Disclosure

The following slides were developed for a presentation to the Kentucky Board of Pharmacy at the 2015 Board Retreat. Parts of the presentation have been edited due to usage agreements. These slides refer to some requirements of USP 797 but are not all inclusive. The slides have been made available at individual request.

T H E K E N T U C K Y B O A R D O F P H A R M A C Y S E R V E S T H E C O M M O N W E A L T H T O

P R O M O T E , P R E S E R V E , A N D P R O T E C T T H E P U B L I C H E A L T H , S A F E T Y , A N D W E L F A R E

T H R O U G H E F F E C T I V E R E G U L A T I O N O F T H E P R A C T I C E O F P H A R M A C Y .

Sterile Compounding Inspections

Objectives

Brief History of USP 797

Inspector Training and Inspection Form

Observations Facility Controls Personnel Matrix Documentation

Objectives

Clarifications Facility Controls

Design Certification and Testing Surface Sampling

Documentation Record Retention Stability References Sterility Testing Compound Record

Personnel Matrix Supervision

Objectives

Where do we go from here? Communications with pharmacists Future Board Meeting updates Future clarifications Nuclear pharmacies Regulation update Report care Out of State permits Non-sterile compounding USP 795

Brief History of USP 797

Published November 2003 Became official January 2004

First major proposed revision December 2007 Became official June 2008

Second major proposed revision September 2015 Comment period November 2, 2015 to January 31,

2016 Becomes official ???

Kentucky Statute

KRS 217.015(31) – “Official compendium” means the official United States Pharmacopoeia, official homeopathic pharmacopoeia of the United States, official national formulary, or any supplement to any of them.

July 2008 Board Meeting, the Board clarified low volume for hazardous drugs to be an average of 5 hazardous compounds/2 week period.

Inspectors Trainings

Critical Point Continuing Education Boot Camp Inspector Training

Inspection Form

Previously 10 questions on hospital, organized healthcare facility or infusion pharmacy inspection form, none on community/retail pharmacy inspection

Updated form 16 pages, universal not practice site specific

Addresses requirements of USP Chapter 797 also incorporates 201 KAR 2:076 ParenteralPharmaceutical Compounding

Divided into sections based on chapter headings and compounding types

2013 Compounding Survey

In-State Pharmacy Permit Holders Response Rate: 1306/1341 (97%) Performing Sterile Compounding: 195 (15% of responders)

High Risk: 33 (17% of sterile compounders or 3% of responders)* 1346 current in-state pharmacy permit holders (as of 8/5/15)

Out-of-State Pharmacy Permit Holders Response Rate: 451/466 (97%) Performing Sterile Compounding: 170 (38% of responders)

High Risk: 82 (48% of sterile compounders or 18% of responders) 669 current out-of-state pharmacy permit holders (as of

8/5/15)* May not be true representation some confusion with hazardous drug compounding

2013 Compounding Survey

In-State Sterile Compounders by Permit Type: Hospital and Hospital/Ambulatory: 114

High Risk: 9 Reality: 2 Community Independent: 36

High Risk: 18 Reality: 14 (5 veterinarian only) Infusion: 23

High Risk: 5 Reality: 0 Long Term Care: 16

High Risk: 1 Reality: 0 Nuclear: 6

Inspection Observations

Facility Controls Personnel Metrics Documentation

Facility Controls

Design Workflow Hazardous Rooms

Cleaning/Maintenance Documentation Environmental Services

ISO Classification Consistent certification

Environmental Sampling Re-sampling Sampling plan

Personnel Metrics

Garbing/Hand Hygiene Minor differences

Aseptic Technique Supervision

Cleaning Documentation

Equipment Training

Documentation

Policies & Procedures Formulaic

Personnel Training Observations, Written

tests, Media fill, Gloved Fingertip Sampling

Facility Conditions Temperature, Pressure

Cleaning Logs Daily, Monthly

Environmental Sampling Surface Sampling

Equipment Maintenance Calibration,

Depyrogenation

Compounding Record Sterility Results Extended BUD

Endotoxin Results

National Hospital Compliance 2015

Most compliant practice setting Home infusion 92.65% Hospital 79.9%

80% wear sterile gloves 76% on-going and annual training and competencies 28% perform sterility testing when it is required 68% daily air pressure/velocity documentation 57% line of demarcation 48% initial gloved fingertip sampling 39% on-going gloved fingertip sampling

National Hospital Compliance 2015

57% initial and on-going media fill testing 62% remedial action when action levels triggered 58% Quality Assurance program specific to CSPs 63% training and competencies in cleaning 37% written hazardous drug confirmation of risk 72% all elements of environmental sampling 31% report using 0.22 micron filter to sterilize

solution (high risk) 10% report performing high risk compounding

National Hospital Compliance 2015

Link to survey results: http://www.pppmag.com/article/1775

Points of Clarification

Facility Controls Facility Design ISO Certification – Non-viable air sampling Viable Air Sampling Surface Sampling

Documentation Record Retention Stability References Sterility Testing Compound Record

Personnel Metrics Supervision

Current Areas of Concern Proposed Clarifications(USP 797 proposed revision published 9/2015)

Lack of ante room or ante room not properly used

Incomplete segregation of compounding rooms

Wood/laminate shelving, doors and accessories

[ENVIRONMENTAL QUALITY AND CONTROL: Facility Design and Environmental Controls]

Creates 2 categories of compounding dependent on room design Segregated area, restricted

BUD Distinct rooms, longer BUD

[4. BUILDINGS AND FACILITIES: 4.2 Facility Design and Environmental Controls]

Facility Design

Current Concern: Hazardous Drugs

Proposed Clarification: USP 800 – Hazardous Drugs

Lack of negative pressure compounding room

[HAZARDOUS DRUGS AS CSPs]

Hazardous compounding must be done under negative pressure

[Chapter 800 – HAZARDOUS DRUGS - HANDLING IN HEALTHCARE SETTINGS: 5.3 Compounding]

Facility Design

Current Areas of ConcernProposed Clarifications(USP 797 proposed revision published 9/2015)

ISO Classified Areas: Certification performed every 6 months and when PECs relocated or rooms altered ISO Classification below

standard ACPH below standard Required pressure

differential not met[ENVIRONMENTAL QUALITY AND

CONTROL]

PEC not at ISO 5 cannot be used for compounding

Ante/buffer rooms not at appropriate ISO level, BUD is limited to Category 1 CSP (12 hr room/24 hr refrigerated)

[5. ENVIRONMENTAL MONITORING: 5.2 Monitoring Air Quality for Nonviable Airborne Particles: DATA EVALUATION AND ACTION LEVELS]

ISO Certification – Nonviable Air Sampling

Current Areas of ConcernProposed Clarifications(USP 797 proposed revision published 9/2015)

ISO Classified areas: Viable air sampling performed every 6 months as part of re-certification Action levels exceeded –

investigation, eliminate, clean and resample

Highly pathogenic microorganisms immediately remedied

[ENVIRONMENTAL VIABLE AIRBORNE PARTICLE TESTING PROGRAM]

ISO Classified areas: Viable air sampling performed monthly using medium for both microbial and fungal Trend data Action levels meet or exceed –

corrective actions taken including resample

Highly pathogenic microorganisms immediately remedied

[5. ENVIRONMENTAL MONITORING: 5.3 Monitoring Air Quality for Viable Airborne Particles: DATA EVALUATION AND ACTION LEVELS]

Viable Air Sampling

Current Areas of ConcernProposed Clarifications(USP 797 proposed revision published 9/2015)

Surface sampling shall be performed in all ISO classified areas on a periodic basis Most pharmacies are

performing at least semi-annually

[ENVIRONMENTAL QUALITY AND CONTROL: Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices, and Cleaning/Disinfection Procedures: SURFACE CLEANING AND DISINFECTION SAMPLING AND ASSESSMENT]

Surface sampling shall be performed at multiple locations in all ISO classified areas at least monthly Trend data Specified areas to sample

PEC exceeding action levels cannot be used to compound

Ante/Buffer rooms exceeding action levels, BUD is limited to Category 1 CSP (12 hr room/24 hr frig)

[5. ENVIRONMENTAL MONITORING: 5.4 Sampling Surfaces for Contamination: DATA EVALUATION AND ACTION LEVELS]

Surface Sampling

Proposed Clarifications(USP 797 proposed revision published 9/2015)

Retained for as long as compounded personnel employed

Silent on how long to retain if personnel no longer employed

Maintained to provided a permanent record and long-term assessment of competency

At least 3 years or as required by state laws

[2.2. Competency Testing in Garbing and Hand Hygiene, 2.3 Competency Testing in Aseptic Technique and 16. DOCUMENTATION]

Record Retention: Personnel Training

Current USP 797

Current USP 797Proposed Clarifications(USP 797 proposed revision published 9/2015)

Silent on: Cleaning Equipment Maintenance Temperature Pressure Room/Hood Certifications Environmental Sampling Compounding Records

Batch and Compounding Records

Sterility and Endotoxintesting

Facility Design and initial qualifications – for as long as facility operational

All other records – at least 3 years or as required by state law[16. DOCUMENTATION]

Kentucky typically 5 years on record retention when addressed

Record Retention – Other Issues

Current Areas of ConcernProposed Clarification(USP 797 proposed revision published 9/2015)

BUD based on chemical and physical stability and sterility: seeing 180 days on high risk preparations

Stability data obtained from: Manufacturer Published literature Stability indicating tests Formulas from API

distributor (PCCA, Medisca)

BUD is capped Stability of all

components and devices must be considered when assigning BUD

[12. ESTABLISHING BEYOND-USE DATES AND IN-USE TIMES: 12.2 Critical Parameters to Be Considered in Establishing a BUD and 12.3 Establishing a BUD for a CSP]

CSP Stability

Current USP 797Proposed Clarifications(USP 797 proposed revision published 9/2015)

Required for: All extended BUDs

regardless of risk level High risk CSPs prepared

in groups ≥25 single dose or multi-dose vials for multiple patients

High risk CSPs exposed to warm temperature for extended period of time

[FINISHED PREPARATION RELEASE CHECKS AND TESTS: Sterility Testing]

Sterility testing of Category 2 CSPs will allow for a longer BUD

[12. ESTABLISHING BEYOND-USE DATES AND IN-

USE TIMES: 12.3 Establishing a BUD for a CSP]

Sterility Testing

Current USP 797Proposed Clarification(USP 797 proposed revision published 9/2015)

Shall meet USP Chapter 71 Sterility Test or a method not described in USP may be used if verification results demonstrate that the alternative is at least as effective and reliable as USP 71 USP 71 - 14 days Rapid Scan – 3 days (non USP) Bioluminescence – 7 days (non

USP)

[FINISHED PREPARATION RELEASE CHECKS AND TESTS: Sterility Testing]

Must be performed in a manner consistent with USP 71, with the exception to batch size requirements in USP 71

[10. RELEASE TESTING: 10.2 Sterility Testing]

Sterility Test

Proposed BUDs Category 2 CSPs(USP 797 proposed revision published 9/2015)

Preparation Characteristics Storage ConditionsMethod of Achieving Sterility

Sterility Testing Performed

PreservativeAdded

Room Temp20-25 C

Refrigerator2-8 C

Freezer-25 - 10 C

BUD Aseptically Prepared No No 1 or more nonsterilestarting component

4 days

1 or more nonsterile starting component7 days

At least 1 nonsterilestarting component

45 days

BUD Aseptically Prepared No No Only sterilecomponents 6 days

Only sterile components9 days

Only sterilecomponents45 days

BUD Aseptically Prepared No Yes 28 days 42 days 45 days

BUD Aseptically Prepared Yes No 28 days 42 days 45 days

BUD Aseptically Prepared Yes Yes 42 days 42 days 45 days

BUD Terminally Sterilized No No 14 days 28 days 45 days

BUD Terminally Sterilized No Yes 28 days 42 days 45 days

BUD Terminally Sterilized Yes No 28 days 42 days 45 days

BUD Terminally Sterilized Yes Yes 42 days 42 days 45 days

Current USP 797Proposed Clarification(USP 797 proposed revision published 9/2015)

Referenced multiple times but not defined

Current practice: Infusion and Community –

have compound record Hospital

Batch Records Certain preparations (TPN,

Chemotherapy)[FINISHED PREPARATION RELEASE

CHECKS AND TESTS: Inspection of Solution Dosage Forms and Review of Compounding Procedures]

Master Formula for CSPs batched or prepared from nonsterile ingredients

Compound Record required for every CSP prepared

[9. SOPs AND MASTER FORMULATION AND COMPOUNDING RECORDS]

Compounding Record

Proposed Master Formulation Record Requirements(USP 797 proposed revision published 9/2015)

Name, strength, and dosage form of the CSP Physical description of the final preparation Identities and amounts of all ingredients and appropriate container-

closure systems Complete instructions for preparing the CSP, including equipment,

supplies, and a description of the compounding steps BUD and storage requirements Quality control procedures (e.g., pH, filter integrity, and visual

inspection) Sterilization method, if applicable (e.g., filter, steam or dry heat) Any other information needed to describe the operation and ensure

its repeatability (e.g., adjusting pH and tonicity and temperature)

[9. SOPs AND MASTER FORMULATION AND COMPOUNDING RECORDS: 9.2 Creating Mater Formulation Records]

Proposed Compounding Record Requirements(USP 797 proposed revision published 9/2015)

Name, strength, and dosage form of the CSP Master Formulation Record reference for the preparation, when used Date and time of preparation of the CSP Assigned internal identification number (e.g., prescription or lot number) Signature or initials of individuals involved in each step (e.g., technician or pharmacist) Name, vendor or manufacturer, lot number, and expiration date of each ingredient and

container–closure system Weight or measurement of each ingredient Documentation of the calculations made to determine and verify quantities and/or

concentrations of components, if appropriate Documentation of quality control procedures in accordance with the SOP (e.g., filter integrity,

pH, and visual inspection) Any deviations from the Master Formulation Record, if used, and any problems or errors

experienced during the compounding of the CSP Total quantity compounded Assigned BUD Duplicate container label if prepared in a batch

[9. SOPs AND MASTER FORMULATION AND COMPOUNDING RECORDS: 9.3 Creating Compounding Records]

Current ChapterProposed Revision(USP 797 proposed revision published 9/2015)

Pharmacy Bulk Package –bear a statement limiting the time frame in which the container may be used once it has been entered

Single-Dose Container – no preservative; vials exposed to ISO Class 5 air may be used up to 6 hours after initial needle puncture

[DEFINITIONS and SINGLE-DOSE AND MULTIPLE-DOSE CONTAINERS]

In-Use Time – the time before which a conventionally manufacturer product or a CSP must be used after it has been opened or needle punctured (e.g., after a container closure of a vial has been penetrated)

Compounded stock solution – in-use time is 6 hours

[12.4 Establishing In-Use Times]

Stock Solution/Pharmacy Bulk Package

Supervision

KRS 315.020(1) No owner of a pharmacy who is not a pharmacist shall fail to place a pharmacist in charge of his pharmacy or shall permit any person to compound or dispense prescriptions, drugs, medicines, or pharmaceuticals, in his place of business except in the presence and under the immediate supervision of a pharmacist

KRS 315.010(11) “Immediate Supervision” means under the physical and visual supervision of a pharmacist

KRS 315.010(25) “Supervision” means the presence of a pharmacist on the premises to which a pharmacy permit is issued, who is responsible, in whole or in part, for the professional activities occurring in the pharmacy

Supervision

Proposed revision: Supervisors of compounding personnel should observe compounding activities on a daily basis [2. PERSONNEL QUALIFICATIONS – TRAINING, EVALUATION AND REQUALFICATION]

Training of compounding personnel Some facilities have technicians training compounding

personnel Some facilities do not have any training on pharmacists

Will perform compounding Will check/supervise compounding

Future Meetings

Communication with sterile compounders Updates to Board Further areas requiring clarification Nuclear pharmacies Regulation update Require continuing education Report cards Out of state permits Non-sterile compounding USP 795

Requested Guidance

Cessation of compounding Retesting of room Compound record