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

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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) un-

intended 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.

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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.

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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 2008ii. 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

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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, m3 FS 209 E, ft3

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 3,520,000 100,000v

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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

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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.