Proposed Revisions to USP Chapter <797>
Pharmaceutical Compounding – Sterile Preparations

This proposed document was compiled by Dr. David W. Newton. Dr. Newton is chairman of the 2000-2005 Sterile Compounding Committee, SCC, of the Council of Experts of the United States Pharmacopeial Convention, Inc., USP. The complete text of the proposed revisions to <797> are also summarized in future publication of IJPC and the full proposed text of <797> will be published in a future 2005 issue of USP's bimonthly official journal, Pharmacopeial Forum, PF. Comments on this summarized proposal should be directed to Dr. Claudia Okeke at cco@usp.org. Please continue to check our website for the date of publication of the full text in PF.

Dr. Newton and Mr. Lawrence A. Trissel, an SCC member, authored a description of the history and rationale of <797>, and USP process in the July/August 2004 IJPC.1

Introduction

When <797> was introduced officially in the 27th Revision of the United States Pharmacopeia, USP 27, on January 1, 2004,2,a it became enforceable by the U.S. Food and Drug Administration. It has since been adopted by some pharmacy regulatory and accrediting bodies, especially some U.S. state boards of pharmacy, and the Joint Commission on Accreditation of Health Care Organizations, JCAHO. As of January 1, 2005, USP 28 is the official source of <797>.3,a

In 2004 on May 14-15, August 6-7, and November 12-13, the USP conducted packaging and compounding workshops in Rockville and Gaithersburg, MD, for which total attendance was approximately 400-500 persons; mostly hospital pharmacists. The predominant audience interest was asking questions related to <797>, which were addressed by SCC members, Dr. Samuel Augustine, Dr. Newton, and Mr. Trissel; Dr. Darryl Rich of JCAHO; and Mr. Eric Kastango, a private pharmacist consultant. Hundreds of questions and comments about <797> were raised at those three workshops, and emailed to USP before and after them. The SCC met October 13-14, 2004, during and within five weeks following which it approved the proposed revisions to <797> that are summarized here.

Summary of USP Revision Process

The process to create or revise USP content, which includes opportunity for public involvement, is described in the front pages of each bimonthly issue of USP's official journal, Pharmacopeial Forum, PF. Following is a four-step outline of this process as it applies to <797>:

1. The SCC considers internal (from USP volunteers and staff) and external (from public sources, "PF provides interested parties an opportunity to review and comment...") comments.
2. A draft containing both current official content and proposed revisions is published in PF.
3. A period of several weeks elapses for opportunity to receive public comments.
4. The SCC reviews received comments, then determines whether additional revision is necessary before the next version is published in PF as an Interim Revision Announcement, IRA, which bears a date for official USP adoption.

The cycle of steps 1-4 may be repeated; thus, one or more years could elapse between currently official <797> in USP 28 and the next official <797>. The next official <797> will appear either in an annual USP revision, e.g., USP 29 in 2006, or in one of the two semiannual supplements to each annual USP revision. The earliest possibility, but an unlikely probability, would be Supplement 2 to USP 28 in late 2005.

Summary of Proposed Revisions to <797>

The revisions to <797> proposed by the SCC during and following the October 13-14, 2004 SCC meeting are condensed in Table 1 (content that is not in <797> in USP 27 and USP 28) and Table 2. These tables are intended to succinctly present the substantive changes in practice standards and important clarifications in the proposed revisions. The <797> section titles and (locations) of proposed revisions are centered in Arial font, under which the proposed revisions are denoted by squares, . The proposed revisions in both tables are listed in order of their occurrence in <797>. With selected proposed revisions, there is some explanation in [brackets], which will not appear in <797>.

Table 1. New Definitions and Standards Proposed for USP Chapter <797>.
Definitions (at end of INTRODUCTION)  PREPARATION. A preparation, or compounded sterile preparation, CSP, is a sterile drug or nutrient prepared in a licensed pharmacy or other health care related facility pursuant to the order of a licensed prescriber, which may or may not contain sterile products.  PRODUCT. A product is a commercially manufactured sterile drug or nutrient that has been evaluated for safety and efficacy by the U.S. Food and Drug Administration, FDA. Products are accompanied by full prescribing information, which is commonly known as the FDA-approved manufacturer's labeling or product package insert.
Immediate Use Exemption from ISO Class 5- (after Low-Risk Conditions- within the Low-Risk Level CSPs section)  Three or fewer sterile products may be prepared in worse than ISO Class 5 air when there is no direct contact contamination, and administration begins within 1 hour and is completed within 12 hours of preparation. [This exemption has been honored by the JCAHO in 2004].
Proprietary Bag and Vial Systems — (after Immediate Use Exemption from ISO Class 5- section within the Low-Risk Level CSPs section)  The storage and beyond use times for attached and activated (closures punctured allowing contact of contents) of these proprietary packaging systems of drug products for intravascular administration (e.g., ADD-Vantage® and Mini-Bag Plus®) are those stated in the FDA-approved labeling of their manufacturers.
SINGLE-DOSE AND MULTIPLE-DOSE CONTAINERS (after the High-Risk Level CSPs section)  Opened or needle-punctured single-dose containers shall be used within one hour if opened in worse than ISO Class 5 air quality (see Immediate Use Exemption from ISO Class 5- under Low-Risk Level CSPs), and any remaining contents must be discarded. Single-dose vials continuously exposed to ISO Class 5 or cleaner air may be used up to six hours after initial needle puncture. Opened single-dose ampuls shall not be stored for any time period.  The beyond use date for opened or entered (e.g., needle-punctured) multiple-dose containers is 28 days, unless otherwise specified by the manufacturer. [USP <51> Antimicrobial Effectiveness Testing requires no testing beyond 28 days, and USP chapters, i.e., <797>, must refer to other USP chapters, i.e., <51>, when possible. Manufacturers' expiration dates apply to properly stored, unopened or unentered containers. Despite receipt of several external comments referring to a 30-day CDC limit, a careful search of CDC documents by SCC members did not locate any specific time limit].  Combining multiple-dose and single-dose sterile products or CSPs for use as multiple-dose applications is prohibited.
HAZARDOUS DRUGS (after the SINGLE-DOSE AND MULTIPLE-DOSE CONTAINERS section) This new section addresses safety precautions and practices when hazardous drugs (e.g., those that can cause abortion, allergy, birth defects, blisters, burns, cancer, cytotoxicity, genetic damage, infertility, irritation, sensitivity, vital organ toxicity, or other adverse effects) are ingredients in CSPs. It refers to applicable state and federal guidelines and standards, and NIOSH Publication No. 2004-165 at www.cdc.gov/niosh/docs/2004-165/ for safe practices. This section refers PET compounding to USP <823>, and it contains a statement about safe practices for all other radioactive sterile compounding. [Currently official <797> requires positive pressure for all sterile compounding, but that is wrong for compounding radioactive and other hazardous drugs].
Surface Sampling with Sterile Swabs or Nutrient Agar Contact Plates (this is a new paragraph in the Environmental Monitoring section)  The procedure is described in new text that is not included here, and the sampling frequency is in Table A. below. Table A. Frequency Intervals for Sampling Microbial Bioburdens on Surfaces of ISO Class 5 (see Table 1) Sources and Glove Fingertips of Compounding Personnel According to Weekly Quantities and Risk Levels of CSPs. CSPs per Week per ISO Class 5 Sourcea Minimum Interval Between Sampling Low-Risk and Medium-Risk Levels High-Risk Level Surfaces in ISO Class 5 Sourcesa,b Fingertips of Gloves Fewer than 100 0 Six months Six months 101 to 300 1-2 Three months Three months More than 300 3 and more One month One month aFor example, each LAFW and barrier isolator. bUse a separate contact plate or swab for one bottom, one side, and one upper surface location.
Physical Inspection (add second paragraph)  Direct visual inspection of highly radioactive CSPs is not required based on maintaining radiation exposures As Low As Reasonably Achievable (ALARA).
STORAGE AND BEYOND-USE DATING (add last sentence)  Technetium-99m/Molybdenum 99 generator systems shall be stored and eluted (operated) under conditions recommended by their manufacturers and applicable state and federal regulations.

Table 2. Revised Standards and Clarifications Proposed for USP Chapter <797>.
INTRODUCTION (first paragraph)  Sterile compounding pertains to all pre-administration manipulations of CSPs, including compounding, storage, and transport, but not to administration of CSPs to patients. (second paragraph)  Sterile compounding differs from nonsterile compounding primarily by requiring the maintenance of sterility when compounding exclusively with sterile ingredients and components, and the achievement of sterility when compounding with unsterile ingredients and components. (indented item a.)  Use of sterile products is not subject to <797> unless their preparation, packaging, and storage deviates from their product package inserts, or their preparation requires sterilization (i.e., involves a high-risk level component). (indented item c.)  Otics are excluded, and "aqueous" is added before "inhalations" in the list of preparations required to be sterile before dispensing and administration to patients.
CSP MICROBIAL CONTAMINATION RISK LEVELS (third paragraph)  The pre-administration storage durations and temperature limits apply in the absence of results from (1) sterility testing, or (2) appropriate repeated or routine simulation testing, e.g., adequate media-fill tests or CSPs prepared identically with Soybean-Casein Digest Medium (see Sterility Tests <71>), that justifies longer storage durations for specific CSPs prepared in specific ISO Class 5 (see Table 1) sources by specific personnel.
Medium-Risk Conditions- (condition 5)  Refrigerated storage is 9 days [The extension from 7 to 9 days was granted after request from home infusion pharmacists who ship refrigerated TPN. This is the only proposed revision that is not based on increasing patient safety by either standards or clarifying text].
Exposure of Sterile Critical Sites (new first paragraph of this section currently titled Critical Site Exposure)  Shall not exceed one hour in worse than ISO Class 5 [see Immediate Use Exemption from ISO Class 5- in Table 1.]
ISO Class 5 Air Sources, Clean Room, Buffer Zone, and Anteroom (first paragraph of this section currently titled Clean Rooms and Barrier Isolators)  A clean room is a compounding environment that is supplied with high efficiency particulate air (HEPA), or HEPA- filtered air that meets ISO Class 7. [The current ISO 8 is deemed too dangerously dirty by some attendees at the 2004 USP workshops, and by the SCC when considering the following two prudent sources: FDA's Current Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (www.fda.gov/cder/guidance/5882fnl.htm), which states "FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards ... under dynamic conditions. An area classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate for less critical activities (e.g., equipment cleaning)." "Understanding Pharmaceutical Cleanroom Design," a paper by John Zang, a professional engineer, in the September 2004 issue of the ASHRAE Journal (American Society of Heating, Refrigerating, and Air-Conditioning Engineers, Inc. At the following website is an abstract and reprint order process: http://resourcecenter.ashrae.org/store/ashrae/newstore.cgi? itemid=22628&view=item&categoryid=894&categoryparent=894&page=1&loginid=1407422. This paper states "A Typical ISO 7 (Class 10,000) Cleanroom ... using 99.97% HEPA filters ... has a supply airchange rate approximately 30 per hour."] (second paragraph of this section currently titled Clean Rooms and Barrier Isolators)  Placement of objects and devices not essential to compounding in buffer zones and clean rooms is dictated by their measured effect on the required environmental quality of air atmospheres and surfaces.
Placement of LAFWs and Barrier Isolators Within ISO Class 7 Buffer Zones or Areas – (second paragraph of this section currently titled Clean Rooms and Barrier Isolators)  Barrier isolators are located, operated, and used according to manufacturers' recommendations.
Cleaning and Sanitizing the Sterile Compounding Areas (first paragraph of this section currently titled Cleaning and Sanitizing the Workspaces)  70% Isopropyl Alcohol, IPA, is not required to be sterile [Neither is it prohibited from being sterile].  IPA used to sanitize gloves, surfaces, and critical sites shall remain at least 30 seconds before such materials are contacted to prepare CSPs.
Personnel Cleansing and Garbing (second paragraph of this section currently titled Personnel Cleansing and Gowning)  The sequence is to don non-shedding coats, gowns, or coveralls; head and facial hair covers; face masks; and shoe covers. Then, hands and arms to the elbows are thoroughly scrubbed with an antiseptic cleanser (e.g., povidone-iodine or chlorhexidine gluconate; refer to Hand Hygiene in Healthcare Settings at www.cdc.gov/handhygiene/).
FINISHED PREPARATION RELEASE CHECKS AND TESTS (first paragraph)  Sterility testing is required for all high-risk level CSPs for central nervous or vascular system, intra-articular, and ophthalmic administration that are prepared in groups more than 25 identical containers, or exposed longer than 12 hours to 20 to 80, or longer than 6 hours to warmer than 80 before being sterilized [These four routes of administration offer the least natural host immune defense against infections. The time limits are intended to minimize the shedding of endotoxins from Gram negative bacilli.]  Bacterial endotoxin (pyrogen) testing is required for all high-risk level CSPs for central nervous and vascular systems, and intra-articular administration under the same above conditions.

References

1. Newton DW, Trissel LA. A Primer on USP Chapter <797> "Pharmaceutical Compounding — Sterile Preparations," and USP Process for Drug and Practice Standards. Int J Pharm Compounding. 2004; 8:251-63.
2. U.S. Pharmacopeial Convention, Inc. U.S. Pharmacopeia 27. Chapter <797> Pharmaceutical Compounding — Sterile Preparations. Rockville, MD: U.S. Pharmacopeial Convention, Inc.; 2003: 2350-2370.
3. U.S. Pharmacopeial Convention, Inc. U.S. Pharmacopeia 28. Chapter <797> Pharmaceutical Compounding — Sterile Preparations. Rockville, MD: U.S. Pharmacopeial Convention, Inc.; 2004: 2461-2477.

Footnote
Each annual USP is copyrighted the year before it becomes official. For example, USP 28 is copyrighted in 2004, but it is official from January 1 through December 31 of 2005.