USP 797: A FOCUS ON ANTIMICROBIAL RISK LEVEL KAREN MILKIEWICZ, PHARMD

USP 797: A FOCUS ON ANTIMICROBIAL RISK LEVEL KAREN MILKIEWICZ, PHARMD

USP 797: A FOCUS ON ANTIMICROBIAL RISK LEVEL ACTIVITY DESCRIPTION On June 1, 2008, The Revision Bulletin to USP Chapter 797, Pharmaceutical Compounding: Sterile Preparations, became official. The objective of 797 is to describe conditions and practices to prevent harm, including death, to patients that could result from (1) microbial contamination (non-sterility), (2) excessive bacterial endotoxins, (3) variability in the intended strength of correct ingredients, (4) unintended chemical and physical contaminants, and (5) ingredients of inappropriate quality in compounded sterile preparations (CSPs). This monograph will focus on bullet 1): assessing and minimizing microbial contamination in CSPs. TARGET AUDIENCE The target audience for this activity are pharmacists in hospital, community, and retail pharmacy settings. LEARNING OBJECTIVES After completing this activity, the pharmacist will be able to: Identify the purpose of USP 797 and the persons responsible for following this guideline Describe the ISO classification system for particulate matter in room air and how it applies to compounded sterile products Identify and understand the three contamination categories for compounded sterile products Describe the quality assurance methods necessary to determine the safety of a compounded sterile product Review the media-fill test procedure as a test for microbial growth 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 50-3515). 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 http://www.nursecredentialing.org/renewalrequirements.aspx Universal Activity No.: 0798-0000-14-183-H04-P&T Credits: 1 contact hour (0.1 CEU) Release Date: November 11, 2014 Expiration Date: November 11, 2016 ACTIVITY TYPE Knowledge-Based Home Study Monograph FINANCIAL SUPPORT BY Pharmaceutical Education Consultants, Inc. 1

ABOUT THE AUTHOR Karen Milkiewicz has a PhD in Medicinal Chemistry from the State University of NY at Buffalo, a BS in Pharmacy from Rutgers University, and over ten years of experience in the pharmaceutical industry. Karen is a Ph.D. scientist and pharmacist with a strong background in the analytical evaluation of scientific data. Currently, she is working both in drug discovery research and as a medical writer and speaker. Karen Milkiewicz, PhD, RPh Research Scientist II, Teva Pharmaceuticals 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. Karen Milkiewicz 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

Title: You Take My Breath Away - Understanding and Treating COPD USP Regulation <797> is the first enforceable standard for sterile compounding. It was issued by the United States Pharmacopeia and endorsed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). It was originally enacted in 2004 i, and the latest revision became official in 2008 ii. The objective of <797> is to describe conditions and practices to prevent harm, including death, to patients that could result from (1) microbial contamination (non-sterility), (2) excessive bacterial endotoxins, (3) variability in the intended strength of correct ingredients, (4) un-intended chemical and physical contaminants, and (5) ingredients of inappropriate quality in compounded sterile preparations (CSPs). USP <797> is a broad regulation, covering several pharmacy policies and procedures. This monograph will focus on USP <797> as it pertains to antimicrobial risk level. USP <797> was developed in response to situations where patients became sick from contaminated CSPs. The regulation outlines the proper procedures for the preparation of CSPs to lessen this risk. It applies to everyone who prepares CSPs and everywhere they are created. This includes hospitals, clinics, pharmacies and physician offices. The regulation states, It is the ultimate responsibility of all personnel who prepare CSPs to understand these fundamental practices and precautions, to develop and implement appropriate procedures, and to continually evaluate these procedures and the quality of final CSPs in order to prevent harm and fatality to patients who are treated with CSPs. Sterile compounding practices are enforceable by both the FDA and JCAHO. JCAHO compliance with USP <797> is required by all JCAHO-accredited pharmacies. As of 2013, 22 state boards of pharmacy specifically require compliance with USP standards for <797>, and 10 additional state boards of pharmacy have developed rules similar to or reference the USP <797> standards. iii Additionally, pharmacies engaging in sterile compounding that successfully undergo accreditation from the Accreditation Commission for Health Care (ACHC) for Infusion Pharmacy Services receive accreditation certificates that specify their compliance with USP <797>. Compounding personnel have many responsibilities. They must ensure that CSPs are accurately identified, diluted, measured, mixed, purified, sterilized, packaged, sealed, labeled, stored, dispensed, and distributed! In order to fulfill all these functions, these personnel must 3

be adequately trained in several areas, including antiseptic hand cleansing, clean area disinfection, the selection and donning of appropriate protective garb, the maintenance of sterility of the compounding area, the identification and measurement of ingredients, and the ability to manipulate sterile products aseptically. All sterile compounding must take place in a cleanroom. Cleanrooms are areas that are specifically designed to reduce and eliminate contamination, whether particulate or microbial. Cleanrooms are used for the preparation of sterile dosage forms because it is essential to control the cleanliness of both the air and room surfaces. The presence of unwanted particles in the air of a cleanroom is a potential source of microbial contamination. Controlling particle count is done by the use of high-efficiency particulate filters. The guidelines used in the United States to classify clean rooms can be found in the Current Good Manufacturing Practice regulations within the Federal Code of Regulations. 21 CFR Part 210 211. iv Cleanrooms are classified as class 1 to 100,000. A clean room has a controlled level of contamination that is specified by the number of particles of a particular size per cubic meter. Uncontrolled air in an urban environment contains approximately 35,000,000 particles the size of 0.5 micron or greater per cubic meter. The following table describes the classification system for cleanrooms. Class Name Particle Count ISO Class U.S. FS 209E ISO, m 3 FS 209 E, ft 3 3 Class 1 35.2 1 4 Class 10 352 10 5 Class 100 3,520 100 6 Class 1000 35,200 1,000 7 Class 10,000 352,000 10,000 8 Class 100,000 3,520,000 100,000 v 4

The cleanroom must have environmental conditions that are designed to maintain sterility of CSPs. Activities in a cleanroom include manipulations of sterile materials: additions, transfers, etc. This is a critical area because any exposed product is vulnerable to contamination. The aseptic operations must be conducted in a controlled environment. In the immediate area in which sterile compounding is taking place, there must be no more than 3520 particles in a size range of 0.5 microns or larger per cubic meter. This level of cleanliness is known as an ISO 5 cleanroom. There are three contamination categories for CSPs described in USP <797>: low, medium, and high risk level. These risk levels are assigned primarily according to the potential for microbial contamination during the compounding of low and medium risk level CSPs or the risk of contamination for not sterilizing high-risk level CSPs. High-risk level CSPs must be sterilized before being administered to patients. The risk level is assigned according to the probability of contaminating a CSP with microbial, chemical, and physical contamination. Each of the levels has its own requirements for quality assurance which includes a media-fill test. A media fill test is a test used to qualify the aseptic technique of compounding personnel. A growth medium is used to simulate the actual drug product. CSPs compounded under the following conditions are all considered to be a low risk of contamination: 1. CSPs compounded entirely under aseptic processing, where the product and packaging are separately sterilized, and all manipulations and transfers are performed under at least ISO Class 5 conditions. Only sterile materials are used. 2. The compounding only includes transfer, mixing, and measuring of no more than three commercial sterile products. There can be no more than two entries into any one sterile container of sterile product to prepare the CSP. 3. Aseptic opening of ampules, using sterile needles and syringes to penetrate disinfected stoppers, and transferring sterile liquids in sterile syringes into sterile containers. 5

4. The CSPs cannot be stored for more than 48 hours at controlled room temperature (20-25 C), more than 14 days between 2 and 8 C, or more than 45 days frozen between - 25 and -10 C. Examples of low risk compounding would include transfers of sterile dosage forms using sterile needles, or aseptic measuring and transferring with not more than three packages of sterile products. Quality Assurance for low-risk CSPs include the following: Maintenance of ISO Class 5 air quality through routine disinfection and air quality testing, visual confirmation that all compounding personnel are utilizing appropriate protective garments, review of all ingredients to ensure the proper identity and amounts were utilized, and visual inspection of the CSPs for particulates and/or leaking. For low-risk CSPs, the media-fill test procedure must be performed at least annually by every person authorized to compound in a low-risk level environment. This test must simulate the most challenging or stressful conditions encountered during low-risk compounding, and must be completed without interruption. Within an ISO Class 5 enclosure, three sets of four 5 ml aliquots of growth media are transferred with the same 10 ml sterile syringe and needle into separate sealed 30 ml clear vials. The vials are sealed aseptically, and are incubated at 20-25 C or 30-35 C for 14 days. The vials are then inspected for microbial growth. In addition to the typical low-risk CSPs, there is a sub-category of low-risk level CSPs. If the workspace used to compound the products is an isolator, laminar airflow workbench or biological safety cabinet that cannot be located within a class ISO 7 buffer area, the administration of CSPs must commence within 12 hours of their preparation (or less if designated by the manufacturer s package insert). These CSPs with a 12 hour or less beyond use date must meet the following 4 criteria: 1. They shall be compounded in an ISO 5 environment in a segregated compounding area. 2. The segregated compounding area must not have unsealed windows or doors leading to outside or to high traffic areas. 6

3. Personnel must follow cleansing and garbing requirements, and sinks cannot be located adjacent to the area. 4. All the specifications for cleaning and disinfection, training of personnel, and sampling and testing must be followed. A second category of risk levels for CSPs is medium risk-level. Medium risk-level CSPs are categorized as CSPs that are compounded under low-risk conditions but one or more of the following conditions exist: 1. Multiple doses of sterile products are combined to prepare a CSP that will be either give to multiple patients or one patient multiple times. 2. There are complex aseptic manipulations involved. 3. The compounding process is unusually long, for example, awaiting complete dissolution or homogeneous mixing. 4. The CSPs cannot be stored for more than 30 hours at controlled room temperature (20-25 C), more than 9 days between 2 and 8 C, or more than 45 days frozen between -25 and -10 C. Some examples of medium risk compounding include the following: 1. Compounding total parenteral nutrition products into a final sterile container using multiple injections, detachments and attachments of nutrient source products. 2. Filling injection or infusion device reservoirs with more than three sterile drug products and evacuation of air from those reservoirs. 3. Transferring from multiple vials or ampules into one or more sterile containers. Quality assurance for medium-risk level CSPs includes all the requirements for low-risk CSPs, and a more challenging media fill test procedure. For medium-risk CSPs, the media fill test procedure is somewhat different from the low risk CSPs. For medium-risk CSPs, the media-fill test procedure must be performed at least annually, must simulate the most challenging or stressful conditions encountered, and must be 7

completed without interruption. In this procedure, six 100 ml aliquots of sterile growth medium are aseptically transferred via gravity through separate tubing into six separate sterile containers. The containers are separated into pairs, and 5 ml is transferred from the first container to the second in the pair, then vice versa. This is then repeated. After each transfer, the container should be agitated for 10 seconds. After the set of two exchanges, a 5 ml aliquot is removed from each container and aseptically injected into sterile 10 ml vials. The vials are sealed aseptically, and are incubated at 20-25 C or 30-35 C for 14 days. The vials are then inspected for microbial growth. High-risk level CSPs are CSPs that are compounded under any of the following conditions. They are either contaminated or at a high risk to become contaminated. 1. Non-sterile ingredients are incorporated or a non-sterile device is utilized. 2. The following components are exposed to lower than ISO Class 5 air quality for more than 1 hour: a. Sterile contents of commercial products b. CSPs without effective antimicrobial preservatives c. Sterile surfaces where preparation, transfer, sterilization, and packaging of CSPs occur. 3. Compounding personnel are not properly gowned and gloved. 4. Non sterile water-containing preparations are stored for > 6 hours before sterilization. 5. After sterilization, the CSPs cannot be stored for more than 24 hours at controlled room temperature (20-25 C), more than 3 days between 2 and 8 C, or more than 45 days frozen between -25 and -10 C. Some examples of high-risk conditions include the following: 1. Dissolving non-sterile powders to make solutions that will be sterilized. 2. Exposure of sterile ingredients to lower that ISO Class 5 air quality for more than 1 hour. 3. Mixing ingredients in non-sterile containers before sterilization. 8

Quality Assurance for high-risk level CSPs includes all those for low-risk level CSPs. Additionally, a media fill test that is representative of high-risk compounding conditions must be performed semiannually by compounding personnel. The test must simulate the most challenging or stressful conditions encountered, and must be completed without interruption. For this test, the compounder must first make up a non-sterile solution of growth media. 25 ml of this solution must be drawn up in three 30 ml syringes. 5 ml from each syringe is then transferred into separate 10 ml vials. The next 10 ml from each syringe should be injected through a sterile filter into three separate sterile vials, and then repeated for 3 more vials. All the vials should then be sealed and incubated at 20-25 C or 30-35 C for 14 days. In addition to the three risk levels described above, <797> also contains a provision for immediate use CSPs. This provision is intended to account for situations where there is a need for emergency or immediate administration of a CSP, where preparing the CSP under the standard conditions would cause a delay in therapy. Only low-risk preparations can be prepared as immediate use CSPs. There are several conditions that must be met for an immediate use CSP to be exempt from the low-risk level requirements. The compounding process must involve only simple transfer of no more than three commercial sterile packages and not more than two entries into any one package. Hazardous drugs may not be compounded as immediate use CSPs. There are also time limits on the compounding of immediate use CSPs. The compounding procedure must be a continuous procedure and may not exceed one hour. Additionally, administration to the patient must begin within one hour of the start of the preparation. If administration has not begun within one hour, the CSP is to be discarded. In summary, those who are involved in the preparation of compounded sterile products have several responsibilities. It is vitally important that the regulations are followed in order to meet the ultimate goal of delivering safe compounded sterile products to patients. 9

References 1. Pharmaceutical compounding-sterile preparations (general information chapter 797). In: The United States pharmacopeia, 27th rev., and The national formulary, 22nd ed. Rockville, MD: The UnitedStates Pharmacopeial Convention, 2004:2350-70. 2. <797> Pharmaceutical Compounding Sterile Preparations Revision Bulletin. Retrieved from http://www.doh.wa.gov/portals/1/documents/2300/usp797gc.pdf 3. Analysis of State Required Compliance with USP <797> Compounding Standards, International Academy of Compounding Pharmacists, 2013. 4. Clean Room Classification, Pharmacists Pharma Journal, Feb 12, 2010 5. Adapted from Federal Standard No 209E, General Services Administration, Washington DC 20407 (September 11, 1992) and ISO 14644-1: 1999, Cleanrooms and associated controlled environments- Part 1: Classification of air cleanliness. 10

ACTIVITY TEST 1. Which of the following organizations is involved in enforcing USP 797 standards? A. The FDA B. JCAHO C. State Boards of Pharmacy D. All of the above 2. Which of the following U.S. FS 209E classes corresponds to the ISO Class 5 cleanroom? A. Class 10 B. Class 100 C. Class 1000 D. Class 10,000 3. Which of the following risk-level CSPs must be sterilized before administration to a patient? A. Low risk B. Medium risk C. High risk D. Both B and C 4. Which of the following storage conditions are correct for a low-risk level CSP? A. The CSPs cannot be stored for more than 48 hours between 20-25 C or more than 14 days between 2 and 8 C. B. The CSPs cannot be stored for more than 30 hours at controlled room temperature (20-25 C) or more than 9 days between 2 and 8 C. C. The CSPs cannot be stored for more than 24 hours at controlled room temperature (20-25 C) or more than 3 days between 2 and 8 C. D. The CSPs cannot be stored for more than 72 hours between 20-25 C or more than 21 days between 2 and 8 C. 5. With regards to the beyond use date for CSPs that are compounded in an isolator, laminar airflow workbench or biological safety cabinet that cannot be located within a class ISO 7 buffer area, the administration of CSPs must commence within: A. 24 hours of their preparation B. 12 hours of their preparation C. 36 hours of their preparation D. None of these are acceptable, the CSP must be discarded. 11

6. Which of the following conditions shows an example of medium-risk compounding? A. Multiple doses of sterile products are combined to prepare a CSP that will be either given to multiple patients or one patient multiple times. B. Aseptic opening of ampules, using sterile needles and syringes to penetrate disinfected stoppers, and transferring sterile liquids in sterile syringes into sterile containers. C. CSPs compounded entirely under aseptic processing, where the product and packaging are separately sterilized, and all manipulations and transfers are performed under at least ISO Class 5 conditions. Only sterile materials are used. D. Non-sterile ingredients are incorporated or a non-sterile device is utilized. 7. Which of the following is NOT an example of high-risk conditions? A. Dissolving non-sterile powders to make solutions that will be sterilized. B. Exposure of sterile ingredients to lower that ISO Class 5 air quality for more than 1 hour. C. Mixing ingredients in non-sterile containers before sterilization. D. Aseptic opening of ampules, using sterile needles and syringes to penetrate disinfected stoppers, and transferring sterile liquids in sterile syringes into sterile containers. 8. The minimal ISO environment required in order to prepare a CSP with a 12 hour or less beyond use date is. A. ISO Class 4 B. ISO Class 5 C. ISO Class 6 D. ISO Class 7 9. Which of the following conditions are TRUE regarding an immediate use CSP? A. The compounding process must involve only simple transfer of no more than three commercial sterile packages and not more than two entries into any one package. B. Hazardous drugs may not be compounded as immediate use CSPs. C. The compounding procedure must be a continuous procedure and may not exceed one hour. D. If administration to the patient has not begun within one hour, the CSP is to be discarded. E. All of the above 10. The following media fill test must be performed by personnel involved in compounding which of the following classes of CSPs? For this test, the compounder must first make up a non-sterile solution of growth media. 25 ml of this solution must be drawn up in three 30 ml syringes. 5 ml from each syringe is then transferred into separate 10 ml vials. The next 10 ml from each syringe should be injected through a sterile filter into three separate sterile vials, and then repeated for 3 more vials. All the vials should then be sealed and incubated at 20-25 C or 30-35 C for 14 days. A. Low risk B. Medium risk C. High risk 12

D. Both B and C Please submit your final responses on freece.com. Thank you. References i. Pharmaceutical compounding-sterile preparations (general information chapter 797). In: The United States pharmacopeia, 27th rev., and The national formulary, 22nd ed. Rockville, MD: The UnitedStates Pharmacopeial Convention, 2004:2350-70. ii. <797> Pharmaceutical Compounding Sterile Preparations Revision Bulletin. Retrieved from http://www.doh.wa.gov/portals/1/documents/2300/usp797gc.pdf iii. Analysis of State Required Compliance with USP <797> Compounding Standards, International Academy of Compounding Pharmacists, 2013. iv. Clean Room Classification, Pharmacists Pharma Journal, Feb 12, 2010 v. Adapted from Federal Standard No 209E, General Services Administration, Washington DC 20407 (September 11, 1992) and ISO 14644-1: 1999, Cleanrooms and associated controlled environments- Part 1: Classification of air cleanliness. 13