STERILE COMPOUNDING MEDICATION ERRORS OF CONTAMINATION: WHEN TRAGEDY DRIVES CHANGE JULIE STRICKLAND, PHARMD

Transcription

1 STERILE COMPOUNDING MEDICATION ERRORS OF CONTAMINATION: WHEN TRAGEDY DRIVES CHANGE JULIE STRICKLAND, PHARMD

2 STERILE COMPOUNDING MEDICATION ERRORS OF CONTAMINATION: ACTIVITY DESCRIPTION Particularly in the area of sterile compounding, tragedy from medication error and adverse events related to compounded sterile products (CSPs) are major driving forces behind new guidance and legislation in pharmacy practice today. In the last five years, there are far too many examples of highly publicized adverse events related to sterile compounding errors that serve both as tragic lessons and a call to improve the processes and techniques affecting the overall quality of CSPs. These events range from multistate fungal meningitis outbreaks to bacterial infections of the eye resulting in permanent vision loss and contaminated parenteral nutrition products leading to bacterial infection. This knowledge based program will focus on USP <797> and lessons learned from medication errors associated with CSPs, engaging the participant in both an account of recent contamination outbreaks and the ripple effect of changes occurring in the practice of compounding pharmacy today as a result of these errors. TARGET AUDIENCE The target audience for this activity is pharmacists and pharmacy technicians in hospital, community, and retail pharmacy settings. LEARNING OBJECTIVES After completing this activity, the pharmacist and pharmacy technician will be able to: Identify the four risk levels of compounded sterile products (CSPs). List three required tests for personnel prior to compounding sterile products. Describe proper personnel cleansing and garbing requirements while compounding CSPs. Describe examples of deviations from USP <797> associated with adverse events related to CSPs. Identify how compliance with USP <797> can prevent medication errors of contamination. WHEN TRAGEDY DRIVES CHANGE ACCREDITATION PHARMACY PharmCon, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NURSING PharmCon, Inc. is approved by the California Board of Registered Nursing (Provider Number CEP 13649) and the Florida Board of Nursing (Provider Number ). Activities approved by the CA BRN and the FL BN are accepted by most State Boards of Nursing. CE hours provided by PharmCon, Inc. meet the ANCC criteria for formally approved continuing education hours. The ACPE is listed by the AANP as an acceptable, accredited continuing education organization for applicants seeking renewal through continuing education credit. For additional information, please visit Universal Activity No.: H04-P&T Credits: 3 contact hour (0.3 CEU) Release Date: December 3, 2014 Expiration Date: December 3, 2016 ACTIVITY TYPE Knowledge-Based Home Study Monograph FINANCIAL SUPPORT BY Pharmaceutical Education Consultants, Inc. 1

3 ABOUT THE AUTHOR Julie Strickland is a Pharm.D. graduate of the University of South Carolina College of Pharmacy. She has experience in both chain and independent pharmacy practice, including ownership, with specific interests in patient safety and promoting positive patient outcomes. She now serves in Conway, SC as the Director of Continuing Education here at PharmCon. Julie Strickland, Pharm.D. Director of Continuing Education, PharmCon FACULTY DISCLOSURE It is the policy of PharmCon, Inc. to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) and/or service(s) discussed in an educational activity. Julie Strickland reports no actual or potential conflict of interest in relation to this activity. Peer review of the material in this CE activity was conducted to assess and resolve potential conflict of interest. Reviewers unanimously found that the activity is fair balanced and lacks commercial bias. Please Note: PharmCon, Inc. does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. 2

4 The Driving Forces of Change Public awareness of highly publicized health issues and health related tragedies are two of the driving forces behind advancements in the practice of pharmacy. While public awareness of health issues seems to drive drug development, tragedies related to medication errors and adverse drug events plays a major part in driving new guidance and legislation related to pharmacy practice. There is no better example of public awareness as a driving force in America than the Ebola outbreak of Although researchers have been searching for a cure for the deadly virus for decades, mass attention in the media has thrown the race to the cure into overdrive. Investigational drugs have been sprung into action and reaction, as the public fearfully waits for news of treatment success or failure. Other diseases like diabetes, heart disease, and breast cancer are also highly publicized, highly researched areas due in part to public awareness. In this decade, entire new classes of antidiabetic medications have come to the U.S. market with hopes of improved efficacy, greater tolerability, and fewer side effects. The novel anticoagulants are also paving a new road for prevention of embolic events in some patients with AF (atrial fibrillation) with less tedious monitoring parameters and superiority of varying end-points when compared to traditional treatment with warfarin. Current guidelines recommend targeted, evidence-based treatment of many different forms of breast cancer. It s not to say that these advancements would not occur without public awareness, but with the Susan G. Komen for the Cure campaign in full swing, breast cancer research is in overdrive and donations for research continue to pour in. In the drug development process, the goal is often to discover medications that have improved safety and efficacy, better outcomes, more pleasant dosing and administration, fewer drug interactions, and less cumbersome monitoring parameters. The marketing around the majority of new medications highlights these factors. The flip side of the goal is to avoid negative outcomes in the population that is being treated. In the context of this monograph, negative outcomes include temporary or permanent harm to a patient or even death. Not only can patient harm or death lead to greater public awareness, it also creates cause for scrutiny of each person, process, and organization contributing to the negative outcome. Particularly in the area of sterile compounding, tragedy from medication error and adverse events related to compounded sterile products (CSPs) are major driving forces behind new guidance and legislation in pharmacy practice today. In the last five years, there are far too many examples of highly publicized adverse events related to sterile compounding errors that serve both as tragic lessons and a call to improve the processes and techniques affecting the overall quality of CSPs. These events range from multistate fungal meningitis outbreaks to bacterial infections of the eye resulting in permanent vision loss and contaminated parenteral nutrition products leading to bacterial infection. If looking back beyond five years, the statistics regarding adverse events associated with compounded products are even worse. According to the PEW Charitable Trusts, over 25 compounding errors have been associated with over 1,000 3

5 adverse events, including 89 deaths since While death and permanent harm to patients have launched these medication errors into the national news, the basic fact that most errors go uncaught and unreported emphasizes that every pharmacist, technician, and organization that prepares CSPs should scrutinize every aspect of the process and employ stringent standards of preparation for each product prepared. In the PEW report, contamination of sterile products was, by far, the most common error. USP <797> Sterile compounding is a necessary component of pharmacy practice in many settings. Often medications are needed in a form or strength that is not commercially available. Another way to look at this is individualized medicine or meeting the need of a patient in the dosage form, route, and strength specific to the patients medical needs. In other instances, drug shortages of commercially made products creates an immediate need for product availability. Compounding products from bulk material is one answer to the demand for medication experiencing shortages. No matter what the reason for needing a CSP, standards to ensure a quality finished product are essential. USP <797> describes conditions and practices aimed to prevent harm to patients that could result from microbial contamination, excessive bacterial endotoxins, variability in intended strength, unintended chemical and physical contaminants, and ingredients of inappropriate quality in compounded sterile preparations. The focus of this article will be on microbial contamination leading to patient harm. Within USP <797>, requirements are in place to prevent harm to patients. These requirements cover areas of sterile compounding related to: the environment, including storage; technician and pharmacist training and testing; preparation procedures; cleaning procedures; aseptic technique; personnel monitoring (procedural testing and sampling); end product testing; and beyond use dating (BUD) The Clean Room Environment An area designated for the function of sterile compounding must meet environmental requirements conducive to the safe preparation of these products. The area must be clean, uncluttered, functionally separated from other areas of the pharmacy, and maintain a state of control with regards to temperature and freedom from contamination. Hazardous drugs are not to be stored with other inventory and have sufficient exhaust ventilation to keep the air clean. Even the actual building materials recommended for the clean room environment are specified within USP <797>. For example, porous materials like grout between floor tiles is not 4

6 allowed in the clean room. Cardboard is also not allowed in the cleanroom. Only supplies necessary to perform compounding should be in the clean room. Any unnecessary supplies or furniture should not be present because logistically every additional item in the clean room will require more effort to maintain the clean environment. Even fatigue mats are discouraged due to the difficulty of removing and cleaning both sides of the mats each day. Although cleaning is essential to maintaining a state of control within the clean room, it is only effective if done properly. Cleaning should begin with the cleanest area and move to the dirtiest area in one direction linear wipes while working from top to bottom and toward the door. Keep in mind the effect of all cleaning activities on the cleanroom environment. A cleaning frequency schedule is essential to the environment of the clean room. According to USP <797> there is a minimum cleaning frequency that should occur within the clean room. Cleaning Frequency Site Primary Engineering Controls (work surfaces) Primary Engineering Controls (all inside surfaces) Countertops and easily cleanable work surfaces Floors Walls Ceilings Storage shelving Carts, doors, refrigerators, incubators Minimum Frequency At the beginning of each shift Before and after each batch After spills Every 30 minutes during continuous compounding When surface contamination is known or suspected Daily Daily Daily Monthly Monthly Monthly Monthly Maintaining a state of control over the quality of air is also important to the clean room environment. The International Organization for Standardization (ISO) class defines how many particles of a particular size are permitted in the air of each particular class. The lower the ISO class, the more controlled the particle sizes are within the air. An ISO class 9 is considered uncontrolled and would contain a particle size count similar to the air outside in a city. An ISO 5

7 class 5 represents the highest particle size count that can be in the environment of a clean room used to prepare CSPs with a limit of 3,520 particles the size of 0.5 microns or greater per cubic meter. Below is a visual representation of the number of particles allowed in each ISO class environment according to the size of the particles in the air. Max concentration limits (particles/m 3 of air) for particles equal to and ISO Class larger than the considered sizes shown below 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm , ,000 2,370 1, ,000 23,700 10,200 3, ,000, , ,000 35,200 8, ,000 83,200 2, ,520, ,000 29, ,200,000 8,320, ,000 Risk Level of the CSP CSPs can be classified based upon the complexity and number of manipulations involved in the compounding, as well as whether the starting products and materials are sterile or not. The risk level determined is later used to assign beyond use dating for the compounded product and also helps determine whether finished product sterility testing needs to be performed. Immediate use CSPs are prepared and administered immediately. This type of compounding may be seen anywhere that there is an immediate need for a medication such as the ER, OR, ICU, or sometimes in clinics. Although these products are not manipulated under sterile conditions, effort should be made to assure that contamination does not occur. Because these products are not mixed under sterile conditions, they must be immediately administered to the intended patient within an hour to lessen the risk of microbial growth. Low-risk compounding involves simple admixtures compounded using closed system transfer methods that are prepared in an ISO Class 5 laminar airflow workbench (LAFW). The starting products are sterile commercial drugs and the complexity of the compound is limited to only a few, simple, aseptic transfers and manipulations. Examples of low risk compounding include: single transfers of sterile dosage forms from vials, ampules, and bags using sterile syringes with sterile needles such as reconstitution of single-dose vials of antibiotics or preparation of hydration solutions measuring and mixing no more than three sterile manufactured products 6

8 Medium-risk compounding involves admixtures compounded using multiple additives and/or small volumes. Sterile starting products are used, just as in the case of low-risk compounding, however more complex manipulations may be required. All compounding that is performed in batches is considered medium-risk. These batches may be intended for use by multiple patients or one patient with multiple times. Compounding takes place in an ISO Class 5 environment. Examples of medium-risk compounding include: filling reservoirs of injection and infusion devices with sterile drug products (chemotherapy or pain management) compounding of total parenteral nutrition fluids using manual or automated devices transferring volumes from multiple ampules or vials into a single final sterile container or product (pooled admixture) batch preparation of syringes batch preparations that do not contain bacteriostatic components and will be administered over several days (chemotherapy or pain management ) High-risk compounding involves non-sterile starting ingredients and are often compounded using open system transfers. These compounds are also prepared in an ISO Class 5 environment. Examples of high-risk compounding include: using non-sterile bulk powders or starting materials to make solutions which will be terminally sterilized (such as morphine) measuring and mixing sterile ingredients in non-sterile devices before sterilization is performed sterile ingredients, components, devices and mixtures are exposed to air quality inferior to ISO Class 5 Pharmacist and Technician Training and Testing The training for both pharmacists and technicians must occur prior to making any CSP for patient administration and must occur again upon any evidence of a break in proper technique. Recertification of technique must be performed annually and records of training hours, process validation, and quality testing/sampling results should be documented. Although USP <797> currently does not specify the number of training hours required for pharmacists and technicians, documentation of training hours is required. Some state boards of pharmacy have specific requirements for training hours. In Texas, for example, pharmacists are required to complete 20 hours of training in sterile compounding and aseptic technique. The course must include written exams, process validation and aseptic technique demonstration, along with media-fill, gloved fingertip, and surface testing. Technicians must complete 40 hours of training in the same areas. There are three different tests required for sterile compounding personnel. They are used to demonstrate effective aseptic technique of compounding personnel. Aseptic technique is ideally taught hands on by personnel capable of consistently demonstrating the technique. The three required tests ensure that properly demonstrated technique translates to an aseptic 7

9 product. These tests are all performed under the same conditions that the compounder would experience when actually preparing a sterile compound. The media-fill test reveals the ability of personnel to aseptically mix a CSP. Growth medium is manipulated in the same manner that a compound is mixed. If the medium grows anything after the test is complete, contamination occurred and more training is necessary to assure aseptic technique is mastered. Media-fill tests are performed initially and annually to assure continued adherence to aseptic technique. Gloved finger-tip sampling the second test required by USP <797>. It is designed to test for the ability of personnel to aseptically gown and glove without introducing contaminants to the sterile garb. After garbing, the personnel touches each gloved fingertip onto contact agar plates just enough to leave an impression to test for contaminants on the glove. This sampling must be successfully demonstrated three times initially and then also annually. Periodic surface sampling of the environment is also required by USP <797> although the timeframe of this periodic testing is not clearly defined. Surface samples reveal the ability of personnel to properly clean the surfaces (counter, hood, walls, floor, etc.) of the cleanroom. In order to properly clean the compounding room, it is important to know what cleaning agents to use and how often to clean each surface of the cleanroom. Cleaning agents will include sterile water for diluting high potency disinfectants, sterile alcohol, germicidal detergent, a sporicidal agent, and bleach or other agent to deactivate hazardous drugs. Sporicidal agents are necessary because while disinfectants, like sterile alcohol, are efficacious for reducing or eliminating bioburden, they do not remove spores. Garbing and Personnel Requirements In order to provide the cleanest environment possible, personnel should not wear makeup, jewelry, perfumes, or artificial nails. Natural nails should be maintained according to organization policy. The order of garbing is important to reducing the amount of contaminants introduced into the clean room. After all, the human body sheds over 1 million skin cells per hour and microorganisms can be found all over human skin cells. The garbing order is as follows: 1. Hair cover, facemask, and beard/eye cover (in any order) 2. Shoe covers: most typically donned one at a time while stepping over the line of demarcation (from dirty to clean) 3. Hand hygiene up to the elbows must last a minimum of 30 seconds in warm water and soap and the use of a nail pick is necessary to clean under nail beds. 4. Low-linting gown (does not have to be sterile) 5. Perform antiseptic hand cleansing with waterless alcohol-based surgical hand scrub with persistent activity. Allow hands to dry. 6. Sterile gloves 8

10 The degarbing order is as follows: 1. Walk out of the cleanroom and into the ante area (area adjacent to the primary engineering control room in which preparations for admixtures are gathered, including labels, gowning, and drug materials) before removing and discarding sterile gloves 2. Remove face mask and gown 3. Keep hairnet, facial hair cover, and shoe covers on until on the dirty side of the line of demarcation 4. Wash hands 5. Exit the area and discard the remaining cleanroom garb End Product Testing and Environmental Monitoring USP Chapter <71> provides guidance for sterility testing by membrane filtration. It is important to note that for batches of more than 25 high-risk CSPs, sterility testing is required. Sterility testing is also required if storage limits are exceeded or if more than 6 hours have lapsed before a CSP is sterilized. Electronic air sampling is required by USP <797> every 6 months. This test the air coming into the clean room. Surface sampling is also used to monitor the environment periodically for use of appropriate cleaning solutions and to test for any non-visible contaminants or microbial resistance to cleaning agents being used. In an ISO Class 5 environment surface samples that reveal greater than 3 colony forming units (CFU) per plate or electronic air samples that reveal greater than 1 CFU/1000 liters of air per plate require action on the part of the organization. Beyond Use Dating (BUD) According to Risk Level Unless manufacture labeling differs from the chart below, this is an interpretation of the standard for BUD described by USP <797>. When considering the implications of BUD and contamination growth, it is essential to adhere to BUD recommendations unless sterility testing is performed on every batch. Beyond Use Dating for CSPs by Risk Level Risk Level Room Temperature (20 to 25 C) Refrigeration (2 to 8 C) Frozen (-25 to -10 C) Immediate use 1 hour - - Low risk not in a clean room 12 hours 12 hours - 9

11 Low risk 48 hours 14 days 45 days Medium risk 30 hours 9 days 45 days High risk 24 hours 3 days 45 days The Tragedies that Forced National Awareness Unsafe practices in compounding pharmacies are a major public health concern due to the potential for adverse events in patients- including death. Throughout the years, drug shortages and lack of proper equipment or staffing has forced hospitals to outsource the compounding of sterile products. Although some would argue that outsourcing to a well-equipped, properly trained compounding pharmacy should lower the incidence of adverse events, it is imperative to have confidence that the outsourcing pharmacy follows all available standards to produce high quality products. While an error in an in-house pharmacy may affect patients in that one particular facility, errors made in a large scale compounding facility may affect patients in many different settings or even states. The following tragedies all involve contaminated CSPs. Parenteral Nutrition Medication Error In 2011, there were 19 cases of Serratia marcescens bacterial infections, including nine deaths, associated with contaminated parenteral nutrition (PN) products. The compounded PN products were prepared and used in 6 different hospitals in Alabama. Upon investigation into the source of the infections, the common characteristic among the victims was the PN product. Environmental sampling at the pharmacy revealed Serratia marcescens in samples taken from the anteroom tap water faucet in the facility that was genetically indistinguishable from the same microbial organism found in the PN isolate of the deceased patient. Using tap water that is not sterile to rinse mixing containers without sterilizing the equipment prior to use is not an acceptable practice to engage in whenever the final product is to be used in a central IV line. The risk of contamination is too great and the consequences are far too costly. In this case, of 19 patients that received the contaminated product, 9 died and the other 10 suffered serious injury. Ophthalmic Injection Medication Errors Repackaging of single-dose 4mL vials of bevacizumab (Avastin) into individual use tuberculin syringes for use in ophthalmic procedures has over the years rendered a history of causing patient harm. Because ophthalmic use of Avastin for neovascular age-related macular degeneration is off-label and not available from the manufacturer in individual-use syringes, there is a necessity for compounding pharmacies to repackage the bevacizumab by method of sterile transfer into individual-use tuberculin syringes. Sterile transfer of a product from a nonsterile product is risky due to the number of factors that can introduce contaminates. When compounding bevacizumab using and demonstrating acceptable standards of sterile 10

12 compounding, there is a low incidence of infection. However, there are far too many examples of pharmacies failing to implement and consistently demonstrate the necessary standards to ensure sterility of the products compounded. The following are some of the findings involved in just a few of the larger outbreaks that have occurred in the last five years although there are several other incidences. In 2010, FDA investigated a cluster of Streptococcus endophthalmitis bacterial eye infections in patients who received injections of bevacizumab (Avastin) repackaged by a pharmacy in Tennessee. From the nine reported cases of adverse events, four patients lost eyesight and one patient developed meningitis and encephalitis. During observation of the pharmacy, a mask was not worn and the personnel preparing the compounds was observed speaking during preparation. The laminar flow workbench also had no vertical barrier. Although the source of the contamination was not directly discovered in this case, the practices involved in the compounding of the product left many potential sources of contamination error. In a different pharmacy a year later, history repeats itself when in 2011, 12 patients developed severe endophthalmitis following intravitreal injection of repackaged bevacizumab (Avastin) from a pharmacy in Florida. During the FDA investigation of these reports, the cultures from unused prefilled syringes of bevacizumab revealed Streptococcus mitus and oralis. Both agents were involved in the patients experiencing endohthalmitis. Of the 12 patients documented, 3 underwent enucleation or evisceration (removal of the eye or parts of the eye) due to the severity of infection. What could have gone so wrong during the sterile transfer of this medication from vial to syringe that adversely resulted in 3 patients literally losing their eye? During the FDA investigation of the pharmacy, it appears that what should have been sterile transfer may not have been sterile at all. Some of the multiple violations that could have led to contamination included observation of, products that were stored and prepared under unsanitary conditions (lack of proper environmental monitoring) and evidence of inadequate training regarding aseptic technique. Specifically, employees were observed handling sterile products with non-sterile gloves and leaning into the laminar flow hood with both their heads and torso. The facility was also noted to fail to conduct any finished product testing on batches of medications. While all of these deviations are considered unsafe practices and all increase the opportunity for contaminants and adverse events, one particular compounding practice stands out the most. The enforcement letter to the pharmacy noted that bevacizumab (Avastin) vials were used over a period of days or weeks following the puncture of the vial plunger. This is in direct conflict with the package insert for the product which states: discard any unused portion left in a vial, as the product contains no preservatives. Everything that was going to be used from the vial should have been used all at once, not left on the shelf to be used again. This error, along with the list of unsafe practices involved in the compounding of this product, most certainly was a recipe for disaster. Before manipulating any commercially made product in any way, it is imperative to gather information provided by the manufacturer, or from current literature that can aid in the preparation of these products. This type of information is needed to determine not only proper storage and handling of the medication, but also expiration dates, and beyond-use dates. 11

13 Clearly, from this reported observation, using a single use product multiple times over more than one day is an error. Even after a long history of adverse events from compounded Avastin products, yet again in 2013, the FDA investigated reports of five cases of eye infections in patients who received Avastin repackaged by a pharmacy in Georgia. Two lots of bevacizumab (Avastin) were contaminated with bacteria. The affected lots of repackaged bevacizumab were distributed to doctors offices in Georgia, South Carolina, Louisiana, and Indiana. Of the five cases, four were reported in Georgia and one case was reported in Indiana. Poor aseptic practices on the part of pharmacy personnel was cited in the FDA warning letter as a possible source of contamination. Specifically, a sporicidal agent was not used as part of the disinfecting program for the clean room and ISO class 5 area (the area in immediate proximity of exposed sterilized containers/closures and filling/closing operations). Also there was equipment and supplies that were not sanitized prior to placement into the ISO class 5 sterile compounding area. With such a long history of problems associated with repackaging bevacizumab (Avastin), why do ophthalmologists continue to use this off-label sterile compound when there are two products on the market that have been approved for wet age related macular degeneration. The answer is simple. While ranibizumab (Lucentis) and aflibercept (Eylea) represent FDA approved options for treatment of wet age related macular degeneration, they are extremely costly. Bevacizumab offers a much more economical alternative that is enticing to both providers and patients. According to ophthalmology literature, when compounded under proper sterile conditions, there are no distinguishable clinical outcomes between the FDA approved therapies and those of bevacizumab. Steroid Injection Medication Error In recent history, the outbreak that has caused the greatest number of adverse events, with a total reported case count of 751 patients, including 64 deaths, is the 2012 multistate fungal meningitis outbreak. This infectious outbreak is associated with injection of pre-filled methylprednisolone acetate from a single compounding pharmacy. This outbreak affected patients in 20 different states and resulted in cases of meningitis, paraspinal/spinal infection, stroke, and peripheral joint infection. The states that reported the highest number of paraspinal/spinal infections correlated to the highest number of deaths in patients among all of the reported adverse events. All of these reported cases have one common denominator; the pharmacy that prepared the medication for injection. In an interview with the CBS News report 60 Minutes, a former technician of the pharmacy that produced all of the contaminated methylprednisolone products was frank when he attributed the potential causes of fungal contamination to employees being overextended and becoming sloppy in the execution of daily activities in the cleanroom. He stated that several times a year mold was found in the cleanroom and they cleaned up as best they could. He also claimed that employer greed led to shortcuts in operations. This statement is validated in the FDA s investigation that discovered the clean room air conditioner was shut off between 8:00 pm and 5:30 am. Given the importance of particle size monitoring and air quality in the clean room, turning off the air 12

14 conditioning every evening would alter the temperature and stability of the products contained in the clean room. At that time, there was no legal platform for a compounding pharmacy to produce large quantities of compounds to supply hospitals and clinics without a valid prescription for each compounded product. A former sales representative for the company, however, described providing compounds to clients with falsified names to use for documentation that the company was producing compounds pursuant to a prescription. Those patients that lived after becoming infected with fungal infection after being injected with the contaminated products are subject to a long difficult battle with unpleasant treatments for their infections. One woman described being in the hospital seven different times for a total of 75 days due to her ongoing fungal infection. In the FDA s investigation report, a long list of problems existed within the clean room of the New England Compounding Center starting with environmental sampling that revealed bacteria and mold samples within the clean room. The report noted discrepancies in record keeping of validating sterile samples. Specifically, although the pharmacy documented a sterile sample from a batch of medication still on premises, the FDA found microbial growth in 50 out of 50 vials sampled from the same lot number as the one reported by the pharmacy to be sterile. From one particular lot, 83 out of 321 vials of methylprednisolone revealed a greenish black foreign matter and 17 vials were observed to contain white filamentous material. Also noted in the report, was a lack of documentation of the effectiveness of the steam autoclave cycle used to sterilize non sterile raw materials. Neither the labeling of the methylprednisolone nor the other raw materials, with exception of the sterile water for injection, indicated that the products were sterile. The guidance of USP <797> is intended to serve as just that, a reference as to the minimal standards necessary to compound quality sterile products. Clearly, although this pharmacy appeared to go through the motions of compliance and with the naked eye appeared to have a top notch clean room, rigorous measures to ensure sterility were not a priority. The results of these failures were tragic and needless. For the patients that lost their lives and others that have suffered a long battle of fungal infection, the unclean environment of the compounding area in this pharmacy is not justifiable under any circumstance. Training and strict adherence to available standards are essential to patient safety and reduction in the number of adverse events from CSPs. Is Product Contamination Really a Medication Error? The National Coordinating Council for Medication Error and Prevention has approved the following as its working definition of medication error: "... any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems including: prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." 13

15 Indeed, if an adverse event occurs or has the possibility of occurring due to a sterility issue associated with a CSP, by definition a medication error has occurred. Contamination is not the only type of error that can potentially lead to an adverse event. Incorrect ingredients (the identity or the purity of the ingredient) and incorrect strength due to inaccurate measurements, instabilities, or incompatibilities are also errors that can lead to adverse events. Certain steps must be taken to ensure removal of contaminants from sterile products by adhering to controls that safeguard against contamination during preparation. Without controls in place, infections and/or pyrogenic responses that pose a life-threatening health risk may occur. This is evident from all of the tragic contamination cases included as examples. Preventing Errors of Contamination Assuming the organization has established a proper cleanroom environment and has the available resources to monitor the environment of the cleanroom, what responsibility does sterile compounding personnel, whether technician or pharmacist, have to the integrity of the final sterile product? The answer is that all responsibility falls on each person that could influence the integrity of the finished product in any way. Especially when it comes to contamination, every compounder should keep in mind that the final product produced will be administered to a patient and has the potential to help or harm the patient. Typical sources of contamination include the air and water supply, non-sterile equipment and materials, employees, and dirty surfaces. Compliance to USP <797> has the potential to significantly reduce medication errors related to all of these typical sources of contamination. While diligence to maintaining the environment of the cleanroom will go a long way toward reducing the chance of contamination of CSPs, skipping or deviating from procedures can lead to contaminated products and adverse events like those in the examples used in this article. One example of an easy way to contaminate the environment of the clean room is to forget a necessary supply once compounding has begun and leaving the clean room to retrieve the item. If it is necessary to leave the clean room, degarbing and garbing again must occur before re-entry into the clean room. Having an inspector mentality is one way to keep alert as to the conditions of the cleanroom. Overlooking a discoloration on a surface or failing to properly clean a spill can be detrimental to the delicate environmental balance of the clean room. Accurate documentation of sampling and testing results, actions taken in response to any contaminant findings, and results of retesting are also key components of safety and reduction of medication errors. Always work on one patient or one batch at a time. This will keep the compounding area free of clutter and reduce the chances that ingredient or amount of ingredient mix ups will occur, especially with special population compounds or batches, like those intended for pediatric or neonatal use. Following organization procedures (along with USP <797> requirements) for wiping down the surface of drugs and supplies with an agent, such as sterile 70% isopropyl alcohol, prior to 14

16 bringing them into the ISO Class 5 area. After moving supplies and drugs into the ISO Class 5 sterile compounding area, disinfect gloved hands prior to beginning compounding. Labeling and compounding documentation should occur outside of the ISO Class 5 area. One way to catch any errors that may have occurred while compounding is to reconcile that the components brought into the compounding area prior to compounding are removed afterwards. More than expected yield in a batch and unused vials are examples of errors that can be identified in the reconciliation process. Current Standards for Sterile Compounding How many more patients need to be harmed before all compounding pharmacies are held to the same standards to ensure that the practices involved in production are sufficient to ensure a final product free of contamination? Every day, quality compounded products are prepared using safe standards of sterile compounding at hundreds of pharmacies across America. Will more government oversight decrease the number of sterile compounding errors that lead to adverse events? In the aftermath of outbreaks and tragic events, like those that occurred as a result of the NECC contaminated CSPs, those involved in oversight work diligently to scrutinize the source of the problem and prevent future occurrences. Often, these events lead to more stringent regulation and greater oversight of the standards. Look at the food industry as an example. Because of the potential to cause public harm, government agencies regulate almost all aspects of the food industry at both federal and state levels. These agencies set food safety standards, conduct inspections, and enforce the standards. Government agencies also release food safety recalls and tracks outbreaks back to potential sources, in much of the same ways that drug recalls and health related outbreaks are tracked and reported. As government oversight over compounding increases, this situation of a contaminated CSP or potential for contamination mirrors the oversight involved in the food industry. Rather than someone becoming ill after eating food from a restaurant that was not cooked to a proper temperature, patients become ill because they are subjected to pathogens that could have been avoided had proper measures been taken to ensure sterility. Environmental conditions are also key components to the safety of CSPs much like the conditions in which food is prepared. Dirty surfaces, improper airflow, and unregulated temperatures can all contribute to tainted products. Upon inspection, food facilities are rated based on their inspection so that anyone who receives food from the facility is aware of the rating. If a facility or restaurant is upholding high standards the rating will reflect that, and consumers will have confidence that the food they consume is safe. Like the food industry, both pharmaceutical manufacturers and traditional compounding pharmacies have guidelines that must be followed in order to produce quality sterile products. USP <797> is the current standard used or adopted by most organizations that participate in sterile compounding. Several organizations have developed guidance and resources that are available to aid in the standardization and improvement of the processes involved in sterile compounding. USP chapter <797> is dedicated solely to sterile compounding. The chapter is currently under revision, however, and the target date for revisions has not been released. 15

17 Further guidance can be found from the American Society of Health-System Pharmacists (ASHP) which has developed a guide to implementation of USP <797> and from the Institute for Safe Medication Practices (ISMP) in the document Proceedings from the ISMP Sterile Compounding Safety Summit; Guidelines for Safe Preparation of Sterile Compounds. The shortfall of these resources, including USP <797> is that it was intended for traditional pharmacy compounding and not for the bulk manufacture of drug products. Unlike traditional pharmacies that compound, the pharmaceutical industry that produces bulk products is subject to rigorous regulations, called Current Good Manufacturing Practices (CGMPs) that are enforced by the FDA and define and safeguard critical aspects employed in the manufacture of all drugs. CGMPs serve as minimum guidelines for practice in the manufacture, processing, packing or holding of drug products. As part of CGMPs, pharmaceutical products are sterilized after the finished product is sealed, further ensuring that contaminants are not present. By following the rigorous standards of CGMPs, there is assurance that the drug products have been produced in a manner that ensures a consistent and quality product that is free of contaminants. Traditional compounding relies on aseptic technique, accuracy of the compounder, and a properly cleaned environment to ensure lack of contaminants. While guidance, like CGMPs, exist for the pharmaceutical industry, most state boards of pharmacies adopt at a minimal the standards of USP <797> for pharmacies that prepare CSPs in a traditional compounding pharmacy. As pharmacies evolve into a compounding role that does not fit the traditional definition of patient specific compounding, oversight and standards must evolve also. In November of 2013, The Drug Quality and Security Act (DQSA) established a new regulatory category to cover the pharmacies that fall under this evolving role of large scale compounding. Under Section 503B, a compounder can now become an outsourcing facility and qualify to have certain exemptions from the FDA drug approval requirements and also from some of the product labeling and directions for use requirements. This new class will cover pharmacies that have evolved beyond the traditional role of compounding pursuant to a prescription. According to the new law, this large scale bulk compounding facility will be inspected by the FDA according to a risk-based schedule. Organizations that are known to compound high risk products will be inspected more often than those compounding low risk products. Since the standards set by USP Chapter <797> were never intended to be used beyond patient specific compounding, there is a race to revise or create new standards to accommodate this newly formed classification of large scale compounding pharmacies. As these standards are created there are specific areas that need to be addressed that are not adequately covered by USP <797>. Proper evaluation and qualification of non-sterile starting ingredients, an environmental monitoring system, and clear processes to validate production are provisions that are enforced under CGMP regulations, but are not well addressed in USP <797>. With a long history of contaminated products associated with compounding products, provisions that specifically address issues like these will be necessary in the standards for large scale compounding facilities. 16

18 Confidence in Outsourcing Compounding Pharmacies If outsourcing to a large scale compounding pharmacy is to be considered a way to decrease the risk of contamination in sterile products, there must be a method for an organization to prove or demonstrate the quality of their products and the standards used to prepare compounded products. Where traditional pharmacy compounding was originally intended to be patient specific pursuant to a prescription, bulk compounding pharmacies have emerged due to the demand for the products on a broader scale. As in the case of the NECC contaminated products, medications prepared in bulk were reaching pharmacies in states all over the U.S. increasing the health risk to a greater number of people. Voluntary registration of outsourcing compounding pharmacies with the FDA is one way that hospitals and clinics will have confidence in the products that they receive. Registration will be evidence that the compounding pharmacy is subject to FDA oversight and inspection. Outsourcing compounding pharmacies that choose not to register with the FDA will be subject to either traditional pharmacy standards or manufacturing standards. Since large scale compounding pharmacies do not fit well into either of these categories, expect a regulatory nightmare for those pharmacies that choose not to register with the FDA. Expected future updates to USP <797>, will hopefully address issues related to quality assurance for outsourcing facilities (bulk compounding) as well. Final Thoughts Although no one may ever know the exact cause of contamination of each of the tragedies included in this article, lessons can be learned based on inspection reports and documented deviations from USP <797> in each of these cases. The most important lesson is that diligence and unfaltering compliance with USP <797> could have prevented all of the adverse events and deaths that occurred as the result of poor quality and lack of environmental controls. In a growing market demanding more and more CSPs, close inspection of pharmacies and stringent organization procedures following the standards of USP <797> will provide assurance of quality and safe compounded sterile products. 17

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20 The Pew Charitable Trusts. Ensuring the Safety of Compounded Drugs: Study Highlights Key Quality Standards. May 21, Available at: Accessed 11/4/14. The Pew Charitable Trusts. U.S. Illnesses and Deaths Associated With Compounded Medications. September 5, Available at: Accessed 11/10/14. Frost BA, Kainer MA. Correspondence: Safe preparation and administration of intravitreal bevacizumab injections. New England Journal of Medicine. Dec. 8, (23):2238. Available at: Accessed 11/11/14. Berg K, Pedersen TR, Sandvik L, Bragadottir R. Ophthalmology. Comparison of Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration According to LUCAS Treat-and-Extend Protocol. September 13, Available at: ; Accessed 11/11/14. Selid PD, Jundt MC, Fortney AC, Beal JR. Intravitreal bevacizumab and aflibercept for the treatment of exudative age-related macular degeneration. Ophthalmic Surgery, Lasers, & Imaging Retina. Jul-Aug Available at: Accessed 11/11/14. US Food and Drug Administration (FDA). Compounding Quality Act Title I of the Drug Quality and Security Act of g/ Accessed November 4, CBS News. Lethal Medicine Linked to Meningitis Outbreak. Published on March 10, Accessed 11/5/14. Food and Drug Administration. Praphon Angtrakool. International Standard ISO Cleanrooms and associated controlled environments. August 21, Available at: Accessed November 5, Eric Kastango. Watch Your Step: IV Room Flow with USP 797. ClinicalIQ. Accessed November 11,