of an IVPB, with a hangar attached for the nurse to administer.