USP Chapter <797>: Updates for 2008

Eric S. Kastango, MBA, RPh, FASHP

Clinical IQ, LLC

Florham Park, NJ, USA

Disclaimer

“Although I am a member of the USP Sterile Compounding Committee, I am speaking in my individual capacity and not as a member of the Committee or as a USP representative. The views and opinions presented are entirely my own. They do not necessarily reflect the views of USP, nor should they be construed as an official explanation or interpretation of <797>.”

USP Chapter <797> Timeline

• Posted on USP website on December 3rd

– www.usp.org

• The General Chapter will become official via a Revised Bulletin with an official date of June 1, 2008

• It is “the” revised chapter based on 3 years of feedback and comments

• 2005-2010 USP SCC has no plans on revising the chapter again.

• Any changes will be driven by scientific evidence and will be taken up by the 2010-2015 USP SCC

Members of the SCC Committee

• Chair - David Newton, Ph.D., R.Ph. • Vice Chair - Lawrence A. Trissel, R.Ph, FASHP

Members:

Samuel Augustine, Pharm. D.

Mary Baker, Pharm.D.

James F. Cooper, Pharm.D.

Donald Filibeck, Pharm.D

Larry Griffin, R.Ph.

Kenneth Hughes, R.Ph.

Eric S. Kastango, MBA, R.Ph.

Keith St. John, M.S.

Laura Thoma, Pharm. D.

James Wagner

Scientific Liaison:

Claudia C. Okeke, Ph.D., R.Ph.

USP Advisory Groups

• Infection Control Advisory Committee

• Radiopharmaceutical Advisory Committee

• Allergen Extract Working Group

• Compounding Isolator Industry Round Table

• Food and Drug Administration

Changes and Clarifications in <797>

• Introduction (Revised)

• Definitions section (new)

• Immediate-Use category (new)

• Low-Risk Level with 12 hour BUD (new)

• Single & multiple-dose containers (new)

• Proprietary vial/bag systems (new)

• Hazardous drugs (revised)

Changes and Clarifications in <797>

• Radiopharmaceuticals (revised)• Allergen Extract CSPs (new)• Cleaning and disinfecting facilities (revised)• Personnel cleansing and garbing (revised)• Environmental controls (revised) • Environmental sampling (revised)

Changes and Clarifications in <797>

• Filter integrity testing for High Risk Level compounding (new)

• Microbiological BUD (revised)

• “Shall vs. Should” Table (new)

• Clarified language throughout

(We hope!)

Key to Understanding <797>:

Read Chapter <797>!!

Introduction

• Complete revision to be more explicit• Acknowledges direct contact is the principal

source of contamination in CSPs • New robust Definitions section for 29 key terms• Alternative technologies proven equivalent or

superior to conventional work practices are OK• 797 applies to CSPs given via application,

implantation, inhalation, injection, insertion, instillation, and irrigation

Responsibilities of Compounding Personnel in <797>

• 14 areas of responsibility are cited

• Emphasizes training and education

• Emphasizes compounding accuracy

• Emphasizes avoiding contamination

• Emphasizes patient safety

CSP Risk Categories

• Immediate Use CSPs

• Low-Risk Level

• Low-Risk Level w/12 hour or less BUD

• Medium-Risk Level

• High-Risk Level

Immediate-Use Category

• Exempt from all requirements in <797>

• Only simple aseptic measuring and transfer are needed

• NMT 3 sterile non-hazardous drugs

• No delays/interruptions

• No contact contamination of ingredients or critical sites

Immediate-Use Category

• Dose must be labeled if not administered by the preparer

• Administration must begin within 1 hour after the start of preparation

• Dose must be discarded if administration has not begun within 1 hour after the start of preparation

(No storing. No recycling.)

Immediate-Use Category

Intended applications:

• At a patient’s bedside

• In an ambulance, ED or during a “Code”

Unintended applications:

• Routine compounding:– Operating rooms, recovery areas– Physician offices

Low-Risk Level CSPs

• Compounded from NMT 3 sterile commercial containers using commercial sterile devices

• Maintained in ISO Class 5 environment in an ISO 7 buffer area at all times

• Only a few basic, closed-system, simple aseptic transfers and manipulations

Low-Risk Level w/12 hour BUD

• Low-Risk Level remains nearly the same • New subsection for an ISO 5 device in an

uncontrolled air environment• Must be in a segregated compounding area not

in a high traffic area-Satellite pharmacy• All personnel cleansing and garbing,

environmental sampling requirements apply• No Hazardous Drugs: “THINK CONTAINMENT”• Administration must begin within 12 hours or as

stated in the package insert, whichever is less

Medium-Risk Level CSPs

• Four or more sterile commercial drug containers

• Multiple pooled sterile commercial products for multiple patients or one patient multiple times

• Complex aseptic manipulations– TPN, PCA

• Compounding requires long duration

High-Risk Level CSPs

• Prepared from non-sterile ingredients• Preparation from sterile ingredients but

exposed to less than ISO Class 5• More than 6 hour delay from compounding to

sterilization• Purity of components is assumed but not

verified by documentation-C of A• Sterilization by filtration - the

manufacturer’s recommended integrity test MUST be performed on the filter– Bubble-Point

Old Expired BUD Paradigm

• Assume the compounded preparation was sterile

• Historically based solely on the drug’s chemical stability

Chapter<797> BUD Paradigm

• Recognizes the possibility that the CSP was inadvertently contaminated during compounding process

• For patient safety, BUD based on two factors:– Drug’s chemical stability in conjunction with

microbiological limits,

• BUD will always be whichever is shorter

Calculated Microbial GrowthCundell AM, USP Committee on Analytical Microbiology,

Pharmacopeial Forum 2002; 28 (6) Stimuli to the Revision Process

Time (Hours) Microbial Count(CFU per mL)

6 10

9 640

12 41,000

18 1.7 X 107

24 6.9 X 109

<797> Microbiological BUD

• There is an ever-present chance, indeed likelihood, that some CSPs will be inadvertently contaminated

• Time and warm temperatures are the enemy, speeding the potential for growth of dangerous amounts of microbial contamination

• Guidance for limits is needed to avoid unacceptable risks of harming patients

Microbiological Beyond-Use Dating

Risk Category Room Temp Refrigerator Freezer

(-10 °C)

Immediate Use

1 hour 1 hour N/A

Low 48 hours 14 days 45 days

Low w/

12-hr BUD

12 hours or less

12 hours or less N/A

Medium 30 hours 9 days 45 days

High 24 hours 3 days 45 days

Single/Multiple Dose Vials

• Definitions of SDV and MDV are in the USP General Notices and Requirements

• Single dose vials – Opened or punctured in ISO 5 environment may be used for up to 6 hours. Opened or punctured in worse than ISO 5 must be used within 1 hour or discarded.

• Single dose ampuls must be discarded after opening and not stored for any time period

Single/Multiple Dose Vials

• Multiple dose vials – Contain antimicrobial preservative(s)

• Designed for entry on multiple occasions. BUD – 28 days after initial entry unless specified otherwise by the manufacturer.

• BUD of 28 days based on USP <51> Antimicrobial Preservative Testing

• Expiration date on vial is based on an unopened, properly stored vial.

Proprietary Bag/Vial Systems

• ADD-Vantage; Add-a-Vial, Minibag Plus, etc.

• Follow the manufacturer’s instructions for handling and storing.

• These devices and their instructions have been approved by the FDA

• BUD ranges from 15 days to 10 weeks

Hazardous Drugs

• Section extensively revised

• NIOSH Guidelines for guidance

• BSC or CACI required

• Hazardous drug storage and preparation in separate negative pressure ISO 7 with ISO 7 ante area

Hazardous Drugs

• Personnel protection specified

• Use of closed-system transfer devices must be within BSC or CACI

• Disposal according to state and federal regulations

Allergen Extracts

• Intradermal and subcutaneous MDVs and SDVs (No IV or IT)

• Unpreserved allergen extracts must fully comply with all aspects of <797>

• Allergen extracts are exempt from personnel, environment, and storage requirements only if all of the following criteria are met:

Allergen Extracts

• Personnel perform hand hygiene with alcohol-based surgical hand scrub

• Hair and beard covers, gown, face mask, and sterile gloves are used

• Compounded by simple aseptic transfer• Must contain an effective amount of

antimicrobial preservative• For one patient only

Allergen Extracts

• Collaboration with AAOA/JCAAI

• Research and discussions with experts in the field

• Results of a peer-reviewed research study of 26,795 injections (>98/patient) with no infections

• Done in an uncontrolled environment

Cleaning and Disinfecting Facilities

• Based on Infection Control Advisory Committee recommendations

• Goal: Reduce bioburden in compounding areas • Use of disinfecting agent such as sterile 70%

IPA• Performed in ISO 5 environment:

1. At the beginning of each work shift2. At the beginning of each batch3. At least every 30 minutes

4. When surface contamination is known or suspected

Cleaning and Disinfecting Facilities

• Cleaning should proceed from buffer area (cleanroom) to ante area

• Use suitable dedicated mops, etc. and disinfecting cleaners

• Floors, counters, work surfaces – at least daily

• Walls, ceilings, shelving – at least monthly

Hand Hygiene

• USP Chapter <797> harmonized with CDC Guidelines for Hand Hygiene

• Hand washing is defined as the vigorous, brief (30 seconds) rubbing together of all surfaces of lathered hands, followed by rinsing under a stream of water.

• Hand washing suspends microorganisms and mechanically removes them by rinsing with water. The fundamental principle of hand washing is removal, not killing.

• Single most important way to reduce the risks of transmitting germs.

Hand hygiene1 is paramount to safety, as this agar imprint of an unwashed hand shows2

1 http://www.cdc.gov/handhygiene/ 2 E Larson. Am J Nurs, AJN. July 1989: 935

Personnel Cleansing and Garbing

• Remove outer garments and jewelry (including piercings above the neck)

• Garb order from dirtiest to cleanest• Don shoe covers, hair covers, face masks• Perform hand/arm hygiene • Don disposable gowns

Personnel Cleansing and Garbing

• Inside the clean area, cleanse hands and arms with alcohol-based surgical hand scrub with persistent activity

• After hands and arms are dry, don sterile powder-free gloves compatible with sterile 70% IPA

• Repeatedly apply sterile 70% IPA to contact areas of gloves whenever nonsterile surfaces are touched (e.g. vials, counter tops, carts)

Compounding Personnel

• Hair net• Beard cover and face

mask• Gown

– Nonsterile

• Gloves– Sterile

• Shoe covers

Personnel Cleansing and Garbing

• All of the cleansing, garbing and gloving requirements also apply to compounding in CAIs and CACIs.

• Exception: If the manufacturer of the CAI or CACI provides written documentation of statistically validated testing supporting any garbing component(s) that are not required.

• Trust but “verify” claims made by vendors to ensure that all risks are understood

ISO Class 5 Sources, Buffer Areas, and Ante Areas

Environmental Controls

• Aimed at creating ISO 5, 7, and 8 environments• ISO 5 – LAFW, BSC, CAI, CACI are “Primary

Engineering Controls”• Must maintain ISO 5 during dynamic (in use)

working conditions• Unidirectional airflow required

Environmental Controls

• ISO 7 buffer area and ISO 8 ante area – are “Secondary engineering controls”

• Must maintain ISO 7 or 8 during dynamic (in use) working conditions

• Airflow and balance testing required at the installation site

• Only personnel and materials essential for compounding and cleaning are permitted

Environmental Controls

• ISO 5 Primary engineering control (LAFW, BSC, CAI, CACI) to be in an ISO 7 environment

• Exception: CAI if its design provides ISO 5 and isolation from the room during dynamic operating conditions as placed and tested at your site (including transferring materials in and out) using CETA testing

• Do your “Due Diligence” to verify the accuracy of any such claim

Missing Research

• Paucity of independent research evaluations and comparisons of pharmacy applications of primary and secondary engineering controls.

• Unlike BSCs, CAIs and CACIs have not be tested independently

• CETA CAG-003-2006 is an important document to ensure consistent testing

Environmental Sampling

Environmental Sampling Task• Dilemma:

– One of the most contentious section of USP Chapter <797>

– Since 1970’s, the US Centers for Disease Control (CDC) has not advocated routine viable environmental monitoring

– The US Food and Drug Administration requires sterile processing operations to perform daily monitoring of viable air, surface and personnel glove fingertip samples

Environmental Sampling

None Daily

US Centers for Disease Control

Routine Viable Microbial Environmental Sampling (ES)

US Food and Drug Administration

Environmental Sampling

None Daily

US Centers for Disease Control

Routine Viable Microbial Environmental Sampling (ES)

US Food and Drug Administration

USP 797

Environmental Sampling

• Designed to demonstrate that the primary and secondary engineering controls, disinfecting procedures, and work practices result in a suitable environment for aseptic compounding

• Utilizes several approaches to assess and evaluate

Environmental Sampling

• Environmental Sampling section has been separated into a facility-related performance metric and a personnel –related performance metric

• Facility-related Environmental Sampling– Viable air sampling via volumetric method (impaction) to occur at least

every 6 months

• Personnel-related Environmental Sampling – Personnel fingertip sampling during initial training, with media fills and

as a competency assessment tool – Surface sampling for viable microorganisms

Environmental Monitoring • Viable Air Sampling

– Gravimetric vs. Volumetric Sampling

Courtesy of MSI, Inc. Houston, TX (www.microbiologyspecialists.com)

Other Changes in <797>

• Radiopharmaceuticals quality assurance based on Advisory Committee recommendations

• Expanded explanatory and descriptive material in many sections

• Clarified language throughout

Closing Thoughts

• USP Chapter <797> is about more than just cleanrooms and facilities– IT IS A QUALITY SYSTEM and PATIENT SAFETY

• Involves– Leadership (embrace evidence-based science and

best practices) even when its not convenient or inexpensive

– Properly educated and trained pharmacists and technicians

– Proper Employee Supervision and Feedback – Control of Critical Practices & Consistent Work

Practices– Documentation-NOT A PRACTICE IN FUTILITY

Be mindful of your practices and remember there is someone who is loved by someone

receiving your CSP