I hope you're doing well and enjoying the start of fall. I also hope that you'll find the following
article about USP <797> by Joseph P. Manfrida, Ph.D. both interesting and useful.
With best wishes,
Dave Gallup
An Overview of USP <797>
By Joseph P. Manfrida, Ph.D., EMLab P&K Analyst
What is USP <797>?
USP <797> is a chapter of the United States Pharmacopeia - National Formulary (USP-NF). It was
written by the national public standards setting organization known as the U. S. Pharmacopeia
to regulate pharmaceutical laboratories that produce and disseminate compounded sterile preparations
(CSPs). USP <797> covers a wide variety of topics including the training of compounding personnel,
how sterile preparations are to be handled and stored, the design of facilities, and the
establishment and maintenance of suitably clean environmental conditions for the production of CSPs.
USP <797> is unique among prior documents addressing these issues in that it was written to be an
enforceable set of standards that can be adopted by state pharmacy regulating agencies as law.
A Brief History of CSP Regulation
USP <797> was written after a long history of earlier attempts to improve patient safety had failed.
Public and government attention was originally drawn to the problem of contaminated and improperly
handled CSPs during the 1960's and 1970's. The American Society of Health-System Pharmacists (ASHP)
released a Technical Assistance Bulletin and the U. S. Pharmacopeia published USP-NF chapter <1206>
in response to the problem in the early 1990's. Both of these publications were recommendations and
guidelines and were not designed to be enforceable by law. Unfortunately, the results were less
than what the releasing organizations had hoped for. In the period from June through December of 2001,
the FDA found that 34% of CSPs tested had product deficiencies.1 Additional problems were
found with pharmacy practices when compared to the guidelines and recommendations issued by the ASHP.
For example, a survey of pharmacy personnel and practices in 2003 determined that only "5% of
pharmacies that compounded risk-level-1 preparations were found to be compliant with garb
requirements."2 Clearly the recommendations and guidelines issued by the ASHP and the
USP were insufficient to assure the safety of public health. Since voluntary compliance was not up to
the task, the USP set out to create a set of legally enforceable regulations that could be adopted by
state boards of pharmacy to use as a basis for accreditation of health care organizations.
In 1938 the U.S. Congress passed the Federal Food, Drug and Cosmetic Act.3 This Act
established the USP-NF as the official set of baseline standard practices that must be followed by
all pharmacies in the United States. All of the chapters numbered between <1> and <999> are enforceable
by the FDA and can be used as the basis for state and federal laws and accreditation standards.
Publication of a chapter on the preparation of CSPs with the chapter number <797> in 2004 effectively
established legally enforceable standards for the preparation of CSPs. Since its original publication,
USP <797> has been revised once.
What types of facilities need to be compliant with USP <797>?
According to USP <797>, the standards outlined in the chapter apply to all facilities and personnel
that prepare CSPs. A CSP is defined as "Compounded biologics, diagnostics, drugs, nutrients,
and radio-pharmaceuticals... that must be sterile when they are administered to patients," and
"Manufactured sterile products that are either prepared strictly according to the instructions
appearing in manufacturers' approved labeling... or prepared differently than published in such
labeling."4 This definition means that USP <797> applies to a wide variety of medical
facilities that regularly produce injections, inhalants, baths, soaks, drops and ointments. In the
case of large hospitals with multiple pharmacies and drug preparation areas, USP <797> can apply to
multiple areas within a single medical facility. It is very important to note that whether or not
USP <797> applies to a given facility is not determined by the facility's size or the number of
patients it serves. The applicability of USP <797> is strictly determined by the nature of what a
facility is preparing. Any facility that prepares CSPs as defined by USP <797> is subject to the
standards and practices it delineates.
Why should a facility be USP <797> compliant?
Any chapter in the USP-NF numbered <1> through <999> is enforceable by the Environmental Protection
Agency (EPA). When a facility is investigated in response to a medical incident, the EPA may fine
the facility for violations of USP <797>. Additionally, many state boards of pharmacy have either
adopted USP <797> as part of their pharmacy certification standards or are in the process of doing
so. States which have made USP <797> part of their standards include: Arkansas, Indiana, Kansas,
Louisiana, Maryland, Massachusetts, Nevada, North Carolina, Ohio, Oklahoma, South Carolina, South
Dakota, Texas, Utah, Virginia, and West Virginia.5 The Joint Commission on Accreditation
of Healthcare Organizations (JCAHO) surveys medical facilities for USP <797> compliance. Many of
the requirements outlined by USP <797> are also mandated by or exceeded by the JCAHO's Medication
Management Standard. Finally, it should be noted that in the past lawyers have used USP-NF chapters
as examples of best practices in civil lawsuits.6 Any organization that fails to meet
the practices outlined in the USP-NF risks legal liability.
Overview of USP-NF chapter <797>
USP <797> concerns itself with many aspects of CSP preparation and storage. The document can be
divided into three sections, CSP handling, personnel training, and environmental sterility.
How CSPs are to be handled is based on the risk classification of the preparation in question.
Low risk level preparations are compounded entirely in high sterility environments using materials
that are themselves already sterile and produced only in single doses. Moderate risk preparations
are similar to low risk preparations with the exception that they are either subject to a longer
process of manipulation during preparation, or they are combined into a single larger preparation
either for administration to multiple patients or to a single patient for an extended duration.
High risk CSPs are those that are either composed of non-sterile components or are exposed to
non-sterile conditions during preparation, thereby requiring them to be sterilized after
compounding prior to use. Each of these different classifications of preparation has increasingly
stringent rules for their preparation that are to be followed. These rules apply both to the
actual handling of the CSP and to the training of personnel who prepare them.
The proper training of personnel who handle CSPs is a running theme throughout the document.
While there are specific sections dedicated just to the training of personnel and the evaluation
of their performance, USP <797> stresses the importance of having well trained personnel in all
parts of the document. In order to train and monitor personnel performance in the most
efficacious manner possible, USP <797> requires personnel to regularly undergo media fill tests.
In these tests personnel are required to perform the entire procedure for compounding a given CSP
using soybean – casein digest medium in place of the normal ingredients of the preparation.
The test is run using conditions as closely emulating actual compounding as is possible. After
the procedure has been executed, the test compound is incubated. Microbial growth indicates that
the test has failed; lack of growth indicates that the subject has passed the test. In the
event of a media fill test failure both the compounding individual and the process itself should
be evaluated for areas that can be improved.
A significant portion of USP <797> is dedicated to establishing and maintaining sterile conditions
in the CSP production area. Laboratory design and engineering control placement are discussed in
order to facilitate maintenance of sterile conditions in the CSP compounding area. Additionally,
practices for maintaining aseptic conditions in a functioning laboratory are outlined. These
practices include testing for viable and nonviable particulates in the air and on surfaces at
least once every six months. Non-viable particles can be measured directly using electronic air
samplers. Viable particles are measured by sampling a volume of air and allowing any particles in
the sample to impact on TSA (for the growth of bacteria) and MEA (for the growth of fungi). Swabs
are used to collect samples off from surfaces. Samples are taken at the critical site of compounding
where the CSPs are actually processed, the buffer area immediately around it and the ante –
area that precedes the buffer area. The amount of nonviable and viable particles detected by the
testing are compared to Table 1 and an ISO Class is assigned to each area. Facilities that are
operating within the parameters of USP <797> will have a critical site of ISO Class 5, a buffer
area of ISO Class 7 and an ante – area of ISO Class 8. If a facility is operating outside
of these parameters corrective action should be taken to bring the compounding facility back
into compliance.
Conclusion
The designation of USP <797> as regulatory law enforceable by the FDA and its adoption as part
of the accreditation standards for pharmacies in an increasing number of states has placed
extensive pressure on medical facilities and organizations to meet or exceed the standards it
outlines. Doing this requires a long-term commitment to regular environmental monitoring,
development of expertise, and an ability to efficiently deploy resources in the pharmaceutical
laboratory where they will have the greatest effect. The USP <797> program at EMLab P&K is
dedicated to providing the material resources and technical expertise needed to meet these
challenges. We will continue to provide the same commitment to quality that you have come to
expect from EMLab P&K in our other services.
Table 1. ISO Classes and particulate levels
| ISO Class |
≥ 0.5 µm Nonviable
particles/m3 |
Viable Airborne
(cfu*/m3) |
Viable Surface**
(cfu/contact plate) |
| 5 |
3,520 |
≤ 1 |
≤ 3 |
| 7 |
352,000 |
≤ 10 |
≤ 5 |
| 8 |
3,520,000 |
≤ 100 |
≤ 100 |
* cfu = colony forming units
** Contact plate areas vary from 24 to 30 cm2. When swabbing is used in sampling,
the area covered should be at least 24 cm2 but no larger than 30 cm2.
References:
1. US Food and Drug Administration. Report:
Limited FDA Survey of Compounded Drug Products.
Accessed 8/19/2009.
2. Morris A.M., Schneider P.J., Pedersen C.A et al. National survey of quality assurance
activities for pharmacy - compounded sterile preparations. American Journal of Health System
Pharmacists. 2003; 60:2567-2576
3. Kastango, Eric S. The
ASHP Discussion Guide on USP Chapter <797>, Compounding Sterile Preparations, p. 1-13. Accessed 8/19/2009.
4. The United States Pharmacopeial Convention. <797> Pharmaceutical Compounding - Sterile
Preparations. National Formulary. 2008, p. 1-61.
5. Jorgenson, James. USP 797 and the NIOSH Alert: A Q&A update for oncology pharmacy and
cancer program administrators. Oncology Issues, September/October 2006, p. 38-41.
6. Kastango, p. 6. Accessed 8/19/2009.
