USP and Environmental · PDF fileUSP and Environmental Sampling . ... Direct Compounding Area ... Prior to compounding and during media fill testing : Quarterly

Michael Berg, Ph.D.

USP <797> and Environmental Sampling

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Overview

History

Sampling

Suggested changes

Investigation of excursions & remediation

USP800

Outline


• A chapter of the United States Pharmacopeia – National Formulary (USP-NF).

• USP-NF establishes standards for medicines, food ingredients and dietary supplements.

• USP <797> establishes best practices and regulations for the production of compounded sterile preparations.

USP <797>


Abbreviations and Terms

• USP-NF: United States Pharmacopeia – National Formulary

• CSP: Compounded Sterile Preparation

• PEC: Primary Engineering Controls

• BUD: Beyond Use Dating

• DCA: Direct Compounding Area

• Buffer Room

• Ante Room


Where Does USP <797> Apply?

• Any facility producing CSPs and any personnel who perform compounding are subject to regulation by USP <797>.

• The Act of Compounding determines regulation, not the nature of the facility.

• Requirements of USP <797> depend on the nature of the compounding being performed.


What is Compounding?

• “Compounding” means any of the following activities occurring in a licensed pharmacy, by or under the supervision of a licensed pharmacist, pursuant to a prescription: – Altering the dosage form or delivery system of a drug – Altering the strength of a drug – Combining components or active ingredients – Preparing a drug product from chemicals or bulk drug

substances


Examples of CSP

• Injections

• Total Parenteral Nutrition (TPN)

• Aqueous bronchial inhalations

• Baths and soaks for live organs and tissues

• Irrigations for internal body cavities

• Ophthalmics (eye)

• Implants


Examples of “NOT Compounding”

• FDA approved, sterile, sealed and self contained reconstitution devices obtained directly from the manufacturer.

• Pills, solutions and other medications that come pre-mixed from the manufacturer and are only dispensed by the pharmacy.


Cleanroom Design

Ante Room Buffer Room

PE

C (IS

O 5)

ISO 8 ISO 7


Cleanroom: Hazardous Compounding

Ante Room Buffer Room

PE

C (IS

O 5)

ISO 7 ISO 7


BUD <12 Hours Low Risk Non-Hazardous

• For low-risk level, non-hazardous CSP only with 12 hour or less BUD.

• No buffer (ISO 7) but

segregated area is required (e.g. away from sinks and windows).


Mission

Mission of the chapter: To prevent harm

• Microbial contamination • Excessive bacterial endotoxin • Variability in intended strength that exceed limits • Use of ingredients of inappropriate quality • Unintended physical and chemical contaminants


History – Chapter <797>

Published 11/2003

Official 1/2004

Revision released 12/2007

Out for public comment 9/2015

Official 6/2008

Enforceable by FDA and 28 State Board of Pharmacies (more or less) Based on current scientific information and best sterile compounding

practices Recognized as the national standard of practice

Provides practice and quality standards for compounding sterile preparations


Current Revision of Chapter <797>

When will the final revision to General Chapter <797> be published? Based on the nature and significance of the public comments received, the chapter will be republished in the Pharmacopeial Forum for another round of public comments. The Compounding Expert Committee is currently reviewing all of the public comments submitted on the proposed revisions to General Chapter <797>. The chapter is currently being revised based on the public input received. Due to the high volume of comments received, USP does not have a date for the republication.

Is <797> still enforceable? Although General Chapter <797> is undergoing revision, the published version of the chapter which became official on June 1, 2008 is currently the official and enforceable standard.

Source: www.usp.org


History – Outbreaks

2001 – Walnut Creek, CA 40 patients exposed (Serratia bacterium), 4 developed meningitis, 1 fatality

2002 – North Carolina patients exposed to Exophiala dermatitidis, 4 developed meningitis, 1 fatality

2004 - USP<797> official

2008 - USP<797> revised

2012 – Framingham, MA Fungal meningitis Case count: 751 Fatalities: 64

2001 - FDA found that 34% of CSPs tested had deficiencies.1

1 US Food and Drug Administration. Report: Limited FDA Survey of Compounded Drug Products. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm155725.htm. 6/18/2009, accessed 8/19/2009

2017 2000

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm155725.htm


Framingham, Massachusetts (2012)

• Fungal meningitis outbreak caused by contaminated vials from the New England Compounding Center (NECC), Framingham, MA

• The case count is now 751 and the death toll 641

• Company had a history of complaints and non-compliance. 2012 investigations demonstrated a “…basic lack of compliance with USP<797> or with safe compounding.”

1 http://www.cdc.gov/hai/outbreaks/meningitis.html (Oct 29, 2013)

http://www.cdc.gov/hai/outbreaks/meningitis.html


Framingham, Massachusetts (2012)

1 http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html (Oct 29, 2013)

http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html


Enforcement

• FDA enforcement (dependent upon mass casualties).

• Requirement in many states for certification.

• Joint Commission on Accreditation of Healthcare Organizations (JCAHO) launched a new Medication Compounding Certification in 2017.


USP Revision – Suggested Changes

1. Reorganization of existing sections.

2. Collapsing of three risk categories (low-, medium-, and high-risk) into two categories (Category 1 and 2).

3. Removal of information on handling hazardous drugs and added cross-references to <800> Hazardous Drugs—Handling in Healthcare Settings.

4. Personnel monitoring (quarterly), Air and surface sampling (monthly).

5. Introduction of the terminology “in-use time.”


Risk Levels – Low Risk

1) Low Risk

• CSPs are compounded with aseptic manipulations within ISO Class 5 using only sterile components.

• Compounding only involves transfer, measuring and mixing manipulations using no more than 3 sterile products.

• CSP administered within following time periods: room temp 48 hours, refrigerated 14 days, frozen 45 days.


Risk Levels – Medium Risk

2) Medium Risk

• CSPs that will be administered either to multiple patients or to one patient on multiple occasions.

• Compounding process includes complex aseptic manipulations other than single-volume transfer.

• Compounding process requires unusually long duration.

Examples:

Compounding of total parenteral nutrition fluids.

Filling reservoirs of injection devices with more than 3 sterile products.


Risk Levels – High Risk

3) High Risk

• Produced with non-sterile components, or process exposes components to conditions worse than ISO 5 for more than 1 hour.

• Requires terminal sterilization.

• Same environmental requirements as medium risk, except more extensive environmental testing is required.


Special Circumstances: Low Risk, BUD Less Than 12 Hours

• If, and only if, the following conditions are met:

– Low risk compound used within 12 hours. – Primary Engineering Control has been demonstrated to

maintain ISO 5 during operations and transfer of material as delineated in CETA CAG-002-2006.

– Surrounding area can be easily cleaned.

• Then the ISO 5 Primary Engineering Control may be located in an out of the way area (away from sinks, windows, doors to the exterior, traffic flow, etc.) that does not meet ISO 7 conditions.


Urgent-Use CSPs

In Rare (Emergency) Circumstances

• CSP is urgently needed • Single patient • Compounding <1hour • Immediate administration of the CSP

…CSP may be prepared in worse than ISO5 conditions.


New Risk Categories

Factors

1) Conditions under which the CSPs are made

• Batch size

• Complexity and length of compounding procedure and complexity of compounding operation

• Inherent nature of the CSP (e.g. supporting microbial growth)

2) Time within which CSPs will be used

• BUD <12 hrs (RT) or <24 hrs (refrigerated)


Proposed Category 1 CSP

PEC placement Not in ISO classified air

Sterility Testing Not required

Endotoxin Testing Not required

BUD ≤ 12 hours RT or ≤ 24

hours refrigerated


Environmental Monitoring

Category 1 Category 2

Buildings and Facilities Primary engineering control (PEC)

Not required to be placed in a classified area

Not required to be placed in a classified area

Recertification Every 6 months Every 6 months

Environmental Monitoring Nonviable airborne monitoring

Every 6 months Every 6 months

Viable airborne monitoring

Monthly Monthly

Surface sampling Monthly Monthly


Personnel Qualifications

Current Proposed

Visual observation of hand hygiene and garbing

Prior to compounding and during media fill testing

Quarterly

Gloved fingertip sampling

Prior to compounding and during media fill testing

Quarterly

Media fill testing Annually for low and medium risk level, Semi-

annually for high risk level

Quarterly


• Non-viable

• Viable – Air – Surface – Gloved finger tip – Media fill test

Environmental Sampling – Types


• Once every six months

• When Primary Engineering Controls are moved or altered

• In response to major servicing of the area around the PEC

• Locations to be sampled: each ISO 5 area, ISO 7 buffer area and ISO 8 ante area

• ISO 14644: # samples=Square Root of the clean room area, at least 1 minute & 2 Liters / sample

Non-Viable Particle Sampling


Total Particle Count

• ISO 14644: Rule of thumb: # samples=Square Root of the clean room area, at least 1 minute & 2 Liters / sample

Area [m2] less than or equal to

Minimum # of samples locations

2 1 10 5 32 8 56 11 104 16 190 21 500 26


ISO 14644 and FED-STD-209E

Number of Particles per Cubic Meter by Micrometer Size

ISO Class 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm

FED STD 209

Class ISO 1 10 2 ISO 2 100 24 10 4 ISO 3 1,000 237 102 35 8 1 ISO 4 10,000 2,370 1,020 352 83 10 ISO 5 100,000 23,700 10,200 3,520 832 29 100 ISO 6 1,000,000 237,000 102,000 35,200 8,320 293 1000 ISO 7 352,000 83,200 2,930 10000 ISO 8 3,520,000 832,000 29,300 100000 ISO 9 35,200,000 8,320,000 293,000


Viable Particle Sampling

• Personnel qualification: Gloved finger tip test, media fill test (annually or semi-annually) • Typically conducted by the head pharmacist/trainer.

• Air sampling: Currently every six months (proposed monthly) • Sampler gets fully garbed

• Prepare equipment in ante room

• Load sampler aseptically

• Position sampler

• Sampling (stand back or leave immediate area)

• Remove and close plate


Viable Testing: Gloved Fingertip

Use two plates with nutrient agar containing neutralizing agents (e.g. lecithin and polysorbate 80).

Do NOT disinfect gloves.

Collect a gloved fingertip and thumb sample from both hands (separate plates) by lightly pressing each fingertip into the agar.

http://www.google.com/url?url=http://www.biomedqc.com/product/gloved-finger-tip-testing-plates/&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwj_4uKsmrPJAhUX8mMKHeAXCY4QwW4IIDAE&usg=AFQjCNHvjP5OuKr0pkxQFHZw8JXsGAukRQ


Viable Testing: Media Fill Test

Manipulations: All sterile ingredients: Transfer sterile culture

medium into the same type of container-closure systems.

Some non-sterile ingredients: Prepare non-sterile culture medium and manipulate accordingly.

Media incubation:

Incubate media-filled vials at 20°–35° for a minimum of 14 days.


Viable Testing: Air Sampling

Air sampling in all classified areas

Volumetric sampling: At least 400 - 1000 liters sample volume (min. of 1000 liters proposed)

During typical operating conditions at least semi-annually (monthly proposed)

Use general microbiological growth medium (e.g. TSA or Soybean Casein Digest Medium)



Decontaminate sampling equipment

Examine media for contamination

Sample at least 400 – 1000 liters (1000 L minimum proposed)

Close the plate, label & transport to lab/incubator

Bacteria testing (e.g. TSA, 2 – 3 days at 30˚C - 35˚C incubation)

Fungal testing (e.g. MEA, 5 – 7 days at 26˚C - 30˚C incubation)

Proposed: dual incubation, one medium



ISO Class Air Sampling Action Levels (CFU/m3)*

5 >1 7 >10 8 >100

* All action levels must be based on sampling in the vicinity of exposed materials/articles during compounding operations.


Viable Testing: Surface Sampling

Testing for contamination of work surfaces

Evaluate disinfection and cleaning procedures

Must be performed in all ISO classified area

Must be performed at the conclusion of compounding activities but before cleaning/disinfection

Media must be supplemented with additives to neutralize effects of disinfectants (e.g. TSA with lecithin and polysorbate 80)

Sampling must be conducted periodically (proposed: monthly)



Contact Plates or Paddles (24 – 36 cm2)

• Easy to use

• Accurate

• Less handling

Swabs

• Can sample curved surfaces

• Convenient

• Less expensive

http://www.google.com/url?url=http://www.biomedqc.com/bio-shield/&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwjq3ca2nLPJAhUT6mMKHYvBC484eBDBbgg6MBI&usg=AFQjCNEvylWTCAYJrp39TxzrJBs9ZwIvpA



ISO Class

Currently Work Surfaces* (CFU per plate or per sample)

Non-work Surfaces

(CFU per plate or per sample)

5 >3 >3 N/A 7 >5 >5 >10 8 >100 >25 >50

* Work surfaces are those surfaces that are in direct contact with materials used in compounding. These action levels are based on the expectation that materials will be disinfected before introduction to an ISO Class 5 area.


Actionable Organisms

CFU count below the action – Characterization must be performed (Microbial Characterization, Identification, and Strain Typing – USP<1113>).

Highly pathogenic microorganisms (e.g., gram-negative rods,

coagulase positive staphylococcus, molds and yeasts) are potentially fatal to patients receiving CSPs and must be immediately remedied through cleaning and disinfection, regardless of CFU count.

If levels measured during viable air sampling exceed the

levels, the genus must be identified, and when possible, identify the species of any microorganism recovered, with the assistance of a credentialed microbiology laboratory.


Investigations and Excursions

Threshold failure or Excursion

Physical Factors • PEC • Cleaning • Environmental conditions

Personnel Factors • Hand washing & garbing • Training


Cleaning and Disinfection

Site Minimum Frequency*

PEC (except for isolator)

beginning and end of each shift; before each batch; every 30 min; after spills

Isolator each time it is opened; decontaminate closed isolator

Work surfaces outside the PEC

Daily

Floors Daily Walls Monthly Ceilings Monthly Storage Shelving Monthly

* If compounding is done less frequently than the cleaning frequencies cleaning must occur before each compounding session begins.


Disinfectants (Appendix II)


Documentation is Key to Providing Good USP Services…

• Copy or original certificate of sterility

• Equipment calibration and training certificates

• Maps to indicate environmental samples

• Document time of sampling also in reference to other activities

• Records for cleaning activities, investigations, results of monitoring…

Quality Control

http://www.google.com/url?url=http://www.mckessonhomecaretalk.com/posts/face-to-face-issues-investigation-into-large-providers-dominate-nahc-discussions/&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwjqlOLNh7fJAhWCdz4KHZ3TBh8QwW4IKDAJ&usg=AFQjCNH1fV6sgOGLIma2mEfHsYp-7xxhow


USP <800> (Hazardous Drugs)

Hazardous Drugs - Handling in Healthcare Settings

• Created to identify requirements for receipt, storage, mixing, preparing, compounding, dispensing, and administration of hazardous drugs to protect the patient, healthcare personnel, and environment.



Self-contained wipe kit – all contents needed to collect and return samples to the lab for analysis

► Tests for 1-10 different drug targets from a single swab or for Platinum (Pt) containing drugs

► Has 6 easy steps to collect a surface sample

► Prepaid shipping included – FedEx, using the provided insulated container

► Results in 15 business days or less

The ChemoAlert Kit…



• Glove Boxes & Hoods

• Patient Infusion

• Floors & Corners

• Telephones

• Light Switches

• Computer Keyboards

• Etc.



USP <797> MIX

• 5-FLUOROURACIL

• CYCLOPHOSPHAMIDE

• IFOSFAMIDE

• METHOTREXATE

View the draft version of USP800 at:

http://www.usp.org/sites/default/files/usp_pdf/EN/m7808_pre-post.pdf


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Questions


Continuing Education Units (CEUs)

To receive a certificate of attendance, you must complete the survey after the webinar:

• Click on the survey link in the “Thank you” email (sent 1 hour after this webinar).

• Complete survey within 24 hours.

• You will receive an email in 2-3 weeks when your certificate is ready.


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Documents

USP and Environmental · PDF fileUSP and Environmental Sampling . ... Direct Compounding Area ... Prior to compounding and during media fill testing : Quarterly