07-15-2011 03:25 PM
I understand that the BUD would be medium risk rather than low risk. Even so that is still 30 hours room temp and 9 days cold. My question is somewhat similar to the one posted by Quyen-B at the beginning of the forum. As a concrete example, I present the following. Using a 20 cc syringe all of the contents of one 10 cc Clonidine 100mcg/ml single dose vial is drawn out. Using a 4 way stopcock 2 ccs are drawn out with a 5 cc syringe out of the 20 cc syringe and capped. A total of 5 syringes with 2 ccs each are prepared. Based on what I am gathering from the info in this forum, these 5 syringes now have a BUD of 30 hours at room temp, 24 hours longer than the vial from which it came? How can the benefit of the doubt you speak of increase? I know you mentioned repackaging and possible FDA ramifications for hospital and non hospital pharmacys but that is another issue all together from what to me appears to be an inconsistency in BUD dating.
07-16-2011 10:06 AM
What is the expiration date of a vial of clonidine from the manufacturer? 2-3 years (somewhere in that range). How did they establish this expiration date? The manufacturer did extensive chemical stability studies of the drug using specific active pharmaceutical ingredients (API) from a specific manufacturer formulated under controlled and validated methods filled in glass vials (from a specific manufacturer) with a stopper (from a specific manufacturer) that has been tested to not leach into the final drug solution or affect the final solution. Anytime any of the components used to manufacture that approved drug solutions changes (source of the API, vial, stopper, the inactive ingredients (to adjust for pH, etc)), the manufacturer needs to requalify all the changed components/ingredients and resubmit their data to the FDA for approval.
The FDA approves drug products and inspects the facility where these "approved" drugs are manufactured to ensure that they comply with 21 CFR Parts 210 and 211 (Human and Animal Drug current Good Manufacturing Practices (cGMPs). Some of these vials are single-dose vials (approved and tested for one puncture). If it is a multiple dose drug vial, then the manufacturer had to test their drug, container, preservative system according to USP Chapter <51> Antimicrobial Effectiveness Test. If it passes, then it is given a 28 day expiration date once puncture. Improper use of SDVs and MDVs have been the sources of numerous outbreaks of bacterial and viral infections. CDC, APIC, FDA, USP and other organizations have put a lot resources into preventing patient injury and death from improper use of vials by physicians, nurses and pharmacists.
As pharmacists, we take approved, tested, validated drugs that have been manufactured under tightly controlled and vigorous conditions and we start manipulating them to prepare patient-specific doses. Historically, we compounded what was required to fill a prescription for a specific patient. Patient care changes and we need to batch medications because that what is required to meet the patient's medical needs.
So, we combine these approved drugs made under controlled and validated systems with a known and tested expiration date with various diluents (D5W, NS, 0.45 NS, etc) and containers (syringes and bags made of of various materials), stopcocks, injection ports, tubing sets but need to give them a beyond use date. What dating do we give these essentially new, untested and unapproved drug solutions? This is how the FDA looks at these solutions and if a pharmacist doesn't make it pursuant to a prescription for a specific patient, they consider it manufacturing. This is why most of the outsourcing companies are registered as a manufacturer with the FDA but with an interesting twist. These new "drugs" from pharmacy outsourcers are not approved and have never undergone through the same NDA, ANDA, or IND process that the innovator or generic manufacturer had to go through. An innovator manufacturer is one that creates a new drug entity from scratch. Approved drugs come from both innovator and generic manufacturers.
Innovator and generic manufacturers will have done some basic chemical testing with various solutions and will publish this information in the package insert. When you consult the package insert you will find the discard time is typically anywhere from immediately to 8 hours. It is short because the manufacturer has no idea where and how these drugs are going to prepared and the longer a potentially contaminated solution sits around, the greater chance that the microbial bioburden will exponentially grow to numbers that can harm or kill patients. Not everything antimicrobial, even antibiotics.
Since those time limits don't work for us as pharmacists, we look to Trissel's Handbook of Injectable Drugs, Kings' Admixture Guide or some other resource. Great! We can give Clonidine in D5W at a concentration of x mg/mL 45 days because Trissel or someone else did the validated chemical testing, which is currently not recognized by The Joint Commission (TJC) because of a CMS requirement. That is a separate issue and needs to be addressed with TJC. So we have good chemical stability but what about microbial stability? Historically, we have assumed that everything we compound is sterile. It ain't so! Probability of contamination is anywhere from 0% to 12.5 % based evidence-based studies and on the complexity of the process, quality of the components used (sterile vs.. nonsterile) the environment, personnel and their aseptic technique. This is when the risk levels get established and were first published in 1993 by ASHP when they published their Technical Assistance Bulletin, which was last updated in 2000. In 1995, USP publishes Chapter <1206>, Sterile Drugs for Home Use and the concept of risk levels continues when in 2004, USP publishes USP Chapter <797>.
So, pharmacists and others (nurses, physicians, etc) take a drug in solution from a tested and validated container system and exposure it to atmospheric air and other conditions that vary widely depending on who is preparing it and where it is prepared but is never tested (chemically or microbiologically) by anyone. Lots of cases of patient injury and death occur from these compounded medications over time so what USP Chapter <797> does is establish a BUD matrix that factors in environment, quality of components, preparation complexity and chemical stability of the CSP.
The vial of clonidine starts with a 2-3 year date on it. We manipulate and combine it with other solutions and create a new formulation and in order to protect the patient from microbial contamination (assuming chemical stability is unaffected), drop the BUD from 2-3 years to the new BUD (time limit) specific to the risk level that it was prepared under and its storage condition. If the clonidine vial is a single dose container, the vial should be discarded since it was never tested for more than one puncture. Chemically, the clonidine is most likely OK but has sterility been maintained? The chapter currently allows a vial that should be discarded after one puncture a life of 6 hours. The definition of a single-dose vial comes from the General Notices Section of the current USP/NF. All professions have been misusing single-dose vials over the years and the USP Sterile Compounding Committee merely highlighted the existing and "legal" definition use of a single-dose vial with a provision to optimize drug utilization (effectively making it a 6 hour multiple-dose vial). If you want to extend the BUD of the clonidine, you need to conduct sterility testing on the batch of clonidine syringes in accordance with USP Chapter <71>. Every batch of drug needs to be tested since human operators can be error-prone and sources of microbial contamination.
I hope this clarifies your understanding of how BUD is assigned from a single-dose vial.
07-26-2011 07:17 AM
My facility is compliant with the single-dose vial beyond use dataing, however, I was curious about all of the recent trials demonstrating the efficiency of certain CSTDs (i.e. PhaSeal) in prolonging the BUD of single use vials. Do you have any inclinations as to whether USP may recognize the ability of these devices to safely prolong the BUD of single dose vials? With all of the drug shortages and expensive medications (i.e. chemo), it would be nice to have the ability to extend the use of certain medication vials in necessary circumstances.
07-26-2011 04:45 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.
08-19-2011 08:37 AM
The highest risk of introducing microorganisms into a vial is at the time of puncturing the vial stopper, rather than during subsequent storage of that punctured vial. I believe the risk of introducing microorganisms at this moment in the process is at least as high when the puncture is made by a CSTD spike, as compared to a traditional needle - the needle is smaller, creates less trauma to the vial stopper. The theory that CSTDs may protect against contamination of the vial would seem to only apply to the period of time during which the vial is subsequently stored. It is does not address the moment of puncture, which is the moment of highest risk. I remain very skeptical of any claims of extending vial BUDs through use of CSTDs.
Forsyth Medical Center
11-18-2011 09:54 AM
Not to beat this subject into the ground, but I have a different scenario and would like an opinion. Currently we make dilutions for the NICU floor. We use a MDV and dilute with SDV SWFI to a desired concentration and place these components in an empty sterile evacuated vial. We place an expiration date 7 days refrigerated. These dilutions are sent to the floor where nurses can draw unit doses from the vial. We are sending this dilution as an MDV, which I think it really is a SDV. Meaning that once this dilution is punctured on the floor (not and ISO class 5 area), then the vial should be discarded. Any thoughts?
11-19-2011 09:04 AM
I'm not sure what you mean that you reconstitute a MDV with SDV SWFI (no preservatives correct?). This vial is not a MDV and should be handled a SDV and must be discarded after 1 hour when used outside of an ISO Class 5 area. What drug are you making for the nurse to use over 7 days? If I understand your question, there are so many things wrong this practice from an USP 797 and infection control practice perspective.
11-20-2011 03:38 PM
Yes I agree that I thought there were so many things wrong with this practice as well. I just recently stepped into a iv room supervisor's position and the current practice here was to create NICU dilutions for Morphine, Dexamethasone, Furosemide, and Insulin. These dilutions were put into sterile evacuated vials and dispensed to the floor with an expiration date of 1 week. On the floor the nurses were using these vials throughout the week as MDV. I am pushing for a change in this practice and I wanted confirmation. I have made the suggestion to dispense as prefilled syringes instead of a bulk vial. Thank you for your input, it has been most valuable.
12-01-2011 01:41 PM
I have a question similar to Sandra's. We have a cardiac surgeon who uses very low dose Chlorpromazine as a post-op sedative on his patients. He requested that we stock this drug in the CVICU Omnicells. We use one single dose Chlorpromazine 25 mg/ml ampule, dilute it in a syringe to a concentration of 1 mg/ml. Then, using a dispensing connector, prepack 1 ml syringes from this. We have been giving these syringes a 7 day expiration date but I have tasked with determining if this is correct or if the expiration should be shorter (or possibly longer - see this Pharmacy One Source thread from last month
http://forums.pharmacyonesource.com/t5/Pharmacy-Practice/BUD-when-using-single-dose-vials-to-prepare... ) Can you comment on this specific scenario?
Eddie Hankins, Pharm D
Critical Care Pharmacist
LeBonheur Children's Hospital
12-01-2011 01:43 PM
Just an addendum to my previous post. The 1 ml syringes of 1 mg/ml Chlorpromazine are kept refrigerated in the CVICU Omnicell.
Eddie Hankins, Pharm D
Critical Care Pharmacist
LeBonheur Children's Hospital