Based on a presentation by Tom N. Petersen, P.E.
Post written by Trish Carney
Highlights of USP 797 (6/1/08 update) Many of the revision points are touched on within the post. However, the following provides a synopsis to clarify revision content breakdown:
- Introduction and Organization of the Chapter
- CSP Microbial Contamination Risk Levels
- Single-Dose v. Multiple Dose Containers
- Hazardous Drugs as CSPs
- Radiopharmaceuticals as CSPs
- Allergen Extracts as CSPs
- Sterilization Methods – three methods were revised and a new section on depyrogenation (removal of pyrogens – endotoxins or exotoxins) added
- Environmental Quality and Control
- Exposure of Critical Sites – exposure to “first air” from HEPA
- Placement of Primary Engineering Controls
- Additional Personnel Requirement
- Personnel Cleansing and Garbing
- Disinfectant and Cleaning
- Five Appendices – shall vs. should, checklists, suggestions for garbing
Overview of USP 797 – June 1, 2008 Update
The purpose of U.S. Pharmacopeia (USP) 797 is to provide the practice standards to help ensure that compounded sterile preparations are of high quality, and is for the pre-administration phase of sterile preparations. It describes the CSP requirements (guidelines, USP 797 procedures and compliance) for CSPs and sets the standards that apply to all settings in which sterile preparations are compounded. Adherence to 797 will reduce the potential for contamination caused by unclean environment, pharmacist error, lack of quality control, incorrect beyond-use dating and other factors. The standard applies to anyone who prepares CSPs and all places where they are prepared. CSPs include drugs, nutrients, biologics, diagnostics and radiopharmaceuticals. The guideline requires environmental controls to include a separate area for compounding that meets a definite level of cleanliness, and monitoring to guarantee that control is maintained.
Important to all preparers and places where CSPs are prepared is that the Joint Commission requires a gap analysis and action plan for USP 797 compliance, and is enforcing USP Chapter 797 within their standards. They may require stricter compliance to 797 than the states’ Board of Pharmacy.
States Board of Pharmacy Positions
The PA State Board posts a Special Notice on their web site which, in part, states that “the provisions of the USP are not part of the Pharmacy Act’s substantive sections or Board regulations.” It further states, “The Board is not authorized to provide advisory opinions or interpretations except through promulgating regulations and adjudicating disciplinary actions, therefore the Board cannot offer any guidance to pharmacists on how to proceed with the new standards set by USP 797 and takes no position on USP 797.” However, in the second half of their statement they caution, “Section 5(a)(12) of the Pharmacy Act provides that the departure from, or failure to conform to, the standards of acceptable and prevailing pharmacy practice is grossly unprofessional conduct. While the Board cannot definitely say that pharmacists will face disciplinary action for the failure to follow USP 797, the possibility does exist.”
USP 797 has been accepted and adopted by several states. It is under review by numerous others. States have the choice to implement 797 exactly or to edit the standards into pharmacy regulations. New Jersey, for example, requires that the buffer zone be an ISO 6 / Class 1,000 clean room.
Compounding Sterile Preparations (CSP) Microbial Contamination Risk Levels
USP 797 assigns each CSP one of five potential contamination risk levels: immediate use, low, low with 12 hours or less beyond use date (BUD), medium, high. The risk level depends on the CSPs compounding environment; its potential for microbial, chemical, and physical contamination; the nature of production of the CSP. It is the responsibility of personnel to determine the correct level.
Barring exemptions for immediate-use (<3) CSPs for non-hazardous sterile drugs only, which must have administration begun within 1 hr. after start of preparation, the levels break down as follows:
- High-Risk Level occurs when CSPs are prepared from non-sterile ingredients, or from sterile ingredients but the environment is below ISO Class 5. It also occurs if more than six hours passes between compounding and sterilization and/or the purity of compounds are not verified by documentation.
- Medium-Risk Level occurs in an ISO Class 5 environment and involves complex procedures, like bulk compounding, which could occur over an extended period. It also includes using pooled sterile commercial products for multiple patients or for one patient multiple times, as in Chemotherapy or pain management administered by an infusion device
- Low-risk level compounding occurs in an ISO Class 5 environment and involves only a few basic, steps. It could apply in reconstituting single-dose vials of antibiotics, simple transfers of sterile products or preparing hydration solutions. There is also a subsection of low risk designed for facilities with no ISO 7 secondary control clean room the low-risk level with 12 hour or less Beyond Use Date (BUD). This category is for those products that are low risk and will be administered within 12 hours of compounding.
Single-Dose vs. Multiple Dose Containers
Single dose vials (SDV), if opened or punctured in a better than ISO 5 area, may be used for up to 6 hours. Opened or needle-punctured single-dose containers must be used within one hour if opened in worse than ISO Class 5 air quality and remaining contents discarded. Opened single-dose ampuls must be discarded and may not be stored for any time period. The BUD for opened or entered multiple-dose containers is 28 days, unless otherwise specified by the manufacturer. Additionally, in Multiple-dose and single-dose sterile products or CSPs for use as multiple-dose applications, combining is forbidden.
Hazardous Drugs as CSPs
The section on hazardous drugs is aimed at protecting handlers from exposure to certain drugs during preparation. It has been revised so that the agents are the same as those listed in the NIOSH guidelines (http://www.cdc.gov/NIOSH/), and references the NIOSH Alert regarding choosing the appropriate Primary Engineering Control (PEC). It recommends PECs that do not recirculate air
When compounding hazardous drugs, a biological safety cabinet (BSC) or compounding aseptic containment isolator (CACI) must be used. All hazardous drugs must be stored and prepared in a negative pressure ISO 7 with an ISO 7 ante area. BSCs or CACIs should be vented to the outside. Of course, waste disposal should be according to state and federal regulations.
Radiopharmaceuticals as CSPs
Highly particulate generating materials, like lead containers, are required to be used for the protection of handlers. ISO Class 8 air is permitted because it is hard to maintain air cleanliness with all of the lead shielding being used.
Therefore, when preparing these CSPs the guidelines are:
- Must be prepared in an ISO 5 containment device in an ISO 8 environment or cleaner
- Principals of ALARA followed (as low as reasonably achievable)
- Allowance for preparation of radiopharmaceuticals under the Low-Risk Level with 12 hr BUD – hot labs in hospitals have better chance of compliance as long as they have ISO Class 5 PEC
Allergen Extracts as CSPs
Unpreserved allergen extracts must fully comply with 797, but most allergen extracts are highly preserved. Preparations using preserved allergen extracts are exempt from certain aspects of USP 797 under certain conditions involving:
- Hand hygiene
- PPE used
- Simple aseptic transfer
- Contain effective amount of preservative
- Single patient only
- Gloves are disinfected with IPA
- Vial stoppers disinfected
- Labeling requirements
Environmental Quality and Control
The related revisions deal with environmental designs and primary engineering control areas, including CAIs (barrier isolators), HEPA filters, buffer and anterooms, and cleanrooms. They clarify ISO cleanliness requirements and placement of equipment in compounding facilities.
- Laminar air flow workbenches (LAFW), BSC, CAI, and CACI contributions can count toward the total number of air changes per hour to meet ISO Class 7 requirements.
- Regarding ISO Class 5 sources, buffer areas and ante areas, there is a circular diagram conceptual representation of the layout concentric circles of control.
- Provide for secondary engineering controls for buffer area and ante area and have HEPA filtered air sources.
- The recirculating ISO Class 5 devices count towards the overall 30 air changes per hour for the buffer Class 7 area.
- Airflow and balance testing are required at installation site.
- There is an exception for CAIs related to providing isolation from the room, if secondary engineering control ISO 7 not available.
Environmental Sampling -
- Designed to demonstrate a suitable environment for aseptic compounding
- Electronic measurement of the total number of airborne particles
- Certification of ISO 5, 7, and 8 environments
- Volumetric air sampling of viable microorganisms
- Glove fingertip monitoring
- Surface sampling
Additional Personnel Requirements
Training requirements -
- Classroom instruction and written exam plus observational evaluation
- Aseptic work practices
- Maintaining ISO Class 5 environment
- Media-fill testing of aseptic work skills
- Outside support personnel must also be trained properly
Cleansing and Garbing -
- Remove outer garments and jewelry, makeup, including earbuds and headsets
- Garb from dirtiest to cleanest parts of body
- Shoe covers, hair covers, beard covers and face masks, even if have no hair
- Hand/arm hygiene
- Disposable non-shedding gowns
- Sterile powder-free gloves compatible w/ IPA
- Repeatedly apply IPA to contact areas of gloves
- Immediate use provision (emergency situation) does not have garbing requirements
- Disinfectant and Cleaning
- Maintenance of compounding areas is overlooked and this was an extensively updated portion of USP 797.
- Designed to reduce bioburden in compounding areas
- Use sterile 70% IPA and germicidal detergent
- To be performed in ISO 5 environment very frequently
- Clean from cleanest to dirtiest
- Use dedicated mops and cleaners
For questions or assistance with regard to indoor air quality and infection control for hospitals, contact Tom Petersen, P.E. at 215-881-9401 or at firstname.lastname@example.org.
USP 797 General Chapter 797 Pharmaceutical Compounding – Sterile Preparations, United States Pharmacopoeia, 2007
Krause, John, USP 797 ‘How Will It Affect Your Compounding Pharmacy?’ Global Society for Contamination Control, 4/7/09, www.gsfcc.org
Thompson, Cheryl, ‘USP Releases Chapter 797 Revision’, Health-System Pharmacy News, 3/12/07
Hung, Joseph C., PhD, ‘Compliance with USP 797 Requirements for Nuclear Pharmacy Facility Design & Environmental Control’, Mayo Clinic Experience,
Kastango, Eric S., ‘A Review of USP’s Updates to Chapter 797: Don’t Just Know About It’, http://www.pppmag.com/
USP 797 Related Organizations:
USP797.org is a privately-owned resource developed to aid public understanding of the USP 797 regulation developed by U.S. Pharmacopoeia, and its JCAHO-mandated schedule for implementation.
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