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Essential Elements of Compounded Sterile Preparations

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Home Study Manual

ESSENTIAL ELEMENTS OF COMPOUNDED STERILE PREPARATIONS HOME STUDY

i DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Accreditation

Activity Title

Essential Elements of Compounded Sterile Preparations - Home Study

Activity Accreditation

Joint Accreditation Status (University of Florida College of Pharmacy / LP3 Network) Knowledge-Based Activity UAN: 0012-9999-16-008-H04-P/T for pharmacists and technicians UAN: 0012-9999-16-009-H03-P/T general law credit for pharmacists and technicians Home Study CPE Credits: 30 CPE Hours (29 CPE Hours General Pharmacy + 1 CPE Hour Law) = 3.0 CEUs Release Date: January 1, 2016 Expiration Date: January 1, 2019

Completion Requirements

To receive CPE credits for this home study activity, participants must complete a learning assessment with a score of 70% and submit a completed evaluation to the University of Florida College of Pharmacy.

Participants registered in the United States: The University of Florida College of Pharmacy will report CPE credits to the CPE Monitor. A paper copy of a statement of credit may be obtained from your NABP e-profile. For pharmacists registered in the state of Florida, University of Florida College of Pharmacy will report credits to the CE Broker.

Participants registered other than in the United States: Pharmacists and technicians will receive a statement of credit by mail.

Intended Audience

This Activity is suited for Pharmacists and Technicians new to sterile compounding or with an existing compounding practice. This Activity serves as a pre-requisite to a Live Event Activity, Essential Elements of Compounded Sterile Preparations - Live Event. While attendance at the live event is not mandatory to receive home study CE credit, participation in the live event will afford the participant opportunity to practice under supervision manual dexterity-related aseptic techniques and work with a broad range of technologies specific to a sterile compounding practice. Declarations and Disclosures

The University of Florida College of Pharmacy believes it is important for the reader to be aware of relevant affiliations and financial relationships regarding the development, design, and facilitation of accredited Activities and any material created in support of an Activity. This Activity, its content, material, and presenters, is independent of any known bias, prejudice, or commercial interest. Content and material presented will provide an in-depth representation with fair, full disclosure, and equitable balance. Topics which are promotional or designed for the purpose of endorsing a specific commercial product will not be presented.

The University of Florida College Pharmacy has requested that LP3 Network Inc. assist with the marketing of this Activity. LP3 Network Inc. is an independent corporation specialized in the development and design of continuing education material.

The University of Florida College of Pharmacy encourages participation in its continuing education programs by all qualified persons without regard to race, sex, creed, national origin, or religion.

The University of Florida College of Pharmacy will make reasonable accommodations for persons with disabilities under the guidelines of the Americans with Disabilities Act and Section 504 of the Rehabilitation Act (federal legislation).

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.


ii DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Financial Support An unrestricted educational grant has been provided by MEDISCA Inc. Copyright Home Study manual: Copyright © 2015 LP3 Network Inc.


iii DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Activity Description: This Knowledge-Based Activity will provide the pharmacist and technician with the necessary comprehension and know-how to meet current standards of practice required for non-hazardous and hazardous drug sterile compounding. Founded on a unique concept known as System P, participants will learn to appreciate the value of establishing a strong compounding practice infrastructure. System P includes the following divisions; Personnel, Property, Procedure, Process, Preparation, and Patient, as its building blocks. Each component of System P is very much dependent on, and in support of, each other. Personnel are a compounding pharmacy’s most important asset; this section covers personnel roles and responsibilities, competencies, practical testing requirements in the form of health and hygiene, garbing, media-fill challenge testing, fingertip touch testing, aseptic techniques, and hazard communication and medical surveillance programs. Personnel work in ISO class clean room environments and with technology categorized into electromechanical, reusable, disposable, personal protective equipment, safety and emergency equipment, deactivation/decontamination supplies and chemical agents, testing equipment and supplies, and the ingredients used to prepare compounded sterile preparations. The clean room and related technology and chemical supplies make up Property. Procedures are the routine scheduled activities performed in a sterile compounding practice that encompasses the management, maintenance, monitoring, calibration, decontamination and disinfection protocols, and environmental testing requirements that help to ensure chemical safe handling, inventory and storage, technology utilization, waste management, and facility and preparation sterility. Synonymous with Process Development, Preparations, and Patients are the detailing of the requirements of Process Development worksheets, Master Formulation Records, and Compounding Records. The home study showcases a sample and most comprehensive Master Formulation Record template; a critical and required center piece for any compounding practice that can be utilizes during the process of establishing formulations, well documenting master formulations and completing compounding records upon receipt of a prescription. Upon concluding this home study, participants will gain a solid foundation and well appreciate the reliance and interdependency between each System P category that is clearly delineated and detailed fulfilling required standards of practice.


iv DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Overall Learning Objectives for Pharmacists 1. Classify traditional compounding pharmacies and outsourcing facilities in order to understand the parameters of practice for each of these

two compounding classifications that fall under the new Drug Quality and Security Act H.R. 3204. 2. Describe the infrastructure and subdivisions of a quality management system for compounding; System P and its related categories. 3. Identify the relevance and impact of Unites States Pharmacopeia chapters and their relationship to a non-hazardous and hazardous

compounding practice. 4. Discuss roles and responsibilities, theoretical and practical skills, and performance verification-related testing required for personnel

involved in non-hazardous and hazardous compounding. 5. Discuss engineering and architectural design concepts and requirements for the safe handling and management of non-hazardous and

hazardous drugs. 6. Describe structural, functional, and operational primary and secondary engineering control requirements for the safe handling and

management of non-hazardous and hazardous drugs. 7. Relate principles of air pressure differentials, airflow dynamics, and critical first air to sterile compounding. 8. Express the relevance of technology used in non-hazardous and hazardous drug compounding; electromechanical, reusable, disposable,

personal protective equipment, safety, emergency, testing, and deactivation/decontamination and disinfection equipment and supplies. 9. Recall procedures involved in the safe handling, maintenance, monitoring, testing and verification of a sterile compounding environment. 10. Describe protocols for the deactivation/decontamination and disinfection of ISO class environments for non-hazardous and hazardous

drug compounding. 11. Outline the relative significance of Process Development as it applies to the development of a Master Formulation Record. 12. Relate the functions of excipients to compounded sterile preparations. 13. Discuss clinical considerations that must be applied to sterile compounding to help to ensure patient safety in a patient-centric practice. 14. Discuss the components of a Master Formulation Record used for compounded sterile preparations. 15. Recall pharmaceutical calculations used in a sterile compounding practice. 16. Repeat a comprehensive series of aseptic techniques related to the compounding of sterile preparations.

Overall Learning Objectives for Technicians

1. Identify the differences between traditional compounding pharmacies and outsourcing facilities under the new Drug Quality and Security Act H.R. 3204.

2. Describe the infrastructure and subdivisions of a quality management system for compounding; System P and its related categories. 3. List Unites States Pharmacopeia chapters and their relationship to a non-hazardous and hazardous compounding practice. 4. List roles and responsibilities, theoretical and practical skills, and performance verification-related testing required in maintaining an

appropriate level of competency when performing non-hazardous and hazardous compounding. 5. Recognize engineering and architectural design concepts required for the safe handling and management of non-hazardous and hazardous

drugs. 6. Recognize structural, functional, and operational primary and secondary engineering controls when compounding and handling non-

hazardous and hazardous drugs. 7. Relate principles of air pressure differentials, airflow dynamics, and critical first air to sterile compounding. 8. Identify relevant technology used in non-hazardous and hazardous drug compounding; electromechanical, reusable, disposable, personal

protective equipment, safety, emergency, testing, and deactivation/decontamination and disinfection equipment and supplies. 9. Recall procedures involved in the safe handling, maintenance, monitoring, testing and verification of a sterile compounding environment. 10. Relate protocols for the deactivation/decontamination and disinfection of ISO class environments to non-hazardous and hazardous drug

compounding activities. 11. Recognize the importance of Process Development leading to the development of a Master Formulation Record. 12. Recognize the functions of excipients found in sterile preparation master formulation records. 13. Recognize clinical considerations a pharmacist-in-charge must consider to ensure patient safety in a patient-centric practice. 14. Explain how to follow and complete a Master Formulation Record used for documenting compounded sterile preparations.

15. Recall pharmaceutical calculations used under the supervision of a pharmacist-in-charge in a sterile compounding practice. 16. Repeat a comprehensive series of aseptic techniques related to the compounding of sterile preparations.


v DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Editors:

Neil Cohen, BSc. CE Coordinator, LP3 Network Inc. Disclosure: MEDISCA INC., Consultant Daphnee Lalonde, BSc., MSc. Program Developer, LP3 Network Inc. Disclosure: MEDISCA INC., Consultant Contributors:

Mark Filosi, BS Pharm., RPh. Compounding Pharmacist and Co-Founder, Family Care Pharmacy Disclosure: Accreditation Commission for Health Care, Surveyor; MEDISCA INC., Consultant Kenneth Latta, BS Pharm., RPh., FIACP., FACA. Senior Associate, Gates Healthcare Associates Disclosure: Health System Consulting Group LLC, Co-Owner and Consultant; Gates Healthcare Associates Inc., Consultant; Accreditation Commission for Health Care(ACHC)/Pharmacy Compounding Accreditation Board (PCAB), Surveyor; North Carolina Board of Pharmacy, Consultant; Visante UK, Consultant; Visante Inc., Consultant; MEDISCA INC., Consultant Christine Roussel, PharmD., BCOP. Clinical Pharmacy Manager, Doylestown Hospital Disclosure: MEDISCA INC., Consultant Ken Speidel, BS Pharm., PharmD., RPh., FIACP., FACA. Senior Associate, Gates Healthcare Associates Disclosure: Accreditation Commission for Health Care (ACHC), Surveyor; Gates Healthcare Associates, Consultant; MEDISCA INC., Consultant


vi DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Table of Contents Accreditation ............................................................................................................................................ i Layout of Home Study Manual ................................................................................................................. 1

Section 1: An Introduction to the Law, Standards of Practice, and System P ............................................. 2

The Drug Quality and Security Act ............................................................................................................ 2

Practice Parameters ................................................................................................................................ 4

FDA Guidance on Compounding Animal Drugs from Bulk Drug Substances ............................................... 5

FDA Guidance on Repackaging of Certain Human Drug Products by Pharmacies ....................................... 8

An Introduction to Sterile Compounding and System P ............................................................................ 9

System P: A Quality Management System .............................................................................................. 10

General Quality Management Principles & Practices .............................................................................. 11

Quality Management and Risk Assessment ............................................................................................ 11

Standards of Practice for Sterile Compounding ...................................................................................... 12

USP Chapter <797> Breakdown .............................................................................................................. 16

USP Chapter <797> Risk Classifications .................................................................................................. 17

USP Chapter <797> Risk Levels and Beyond-Use Dates ........................................................................... 18

Applying the ‘Suitability Factor’ to a Quality Management System ......................................................... 19

Analytical Verification Parameter of a Quality Management System ...................................................... 20

Section 2: P1 - Personnel ....................................................................................................................... 21

Personnel Training Requirements .......................................................................................................... 22

Standard Operating Procedures as a means of Personnel Training .......................................................... 22

Modes of Personnel Training ................................................................................................................. 23

Training Requirements .......................................................................................................................... 23

Personnel Roles and Responsibilities ..................................................................................................... 24

Personnel Performance Assessment Testing Requirements .................................................................... 24

Sample Media-Fill Challenge Test ........................................................................................................... 25

Personnel and Hazardous Drug Compounding ........................................................................................ 26

Hazard Communication Program ........................................................................................................... 26

Medical Surveillance Program ................................................................................................................ 27

Section 3: P2 - Property ......................................................................................................................... 28

Facility Design: Primary and Secondary Engineering Controls ................................................................. 29

Secondary Engineering Controls .......................................................................................................... 30

Compounding-specific ISO Class Clean Room Requirements for Non-Hazardous Drug Compounding ...... 31

Compounding-specific ISO Class Clean Room Requirements for Hazardous Drug Compounding .............. 31

Additional ISO Class Clean Room Requirements ..................................................................................... 31

Effect of Turbulent Air ......................................................................................................................... 32

Air Filter Systems ................................................................................................................................. 33

The "Funnel Effect" .............................................................................................................................. 34

General Principles of Air Flow .............................................................................................................. 35

General Principles of Containment of Hazardous or Bioengineered Drugs ......................................... 35

Airborne Particulate Count .................................................................................................................. 36

Microbial Counts ................................................................................................................................... 36

Humidity Control .................................................................................................................................. 37

Clean Air Exchange ............................................................................................................................... 37


vii DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Frequency per Hour ............................................................................................................................. 37

Filter Coverage ...................................................................................................................................... 38

Facility Design Characteristics ................................................................................................................ 39

Common Errors in Facility Design ........................................................................................................ 40

Facility Design Diagram.......................................................................................................................... 41

Functional and Operational Considerations in Facility Design ............................................................ 42

Verification of Facility Design Plans ..................................................................................................... 44

Primary Engineering Controls................................................................................................................. 45

Compounding Aseptic Isolator / Compounding Aseptic Containment Isolator ................................... 46

Biological Safety Cabinets .................................................................................................................... 47

Containment Ventilated Enclosure or Vented Balance Safety Enclosure ............................................ 48

Automated Compounding Devices ....................................................................................................... 49

Sterilization Equipment ......................................................................................................................... 51

Material Types of Reusable and Disposable Devices ........................................................................... 52

Filtration Systems for Large and Small Volumes .................................................................................. 53

Compatibility Characteristics between Filters and Chemicals.................................................................. 55

Transferring Devices ............................................................................................................................ 56

Disposable Syringes and Needles ........................................................................................................... 57

Needles ................................................................................................................................................. 58

Disposable Tubing and Transfer Sets ...................................................................................................... 58

Packaging Devices and Materials ........................................................................................................... 62

Closed System Transfer Devices ............................................................................................................. 64

Personal Protective Equipment .............................................................................................................. 65

Testing Technology ................................................................................................................................ 66

Non-viable Particulate Monitoring Technology ...................................................................................... 67

Viable Particulate Monitoring Technology ............................................................................................. 68

Sterility Testing Technology for Compounded Sterile Preparations ......................................................... 69

Membrane Filtration ............................................................................................................................. 69

Membrane Filtration Method for Sterility Testing Technology ................................................................ 70

Direct Inoculation .................................................................................................................................. 71

Inoculation-Oil Test Technology ............................................................................................................. 72

Endotoxin Testing Technology ............................................................................................................... 73

Indicator and Integrator Test Technology ............................................................................................... 74

Growth Media Technology..................................................................................................................... 75

Section 4: P3 - Procedure ....................................................................................................................... 76

Equipment and Technology Management .............................................................................................. 77

Durable Medical Equipment and Automated Compounding Devices ...................................................... 77

Calibration and Monitoring .................................................................................................................... 77

Sampling and Testing ............................................................................................................................. 77

Environmental Monitoring..................................................................................................................... 77

Chemical Safety Standards ..................................................................................................................... 78

Chemical Safety and Storage Requirements ........................................................................................... 80

Hazardous Drug Storage Requirements .................................................................................................. 80

Environmental Management - Sterile Rooms and Work Area ................................................................. 81

General Principles of Deactivation/Decontamination and Disinfection ................................................... 82


viii DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Efficacy of Disinfecting Agents ............................................................................................................... 83

Some General Characteristics of Disinfecting Agents .............................................................................. 84

Schedules for Disinfection ..................................................................................................................... 85

Daily versus Monthly Cleaning and Disinfection ..................................................................................... 86

Sample of Weekly Disinfection Schedule ................................................................................................ 87

Procedures for Deactivation/Decontamination and Disinfection for Hazardous Drug Compounding ....... 88

Spill Control ........................................................................................................................................... 88

Procedures for Handling Hazardous Drugs ............................................................................................. 89

Discriminating between Disinfection, Sterilization, and Depyrogenation ........................................... 90

Section 5: P4 - Process ........................................................................................................................... 91

Process Development ............................................................................................................................ 92

Excipients Used in Compounded Sterile Preparations ............................................................................. 93

Antioxidants .......................................................................................................................................... 94

Preservatives ........................................................................................................................................ 95

Osmolarity ............................................................................................................................................ 95

Efficacy Enhancers ................................................................................................................................. 95

Solvents and Co-Solvents ....................................................................................................................... 95

Selection of Solvents and Co-solvents: ................................................................................................... 96

Parenteral Solutions Used in Sterile Compounding ................................................................................. 97

Base Solutions and Components of Parenteral Admixtures .................................................................... 98

pH Adjusters and Compounded Sterile Preparations .............................................................................. 99

A pH Testing and Adjusting Procedure ................................................................................................... 99

Balancing Physiological pH with required pH of a CSP ...........................................................................100

Commonly Used pH Adjusters ...............................................................................................................100

Buffering a Preparation ........................................................................................................................101

Active Pharmaceutical Ingredient Characteristics in a Compounded Sterile Preparation ........................101

Chemical Sensitivities Associated with Sterile Preparations ..............................................................102

Heating, Freezing, and Thawing of a Sterile Preparation ...................................................................103

Section 6: P5 - Preparation....................................................................................................................104

Verification of Preparations ..................................................................................................................105

End-Stage Filtration of Compounded Sterile Preparations .................................................................105

Wet and Dry Heat Sterilization of Compounded Sterile Preparations ..................................................106

Quarantine Inspection of Compounded Sterile Preparation...................................................................107

Section 7: P6 - Patient ...........................................................................................................................108

Patient and Caregiver Instruction and Counselling ................................................................................109

Patient Monitoring ...............................................................................................................................109

Event Recording and Reporting .............................................................................................................109

Clinical Considerations related to Sterile Compounding ........................................................................110

Section 8: Master Formulation Record Template ...................................................................................113

Master Formulation Record Signatories ................................................................................................114

CSP Shipping Requirements ..................................................................................................................121

CSP Test Results Summary ....................................................................................................................122

Section 9: Pharmaceutical Calculations for Compounded Sterile Preparations .......................................124

Section 10: Aseptic Manipulations in Sterile Compounding ...................................................................152

Aseptic Techniques: Personnel Preparation .......................................................................................153


ix DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Aseptic Techniques: Moving into and between ISO Class Environments ................................................154

Aseptic Techniques: Moving out of and between ISO Class Environments .............................................155

Aseptic Techniques: Hazardous Drug Compounding ..............................................................................156

Working in the Clean Room ................................................................................................................157

General Rules Regarding Aseptic Manipulations ................................................................................158 Aseptic Manipulation - Opening Sterile Packaging .................................................................................................................. 159 Aseptic Manipulation - Opening and and Swabbing a Vial or Bottle ....................................................................................... 160 Aseptic Manipulation - Swabbing Rubber Stoppers and Entry Ports ....................................................................................... 161 Aseptic Manipulation - Needle-to-Syringe Connection (Luer) ................................................................................................. 162 Aseptic Manipulation - Needle-to-Syringe Connection (Slip) ................................................................................................... 163 Aseptic Manipulation - Removing or Recapping a Needle Guard ............................................................................................ 164 Aseptic Manipulation - Syringe-to-Vented Dispensing Pin Connection (Luer) ......................................................................... 165 Aseptic Manipulation - Needle-from-Syringe Removal ............................................................................................................ 166 Aseptic Manipulation - Syringe-from-Plunger Removal ........................................................................................................... 167 Aseptic Manipulation - Air Bubble Removal from Syringe ....................................................................................................... 168 Aseptic Manipulations & Techniques - Syringe Volume Reading and Adjustment .................................................................. 169 Aseptic Manipulation - Luer-to-Luer Adaptor Connection ....................................................................................................... 170 Aseptic Manipulation - Syringe-to-Syringe Via Adaptor Mixing ............................................................................................... 171 Aseptic Manipulation - Syringe-to-Cap Connection (Luer & Slip) ............................................................................................ 172 Aseptic Manipulation - Syringe Plunger Draw (Single Handed) ............................................................................................... 173 Aseptic Manipulation - Syringe Plunger Draw (Two Handed) .................................................................................................. 174 Aseptic Manipulation - Swabbing Ampule Neck ...................................................................................................................... 175 Aseptic Manipulation - Ampule Fluid Shift from Stem ............................................................................................................. 176 Aseptic Manipulation - Ampule Opening ................................................................................................................................. 177 Aseptic Manipulation - Filter Needle........................................................................................................................................ 178 Aseptic Manipulation - Opening Filter Steri-wrap .................................................................................................................... 179 Aseptic Manipulation - Handling a Disc Filter (Luer) ................................................................................................................ 180 Aseptic Manipulation - Handling a Disc Filter (Slip) ................................................................................................................. 181 Aseptic Manipulation - Handling Cartridge Filter ..................................................................................................................... 182 Aseptic Manipulation - Large Volume Filter Barrels ................................................................................................................. 183 Aseptic Manipulation - Needle Insertion into Vial ................................................................................................................... 184 Aseptic Manipulation - Injection into Evacuated Glass Bottle ................................................................................................. 185 Aseptic Manipulation - Venting a Bottle .................................................................................................................................. 186 Aseptic Manipulation - Bag-to-Tubing Connection (Vented) ................................................................................................... 187 Aseptic Manipulation - Drawing from Beaker .......................................................................................................................... 188 Aseptic Manipulation - Transfer Set Vented Spike Connection ............................................................................................... 189 Aseptic Manipulation - Transfer Set Stop Clamp ..................................................................................................................... 189 Aseptic Manipulation - Venting a Vial with Vented Spike ........................................................................................................ 190 Aseptic Manipulation - Liquid Withdrawal from Vial with Syringe-to-Needle Connection ...................................................... 191 Aseptic Manipulation - Air Exchange in Withdrawing ("Milking") ........................................................................................... 192 Aseptic Manipulation - Drawing from Spiked Bottle ................................................................................................................ 193 Aseptic Manipulation - Drawing from Spiked IV Bags .............................................................................................................. 194 Aseptic Manipulation - Injection into a Plastic IV Bag .............................................................................................................. 195 Aseptic Manipulation - Syringe Ejection through Needle into IV Bag Port .............................................................................. 196 Aseptic Manipulation - Syringe Ejection through Needle into Vented Bottle .......................................................................... 197 Aseptic Manipulation - Eye Dropper Bottle Tip Sparing Technique ......................................................................................... 198 Aseptic Manipulation - Injection into Eye Dropper Bottle ....................................................................................................... 198 Aseptic Manipulation - Positive and Negative Pressure Plunger Effect ................................................................................... 199 Aseptic Manipulation - Transferring from Bottle-to-Vial with Mechanical Transfer Device .................................................... 200 Aseptic Manipulation – Membrane Filtration Method of Sterility Testing .............................................................................. 201 Aseptic Manipulation – Closed System Transfer Devices for Hazardous Compounding .......................................................... 202

References ...........................................................................................................................................203


x DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.


1 DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding is for educational reference purposes only and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO PHARMACISTS: Any treatments, therapies or standards of practice must be fully investigated and prescribed only by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be ful ly investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia.

Layout of Home Study Manual This manual is divided into the following sub-sections:

Introduction to the law, standards of practice, and System P

System P - A Quality Management System

1. Personnel 2. Property 3. Procedure 4. Process 5. Preparation 6. Patient

Master Formulation Record template

Pharmaceutical calculations

Aseptic techniques



Section 1: An Introduction to the Law, Standards of Practice, and System P The Drug Quality and Security Act The Drug Quality and Security Act (DQSA H.R. 3204) resulted in two distinct classifications within compounding which includes:

1. A Traditional Compounding Pharmacy 2. An Outsourcing Facility

Differentiations regarding practice parameters between these two classifications of pharmacy services are outlined in the next few tables.

Practice Parameters

Traditional Compounding Pharmacy (503A Classification)

Outsourcing Facility (503B Classification)

Compounding Requirements

1. Cannot compound copies of commercially

available drugs. 2. Compounding must be performed by a licensed

pharmacist, pharmacy technician, or physician in a licensed pharmacy or federal facility.

3. Compounding performed upon receipt of a prescription for an individual patient.

4. Anticipatory compounding in limited quantities before the receipt of a valid prescription order for an individual patient must be limited to the history for a particular drug associated with an individual patient or the history of a prescriber with whom the compounder has an established relationship.

5. Cannot compound for office-use or a hospital unless prescription is for a specific patient.

6. For pharmacies in states that have not signed a memorandum of understanding (MOU) with the FDA, a maximum of 5% of the total prescription orders dispensed or distributed by the pharmacy can be distributed or sold as interstate commerce. Pharmacies in states that have signed an MOU with the FDA can distribute or sell compounded preparations as interstate commerce (30% maximum).

1. Cannot compound copies of commercially

available drugs. 2. Engaged in the compounding of sterile

preparations. 3. Compounding must be under the direct

supervision of a licensed pharmacist, but is not required to be a licensed pharmacy.

4. Compounding can be performed before, with or without receipt of a prescription for an individual patient.

5. Compounded preparation must be on the FDA drug shortage list or on the FDA list identifying the bulk drug substances for which there is a clinical need.

6. Can only sell compounded drugs to a healthcare facility that provides medical services directly to patients or a network of licensed providers.

7. Can distribute compounded preparations for office-use and hospitals.

8. Can distribute or sell compounded preparations in interstate commerce (no maximum).



The Drug Quality and Security Act

Practice Parameters



Ingredient Requirements

1. Drugs must have a USP-NF monograph, or be

components of an FDA approved drug, or be on the FDA-approved list of bulk drug substances that may be used to compound drug products.

2. Cannot compound with drugs that are on the FDA list of drugs that demonstrate difficulty to compound.

3. Cannot compound with drugs that are on the FDA list of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness.

1. Drugs must have a USP-NF monograph, or be

components of an FDA approved drug list, and be on the FDA-approved list of bulk drug substances that may be used to compound drug products; and/or bulk ingredients must be on the drug shortage list or on a list approved by the secretary of the FDA. These are the only two allowable sources of APIs.

2. Cannot compound with drugs that are on the FDA list of drugs that demonstrate difficulty to compound.

3. Cannot compound with drugs that are on the FDA list of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness.

4. Cannot compound drugs subject to Risk Evaluation and Mitigation Strategy (REMS) unless the pharmacy uses comparable controls to the REMS.

5. Must have a valid Certificate of Analysis and come from an FDA registered supplier.

FDA Registration Requirements

None

Mandatory annual registration

FDA Reporting Requirements

None

1. Upon registering and biannually, the outsourcing

facility must submit a report identifying all drugs compounded.

2. Outsourcing facility must report serious adverse events within 15 days and conduct follow-up investigation and reporting.

Standards of Practice

USP

cGMP

Governing Authority

Primarily regulated by State Boards of Pharmacy; FDA retains some authority over their operations.

FDA; however some states also require licensure.



Practice Parameters The following table illustrates under what circumstance each of the two classifications of pharmacies can perform acts of compounding. It is imperative that all compounding personnel respect these parameters of practice as defined by the DQSA.

Circumstances under which a Traditional Compounding Pharmacy and an Outsourcing Facility may Conduct Business

Circumstance Traditional Compounding Pharmacy

(503A Classification) Outsourcing Facility (503B Classification)

Drug shortages Yes, with a patient-specific prescription. Yes

Compounding for Office Use

Pharmacies cannot compound for office use or hospitals unless associated with a patient-specific prescription

order. Numerous state boards of pharmacy indicate that they allow 503A pharmacies to compound for office use. State boards of pharmacy will have to consider how to

deal with the new HR 3204 provisions in their standards of practice.

Compounding with a Patient-specific

Prescription Order Yes

However, those prescriptions must be prepared in accordance with Good Manufacturing Practices. This

has major economic and operational implications.

Compounding without a Patient-specific

Prescription Order

Anticipatory compounding in limited quantities before the receipt of a valid prescription order for an individual

patient must be limited to the history for a particular drug associated with an individual patient or the history of a

prescriber with whom that compounder has an established relationship.

Yes

Compounding for a Hospital

Must be patient-specific. Does not require a patient-specific prescription.

Compounding for Interstate Commerce

If the state did not sign an MOU with the FDA: 503A pharmacy is permitted a maximum interstate distribution

of 5% of the total prescription orders dispensed or distributed by the pharmacy. (Does not specify if it is 5% of

the total number of prescription orders or the total prescription order preparation size/amount). If the state signed an MOU with the FDA: 503A pharmacy would be

permitted more than 5% total prescription interstate distribution (up to 30%). It does not specify whether the state it distributes to needs to have signed an MOU with

the FDA as well.

Yes



FDA Guidance on Compounding Animal Drugs from Bulk Drug Substances In May 2015, the FDA released a new proposed guidance on its enforcement policies for compounding of veterinary preparations from bulk drug substances. This differs from the AMDUCA act as the FDA guidance document refers to compounding from bulk substances

1 whereas AMDUCA refers to extra-label drug use provisions from approved animal and human drugs.

The FDA guidance delineates 3 sets of policies which are summarized on the following pages:

- Bulk ingredient compounding by a 503A state-licensed pharmacy - Bulk ingredient compounding by a licensed veterinarian - Bulk ingredient compounding by a 503B outsourcing facility

Practice Parameters



Prescription Requirements

1. Must come directly from the prescribing veterinarian or from the patient’s owner/caretaker to the compounding pharmacy.

2. Individually identified animal patient and identification of the species of animal.

3. The drug is not intended for use in food-producing animals and the statement “This patient is not a food-producing animal.”

4. If the drug bulk substance is a component of an approved animal or human drug, a statement that the change between the compounded drug and the FDA-approved drug would produce a clinical difference. For example, “Compounded drug X would produce a clinical difference for the individually identified animal patient because the approved drug is too large a dose for the animal and cannot be divided or diluted into the small dose required.”

5. The statement “There are no FDA-approved animal or human drugs that can be used as labeled or in an extra-label manner under section 512(a)(4) or (5) and 21 CFR part 530 to appropriately treat the disease, symptom, or condition for which this drug is being prescribed.”

1. Individually identified animal patient or an order from a licensed veterinarian for veterinarian office use where the animal species and condition is identified.

2. The drug is not intended for use in food-producing animals and the statement “This drug will not be dispensed for or administered to food-producing animals.”

1 Bulk substances are defined by the FDA as “any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes and active ingredient or a finished dosage form of the drug, but the term does not include intermediates used in the synthesis of such substances.”



FDA Guidance on Compounding Animal Drugs from Bulk Drug Substances

Practice Parameters




1. The compounded medication must produce a clinical difference for that individually identified animal patient as determined by the veterinarian.

2. If the drug bulk substance is a component of an approved animal or human drug, there must be a change between the compounded drug and the comparable FDA-approved animal or human drug.

3. If there is an FDA-approved animal or human drug with the same active ingredient(s), the pharmacy determines that the compounded drug cannot be made from the FDA-approved drug(s), and documents that determination.

n/a

Ingredient Requirements

1. Bulk drug substances must be manufactured by an establishment that is registered under section 510 of the FD&C Act (21 U.S.C. 360) (including a foreign establishment).

2. Bulk drug substances must be accompanied by a valid certificate of analysis.

1. The drugs are compounded only from bulk drug substances appearing on Appendix A of the FDA draft guidance on compounding animal drugs from bulks substances.

2. Bulk drug substances must be manufactured by an establishment that is registered under section 510 of the FD&C Act (21 U.S.C. 360) (including a foreign establishment).

3. Bulk drug substances must be accompanied by a valid certificate of analysis.

Compounder Requirements

The drug is compounded by or under the direct supervision of a licensed pharmacist.

The drug is compounded by or under the direct supervision of a licensed pharmacist.

Standards of Practice

USP <795> and <797> cGMP

Selling and Transferring

Requirements

The drug is not sold or transferred by an entity other than the entity that compounded the preparation.

2

The drug is not sold or transferred by an entity other than the outsourcing facility.

3

Reporting Requirements

Must report product defects and serious adverse events to the FDA within 15 days and conduct follow-up investigation and reporting.

1. Must report product defects and serious adverse events to the FDA within 15 days and conduct follow-up investigation and reporting.

2. Biannual reporting of all drugs compounded.

2 A sale or transfer does not include administration of a compounded drug by a veterinarian to a patient under his or her care. 3 A sale or transfer does not include administration of a compounded drug by a veterinarian to a patient under his or her care.



FDA Guidance on Compounding Animal Drugs from Bulk Drug Substances

Bulk ingredient compounding by a licensed veterinarian

Prescription Requirements

1. Individually identified animal patient and identification of the species of animal. 2. The drug is not intended for use in food-producing animals and the statement “This patient is

not a food-producing animal.” 3. If the drug bulk substance is a component of an approved animal or human drug, a statement

that the change between the compounded drug and the FDA-approved drug would produce a clinical difference. For example, “Compounded drug X would produce a clinical difference for the individually identified animal patient because the approved drug is too large a dose for the animal and cannot be divided or diluted into the small dose required.”


1. The compounded medication must produce a clinical difference for that individually identified animal patient as determined by the veterinarian.

2. If the drug bulk substance is a component of an approved animal or human drug, there must be a change between the compounded drug and the comparable FDA-approved animal or human drug.

3. There are no FDA-approved animal or human drugs that can be used as labeled or in an extra-label manner.

Ingredient Requirements 1. Bulk drug substances must be manufactured by an establishment that is registered under

section 510 of the FD&C Act (21 U.S.C. 360) (including a foreign establishment). 2. Bulk drug substances must be accompanied by a valid certificate of analysis.

Compounder Requirements

The drug is compounded and dispensed by the veterinarian to treat an individually identified animal patient under his or her care.

Standards of Practice USP <795> and <797>

Selling and Transferring Requirements

The drug is not sold or transferred by the veterinarian compounding the drug.4

Reporting Requirements Must report product defects and serious adverse events to the FDA within 15 days and conduct follow-up investigation and reporting.

4 A sale or transfer does not include administration of a compounded drug by a veterinarian to a patient under his or her care or the dispensing of an animal drug compounded by the veterinarian to the owner or caretaker of an animal under his or her care.



FDA Guidance on Repackaging of Certain Human Drug Products by Pharmacies

In February 2015, The FDA released a new proposed guidance on its enforcement policies for repackaging of drug products. FDA defines repackaging as the act of taking a finished drug product from the container in which it was distributed by the original manufacturer and placing it into a different container without further manipulation of the drug. Repackaging also includes the act of placing the contents of multiple containers (e.g., vials) of the same finished drug product into one container, as long as the container does not include other ingredients. The FDA does not consider the following an act of repackaging: If a drug is manipulated in any other way, if the drug is reconstituted, diluted, mixed, or combined with another ingredient.

In 2015, the FDA also released a proposed guidance on mixing, diluting, or repackaging biological products outside the scope of an approved biologics license application. The FDA defines a biological product as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

Product Beyond-use Date State-Licensed Pharmacy Conditions

Non-sterile

“In use” time per the product labeling or expiration whichever is sooner

No specified in use time: BUD is less than or equal to the expiration date on the original drug product being repackaged

Repackaged in accordance with USP <795>

Sterile

• “In use” time per the product labeling or expiration whichever is sooner

• No specified in use time: BUD is less than or equal to the expiration date on the original drug product being repackaged or the below BUD, whichever is shortest: - ≤ 30 hours if stored at controlled room temperature;

- ≤ 9 days if stored in a refrigerator; or - ≤ 45 days if stored in a solid frozen state between -

25°C and -10°C

There is no option to extend the BUD by sterility testing or other means


Biologics

No longer than 4 hours, or is equal to the time within which the opened product is to be used as specified in the approved labeling, whichever is shorter; or

24 hours if microbial challenge testing is performed using same container and process.




An Introduction to Sterile Compounding and System P There are many sequentially ordered tasks that need to be performed in order to ensure the integrity, sterility, stability, and strength of a compounded sterile preparation (CSP). Within each task, there may be additional sequentially ordered tasks; we often refer to these as Standard Operating Procedures (SOPs). Furthermore, there are relationships that exist between tasks. These tasks now become interdependent. We have created a system for categorizing all the tasks, roles and responsibilities required as set forth in standards of practice and scientific principles. We refer to this organized and inter-related infrastructure as System P. System P is a hierarchy of sorts that simply states personnel work within a property or facility utilizing a broad range of technology. These personnel follow procedures that are in support of a sterile compounding practice’s overall operation. Within that operation, there exists Master Formulation Records (MFRs). These MFRs are made up of a formula, its own pre-, in-, and post- qualification protocols, technological requirements, and then some. Once the process of establishing a MFR is complete and verified, it can be used along with a prescription from a licensed physician and becomes a Compounding Record (CR). All this, of course, is for the benefit of a patient.

System P

P Category

Name of Category

Description of Category

P1 Personnel All employees within your compounding practice; their roles and responsibilities, training and competency.

P2 Property Everything you own; facility, technology and chemicals.

P3 Procedure All procedures once removed and in support of a MFR, CR, and CSP.

P4 Process All MFR’s in development; synonymous with development and rehearsal of MFR’s; commonly referred to as process development.

P5 Preparation The MFR used to finalize a CR, the CR and the final CSP.

P6 Patient All clients receiving compounded medications from your practice; their counselling, monitoring and outcome measures.



System P: A Quality Management System Personnel, in the context of System P include theoretical and practical training requirements for all personnel working in a sterile compounding practice. This includes Fingertip Touch Tests (FTTs), Media-Fill Challenge (MFC) tests, and a wide range of competency assessments, certifications and re-certifications. Once personnel skill levels are well assessed, careful consideration needs to be given to the delineation of responsibilities amongst personnel. Personnel include all pharmacists, technicians and support staff that will be responsible for, in any manner, tasks that will affect the integrity, sterility, strength and stability of a compounded sterile preparation. Property, in the context of System P is defined as any and all facility structures of a sterile compounding practice; Secondary Engineering Controls (SECs), Primary Engineering Controls (PECs), electromechanical equipment, reusable and disposable devices, Personal Protective Equipment (PPE), safety and emergency equipment, disinfecting and decontaminating supplies, and testing technology. All technology undergoes the processes of selection, installation, verification, calibration, and in some instances certification, prior to the point of first use. Chemicals in the form of Active Pharmaceutical Ingredients (APIs) and all excipients also fall under property. Chemicals must also undergo a certain level of scrutiny. As such each chemical purchased should be accompanied by a Certificate of Analysis (C of A). For the purposes of safety a Safety Data Sheet (SDS) should also be acquired and made available to all personnel all the time. Procedure, in the context of System P are all tasks, once removed, and in support of a compounded sterile preparation. It includes the general operation and verification of a compounding facility, and its maintenance, monitoring, control, decontaminating, disinfecting, both internal and external to ISO class environments. It also includes the maintenance, decontaminating, disinfecting, monitoring, control and calibration of technology. Finally, Procedure involves selection, inventory control, safe handling, and the recall capability of active pharmaceutical ingredients and excipients, hazardous drugs, and controlled substances. Process, in the context of System P is synonymous with Process Development (PD) during the establishment and refinement of a Master Formulation Record. It includes the verification of the formulation, its procedure, and all pre-, in-, and post- qualification related protocols. It includes the selection of appropriate aseptic techniques, equipment and devices, mathematical calculations, packaging, filtration and sterilization methods, and the establishment of a Beyond-Use Date (BUD). A major component of Process is the internal and external testing of protocols associated with a MFR and is conducted during PD leading toward the establishment of the MFR. Preparation, in the context of System P is defined as all tasks performed in support of the development of a sterile preparation. All that is necessary to follow a MFR is included in Preparation. It includes such elements of a MFR as personnel selection, ISO class environment assignment, aseptic technique selection, filtration, sterilization, inspection, packaging, labeling, of the CSP. Patient, in the context of System P is defined as all health care related activities that take place upon issuing a CSP to a patient or caregiver focusing on initial counselling. Instructions, oral and written include administration, indications, cautions, and possible explanations of contraindications. It will also include patient care monitoring practices; patient outcome, adverse event reporting, statistical recording and applicable reporting.



General Quality Management Principles & Practices

General Quality Management Principles & Practices

Action Items

Document all activities re: monitoring, controlling, maintaining, evaluating

Document all auditing practices and results of audits for:

Sterility-related factors: successes and failures

CSP Techniques

Accuracy and error prevention

Medication administration and management

Therapeutic outcome measures and adverse drug reactions

Corrective actions

Business practices

Reporting adverse events

Quality Management and Risk Assessment There are two types of risk; regulatory and clinical. While standards of practice-related risk equates to USP Chapter <797> and its related chapters along with State, Provincial and Federal laws and regulations, clinical risk relates to medical matters and conditions not addressed in regulatory guidelines. As a licensed professional you must sometimes evaluate clinical risk and determine whether or not it will affect a specific regulation. You must always use your professional judgment.



Standards of Practice for Sterile Compounding Along with USP Chapter < 797> there are other standards of practice that require due consideration. Please find below a list of additional USP chapters that require your immediate attention.

USP Chapters Relevant to Sterile Compounding

USP Chapter USP Chapter Subject

797 Pharmaceutical Compounding – Sterile Preparations

800 <Proposed> Hazardous Drugs – Handling in Health Care Settings

1160 Pharmaceutical Calculations in Prescription Compounding

1163 Quality Assurance in Pharmaceutical Compounding

1176 Prescription Balances and Volumetric Apparatus

USP Chapters Relevant to Sterile Compounding


General Notices and Requirements

11 USP Reference Standards

17 Prescription Container Labeling

698 Deliverable Volume

699 Density of Solids

1072 Disinfectants and antiseptics

1079 Good Storage and Distribution Practices for Drug Products

1121 Nomenclature

1163 Quality Assurance in Pharmaceutical Compounding

1196 Pharmacopeial Harmonization

1231 Water for Pharmaceutical Purposes

1265 Written Prescription Drug Information - Guidelines



Standards of Practice for Sterile Compounding

Equipment-related: USP Chapters Relevant to Sterile Compounding


1 Injections

21 Thermometers

31 Volumetric Apparatus

41 Balances

791 pH

1251 Weighing on an Analytical Balance

Packaging-related: USP Chapters Relevant to Sterile Compounding


381 Elastomeric Closures for Injections

601 Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers

659 Packaging and Storage Requirements

660 Containers – Glass

661 Containers - Plastic

671 Containers – Performance Testing

1177 Good Packaging Practices

1178 Good Repackaging Practices

1136 Packaging and Repackaging – Single Unit Containers

1151 Pharmaceutical Dosage Forms

1191 Stability Considerations in Dispensing Practice

1660 Evaluation of the Inner Surface Durability of Glass Containers




Preparation Safety-related: USP Chapters Relevant to Sterile Compounding


61 Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests

62 Microbiological Examination of Non-Sterile Products: Tests for Specified Microorganisms

71 Sterility Tests

85 Bacterial Endotoxin Test

151 Pyrogen Test

788 Particulate Matter in Injections

1031 The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants

1035 Biological Indicators For Sterilization

1066 Physical Environments That Promote Safe Medication Use

1111 Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use

1113 Microbial Characterization, Identification, and Strain Typing

1116 Microbiological Control and Monitoring of Aseptic Environments

1209 Sterilization: Chemical and Physicochemical Indicators and Integrators

1211 Sterilization and Sterility Assurance of Compendial Articles

1222 Terminally Sterilized Pharmaceutical Products

1223 Verification of Alternative Methods to Antibiotic Microbial Assays

1229 Sterilization of Compendial Articles

1229.1 Steam Sterilization by Direct Contact

1229.2 Steam Sterilization of Aqueous Liquids

1229.3 Monitoring of Bioburden

1229.4 Sterilization Filtration of Liquids

1229.5 Biological Indicators for Sterilization

1229.6 Liquid Phase Sterilization

1229.7 Gaseous Sterilization

1229.8 Dry Heat Sterilization

1229.9 Physicochemical Integrators and Indicators for Sterilization

1229.10 Radiation Sterilization




Useful Vendor Qualification: USP Chapters Relevant to Sterile Compounding


51 Antimicrobial Effectiveness Testing

191 Identification Tests - General

197 Spectrophotometric Identification Tests

201 Thin-Layer Chromatographic Identification Tests

621 Chromatography

726 Electrophoresis

731 Loss on Drying

736 Mass Spectrometry

741 Melting Range of Temperature

781 Optical Rotation

785 Osmolality and Osmolarity

786 Particle Size Distribution Estimation by Analytical Sieving

811 Powder Fineness

823 Positron emission Tomography Drugs for Compounding, Investigational and Research Uses

831 Refractive Index

851 Spectroscopy and Light Scattering

1015 Automated Radiochemical Synthesis Apparatus



USP Chapter <797> Breakdown The table below is a breakdown of the sub-sections of USP Chapter <797>.

Breakdown of USP 797

Compounding personnel:

Roles and Responsibilities

Education and Training

Personnel training and evaluation:

Aseptic manipulations

Media-Fill Challenge Test

Quality Assurance program implementation for CSPs

Basis of low, medium and high risk CSP classification

Patient or caregiver training

Patient monitoring and adverse events reporting

Equipment used in CSP preparation

Verification of Automated Compounding Devices

Environmental Quality Control during CSP processing

Quality Assurance practices for low, medium and high risk CSPs

Verification of compounding accuracy and sterilization

Release checks, inspections and tests for processed CSPs

CSP Storage and Beyond-use Dating

Packaging, handling, storage, and transportation of CSPs

Maintaining product quality and control after CSPs release



USP Chapter <797> Risk Classifications United States and Canada A key component of USP Chapter <797> is the classification of risk. Below are examples of low, medium and high risk preparations.

Sterile Compounding Conditions by Risk-Level Category as per USP

Low Risk

Compounding with sterile ingredients

Compounding using not more than 3 manufactured sterile products and not more than 2 entries into any one sterile container

Preparations compounded in an ISO Class 5 environment

Example: Reconstitution of sterile powders

Medium Risk

Multiple doses of sterile products pooled to prepare a single preparation

Processes including complex aseptic manipulations other than the single-volume transfer.

Compounding processes requiring unusually long durations, such as that required to complete dissolution or homogenous mixing

Example: TPN solutions mixed with an automatic compounding device

High Risk

Compounding with non-sterile components or ingredients

Compounding with ingredients or devices exposed to air quality worse than ISO Class 5 for more than 1 hour

Example: Morphine injection made from non-sterile powder or tablets.



USP Chapter <797> Risk Levels and Beyond-Use Dates The table below illustrates the relationship between risk classifications of CSPs and Beyond-Use Dates (BUDs).

Risk Level Beyond-Use Dates

Storage Conditions Low Risk Medium Risk High Risk

Room temperature: ≥ 20°C and ≤ 25°C. 48 hours 30 hours 24 hours

Refrigerated: ≥ 2°C and ≤ 8°C 14 days 9 days 3 days

Frozen: ≥ -25°C and ≤ -10°C 45 days 45 days 45 days



Applying the ‘Suitability Factor’ to a Quality Management System System P is a Quality Management System (QMS). Regardless of the QMS you employ in your sterile compounding practice, you need always perform four key functions:

The Four Key Functions of a Quality Management System

Control

Perform

Validate

Document

Critical to the success of a sterile compounding practice is the function of verification. To ‘Validate’ is to apply a method that is designed to provide assurances and confirmation that a process has achieved its desired outcome. Simply put, verification is a process to test a process. There are three main sub-divisions of verification; efficacy, reliability and validity. Verification applies to any and all compounding personnel, technology, processes and procedures. Personnel, technology, processes and procedures need to be evaluated on their own merit, but also together, as a functional unit. Only when your verification protocol fulfills all three principal criteria, can you securely declare that you have successfully created suitable and applicable verification procedures.

Efficacy: Desired outcome. (Is this what you wanted to measure?)

Reliability: Repeatable outcome. (Can you measure it again under different circumstances?)

Validity: Sound outcome. (Can you rely on the measure?) Regulatory bodies do not always advocate the same guidelines with respect to verification and therefore these different guidelines should be compared and contrasted when establishing a verification protocol. It is beneficial to evaluate and assess each guideline to note their similarities, differences, advantages and limitations. Below are the three (3) main sub-divisions of analytical verification parameters:

Analytical Verification Parameters

Efficacy Reliability Validity

Detection Limit Accuracy Quantification Limit

Readability Precision: Robustness

Permissible Limit MIN Repeatability Specificity

Permissible Limit MAX Ruggedness Sensitivity

Range Reproducibility

Linearity



Analytical Verification Parameter of a Quality Management System The table below defines the analytical verification parameters applicable to sterile compounding. They can be used for such qualification purposes as technology selection, test protocol assessment and process development when establishing a master formulation record for your sterile compounding practice.

Analytical Verification Parameter

Parameter with Catch Phrase Short Explanation and Example

Detection Limit “Something might be there”

The lowest measurement detected by a device, but not necessarily reliably measured. (Example: 19 mg on 20 mg minimal permissible limit balance)

Readability “Zoom in a little more”

The smallest measurement increment that an instrument can report. (Example: 0.001 g on a 3-point analytical digital electronic balance)

Permissible Limit MIN “You cannot go lower”

Establishment of the smallest value that can be reliably measured. (Example: Minimum volume measurable in a 0.5 mL dispensing syringe)

Permissible Limit MAX “You cannot go higher”

Establishment of the largest value that can be reliably measured. (Example: Greatest pressure exerted during end-stage filtration)

Range “Here’s what can be measured”

Establishment of the range of values that an instrument can reliably measure. (Example: The temperature min-max of a thermometer)

Accuracy “Right on target”

Comparing the performance of an instrument to a gold standard. (Example: Comparison between weight and designated weight on balance)

Precision “Same spot; not on target”

Ensuring consistent results when a method is repeated. (Example: Consistent baseline for microbial sampling over a DCA)

Repeatability (Precision sub-set) “Do that again with the same technology”

Ensuring consistent results when the same person repeats a method using the same equipment. (Example: Same personnel repeating pH measure twice)

Ruggedness (Precision sub-set) “You try this now”

Measuring the difference in results between two different personnel using same procedure. (Example: Two personnel passed the same Finger Tip Touch Test)

Reproducibility (Precision sub-set) “Where else can this be done?”

Comparison of data from same procedure in different settings. (Ex: Same sterility test findings; in-house vs independent lab procedures)

Linearity “Always a straight line…on the graph”

Establishment of a technology’s trustworthiness across its range (Example: pH is accurate from 1-to-10)

Quantification Limit “Sorry just a little louder, I can’t hear you”

Setting the signal-to-noise threshold on a technology or data set. (Example: Baseline CFU count for a viable air sampler)

Robustness “Can withstand change”

Ensuring minor changes in independent variables don’t alter results. (Example: Incubator humidity might affect microbial growth)

Specificity “Might be under-estimated”

Increasing the signal to noise ratio such that noise is not considered. (Example: Degradants measured with parent compound in HPLC)

Sensitivity “Might be over-estimated”

Lowering the signal to noise ratio such that low noise levels are permitted. (Example: False negative on an endotoxin test)



Section 2: P1 - Personnel

Personnel Quality Management

Pharmacist Education & Training

Technician Education & Training

Hazard Communication Program

Delineation of Responsibility

Performance Assessment

Behavior, Health & Hygiene

Medical Surveillance Program

Finger Tip Touch Test

Media-Fill Challenge Testing

Re-Training & Re-Certification

Verification

Documentation

Definition of Personnel Quality Management

Personnel, in the context of System P include theoretical and practical training requirements for all personnel working in a sterile compounding practice. This includes Fingertip Touch Tests (FTTs), Media-Fill Challenge (MFC) tests, and a wide range of competency assessments, certifications and re-certifications. Once personnel skill levels are well assessed, careful consideration needs to be given to the delineation of responsibilities amongst personnel. Personnel include all pharmacists, technicians and support staff that will be responsible for, in any manner, tasks that will affect the integrity, sterility, strength and stability of a compounded sterile preparation.



Personnel Training Requirements Personnel training may be performed in the following manner:

Personnel Training

Routinely - According to a predetermined schedule

Randomly - Without notice, to prevent complacency

Reactively - In response to an adverse event

Retroactively - When the need is apparent

Proactively - To prevent adverse situations from arising in the future

Depending on the nature of the subject, competency assessments can be performed at varying intensities, frequencies, and duration. For example, a simple 10-minute conversation between a pharmacist-in-charge and an employee can be used to determine if an employee is up-to-date on information that they are expected to know, and can be scheduled at a frequency deemed appropriate for the employee. Alternatively, the employee can take a 5-minute quiz. In general, and when possible, increasing the frequency of competency assessments in exchange for shorter durations is more beneficial and will accelerate learning. The scheduling of various competency assessments of different subjects for employees needs also to be evenly spread out over time according to intensity and duration, in a manner that holds employees responsible for their learning. All successful sterile compounding pharmacies rely on the theoretical knowledge and practical skills of its personnel. Although pharmacists and technicians should be hired based on their education and experience, employee training is essential not only to reinforce concepts but to clarify the manner in which one must proceed.

Standard Operating Procedures as a means of Personnel Training Seeing as how all personnel must sign off on their comprehension and competency related to SOPs, they can be used as a source of training. While Standard Operating Procedures are learned and practiced, personnel may make recommendations for improvement. This behavior can further the competency of personnel and enhance the relationship between pharmacist, technicians, and the pharmacist-in-charge. The pharmacist-in-charge will review requests for change on a regular basis and make informed decisions, which will be promptly implemented into rewritten SOPs, and then shared with all implicated personnel. Once personnel have been trained on SOPs, they must adhere to them as they are written. Standard operating procedures are a means to ensure safe and effective medications. SOPs provide a means upon which behaviors are standardized to accomplish all compounding-related tasks. Adherence to SOPs without deviation will affect the safety and efficacy of compounded sterile preparations.



Modes of Personnel Training Personnel training must be provided in the following modes of delivery:

1. Theoretical study 2. Practical application 3. Verbal discussion 4. Finger Tip Touch Test (FTT) 5. Media-Fill Challenge test (MFC) 6. Visual observation of garbing and aseptic techniques 7. Written and practical competency assessments

Training Requirements While an SOP explains how something is performed, it doesn’t provide reason and rationale as to why it is performed. Therefore, theoretical knowledge must accompany the procedure found in a standard operating procedure. This provides ample opportunity for the identification of training subjects and the establishment of training material. Presented in alphabetical order is a listing of theoretical training requirements.

Theoretical Training Requirements

Action levels for change End-stage filtration Personal health and hygiene

Adverse event reporting Environmental control Personal Protective Equipment

Airflow dynamics Error prevention Primary Engineering Controls

Aseptic environments Garbing and gowning Recall and traceability

Aseptic techniques Hazard communication Secondary Engineering Controls

Automated Compounding Devices HIPPA Regulations Standards of practice

Biological Safety Cabinets Inventory control management Sterility testing of CSPs

Deactivation of chemicals ISO class environment activities Sterilization; wet and dry heat

Depyrogenation of glassware Laminar Airflow Workstations (LAFWs) Quality, risk, and verification

Disinfection of surfaces Medical surveillance Workflow efficiencies

Documentation of logs and forms Microbiological control

Endotoxin testing of CSPs Moving between ISO class environments



Personnel Roles and Responsibilities While each personnel working in a sterile compounding facility may have different roles and responsibilities and consequently require different training, each must be able to train the other. When there is a noticeable breach in protocol it must be able to be observed. Personnel must understand the range of tasks they are permitted to undertake as well as the limits to their responsibilities. Personnel roles and responsibilities must be delineated in written Standard Operating Procedures.

Personnel Performance Assessment Testing Requirements Personnel are required to perform specialized tests prior to the start of their roles and responsibilities and on an ongoing basis thereafter. These tests include:

1. Finger Tip Touch Test 2. Media-Fill Challenge Test

Depending on when they are performed, they are indirectly reflective of performances related to garbing and gowning, and aseptic techniques, respectively. The FTT test must be performed three consecutive times after garbing, gowning, and gloving, and then after a MFC test. The MFC tests must mimic the aseptic processes, level of difficulty, fatigue, and facility conditions encountered within an individual’s day-to-day practice expected within the compounding facility. Higher risk preparations should be singled out and have their own design parameters for a MFC test. The MFC test, as it applies to high risk compounding, must be performed prior to personnel authorization to perform sterile compounding, following a positive sterility test for a CSP, and at regular intervals thereafter.



Sample Media-Fill Challenge Test

Below is a sample Media-Fill Challenge Test Protocol.



Personnel and Hazardous Drug Compounding The United States Pharmacopeia (USP) Chapter <800> provided standards of practice for working with Hazardous Drugs (HDs). Under USP <800>, personnel are obligated to undergo hazard communication training and possible medical surveillance if exposure during an incident or accident warrants this measure of prevention and monitoring. Specific training in the management, manipulation and handling, and compounding with hazardous drugs are essential. The National Institute for Occupational Safety and Health (NIOSH) has reclassified many chemicals in its publication entitled:

NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2014 This NIOSH document is currently enforceable. The Federal regulation entitled, H.R. 3204: Drug Quality and Security Act will enforce the USP Chapter <797>. The USP Chapter <797> will make reference to the USP Chapter <800>. This assumes your sterile compounding practice qualifies under the conditions of 503a as opposed to 503b of the Drug Quality and Security Act. Given the information in current literature and the understanding of the possible consequences of chemical exposure, it is imperative that adequate attention be paid to the prevention of occupational hazards and occupational health and safety in general. In the long run, ignoring this does not seem to be a financially viable option, much less a moral one. The time and effort put forth toward the health and welfare of personnel must meet the requirements of USP Chapter <800>.

Hazard Communication Program The most important aspect of an exposure control program is personnel education and training. Pharmacy personnel must be educated and trained in all aspects of working with hazardous substances. Any personnel member who is expected to handle or come in contact with a hazardous substance should complete a thorough training program that includes, but is not limited to, the following:

Understanding the risks of hazardous drugs

Identifying and labeling of hazardous drugs

SDS interpretation

Storing, handling, transporting and disposing of hazardous drugs

Use, maintenance and decontamination of engineering controls

Personal Protective Equipment (PPE)

Managing spills and use of spill kits

Use of emergency equipment including eyewash stations, deluge shower, and first aid equipment An effective and complete hazardous materials training program is the single most effective tool in preventing hazardous drug exposure. Notwithstanding a high quality training program is a medical surveillance program.



Medical Surveillance Program Despite engineering and administrative controls, healthcare workers may still be exposed to hazardous drugs when at work each day. Medical Surveillance was first recommended by OSHA 20 years ago as a tool aimed at early identification of adverse health effects in healthcare personnel exposed to hazardous drugs. The program involves the monitoring of the health of personnel to detect the biological effects and adverse events as early as possible in healthcare workers, both on an individual level and as an aggregate for exposed employees working in the particular environment. While a strong recommendation from Occupational Safety Health Agency (OSHA), the National Institute for Occupational Safety and Health (NIOSH), and the American Society of Health Systems Pharmacy (ASHP), there has historically been poor compliance due to lack of regulatory enforcement. The release of USP Chapter <800> and the promulgation of new legislation related to safe handling of hazardous drugs by several states has resulted in a reinforcement of safe handling guidelines and increased the regulatory oversight of hazardous drug handling. The first step in any medical surveillance program is the identification of personnel who may be exposed through either direct or indirect exposure.

Direct exposure includes activities such as receiving, handling, managing inventory, compounding, packaging and administering hazardous drugs. These direct exposure activities are most often conducted by pharmacists and pharmacy technicians.

Indirect exposure includes activities such as decontaminating/deactivating of hazardous compounding areas and removal or handling of hazardous waste (including the waste of patients within 48 hours of chemotherapy administration).

Components of a comprehensive medical surveillance program includes a thorough history of the employees’ baseline medical health (including reproductive history) and occupational history estimating previous hazardous drug handling and exposure. Baseline data is essential as, in with any population, people there will be incidental findings of abnormal laboratory values that are unrelated to their job. In the event of acute exposure, the initial response should be well defined and the surveillance follow up should be outlined in a policy. Whenever possible, the exposure management and follow-up should be tailored to the drug of exposure. Immediately after an exposure, it is often too early for the onset of toxic effects, thus personnel should be followed over time, and the initial labs in that immediate period may be appropriate as a baseline. The individual who has been exposed should be counselled based on drug exposure specific risks and toxicities, including what symptoms to report and recommended follow up. Medical surveillance is part of a comprehensive program with the end goal of minimizing adverse events. Other facets of the comprehensive program include proper engineering controls, environmental monitoring, and an effective and complete training program.



Section 3: P2 - Property

Property Quality Management

Engineering Design & Conformity

Primary and Secondary Engineering Controls

Containment Primary and Secondary Engineering Controls

Electromechanical Equipment

Automated Compounding Devices

Reusable & Disposable Devices

Personal Protective Equipment

Safety and Emergency Equipment and Supplies

Sanitization, Disinfection, Decontamination and Neutralization Supplies

Testing Equipment and Supplies

Certification Process

Re-Certification Process

Verification

Documentation

Definition of Property Quality Management

Property, in the context of System P is defined as any and all facility structures of a sterile compounding practice; Secondary Engineering Controls (SECs), Primary Engineering Controls (PECs), electromechanical equipment, reusable and disposable devices, Personal Protective Equipment (PPE), safety and emergency equipment, disinfecting and decontaminating/deactivation supplies, and testing technology. All technology undergoes the processes of selection, installation, verification, calibration, and in some instances certification, prior to the point of first use. Chemicals in the form of Active Pharmaceutical Ingredients (APIs) and all excipients also fall under property. Chemicals must also undergo a certain level of scrutiny. As such each chemical purchased should be accompanied by a Certific ate of Analysis (C of A). For the purposes of safety a Safety Data Sheet (SDS) should also be acquired and made available to all personnel all the time.



Facility Design: Primary and Secondary Engineering Controls In a sterile compounding facility, air is drawn from an ambient environment, through pre-filters, then through High-Efficiency Particulate Air (HEPA) or Ultra-Low Particulate Air (ULPA) filters, and finally into a clean room; an International Standards Organization classified room. These ISO classified rooms are referred to as Secondary Engineering Controls. The pre-filters are responsible for the removal of large particulate matter that can be damaging to the more sensitive HEPA or ULPA filter. The HEPA or UPLA filters are responsible for the removal of microbes in the air. Depending upon the flow rate of air passing through the clean room, the ISO classification could change. Different rooms in a sterile compounding practice serve different functions; each room requiring a different ISO classification. Inside SECs are PECs, in the form of Laminar Air Flow Workstations, Biological Safety Cabinets, and Containment Ventilated Enclosures formerly referred to as Vented Balance Safety Enclosures used for their particular use during the weighing of powders. Biological Safety Cabinets are referred to as Containment Primary Engineering Controls (C-PECs). C-PECs are required when Hazardous Drugs (HDs) are used to prepare a CSP. The facility in which sterile compounding must be performed is in support of the establishment and maintenance of ISO class environments of either a positive or negative pressure depending on whether non-hazardous or hazardous drug compounding is being performed. A positive pressure room is simply defined as a room whereby the amount of air entering the room is greater than the amount of air leaving the room; making it positively pressurized. A negative pressure room is the opposite; air in is less than air out. The parameters that need to be controlled in order to achieve a designated ISO classification for a clean room include:

1. Air velocity (meters/second) 2. Air flow rate(meters

3/second) or (Liters/second)

3. Air pressure differential 4. Area of room 5. Area of air return (meters

2)

Clean Room Classifications

ISO Class

Federal Standard 209E

Airflow Type

Air Velocity (feet/minute)

Air Change Rate (air changes per hour)

HEPA Filter Ceiling Coverage (%)

Non-Viable Particulate Count (≥0.5 µm/m

3)

5 Class 100 Laminar 40–100 360 [240–480] 100 3,520

6 Class 1000 Mixed 25–40 115 [70–160] 25 35,200

7 Class 10,000 Mixed 10–15 60 [30–90] 15-20 352,000

8 Class 100,000 Mixed 5–10 36 [20–48] 5-10 3,520,000

>9 - Mixed - - - >35,200,000



Secondary Engineering Controls One of the most important aspects of facility design is the ability to attain, maintain and recover a controlled environment. Three factors that contribute the maintenance of the controlled environment are airflow dynamics of the SEC and PEC systems, appropriate disinfecting and personnel behavior. The relationship between the engineering design and personnel behavior in reaching the desired ISO classification can be best described as multiplicative. It stands to reason that when P1: Personnel and P2: Property are combined with P3 Procedure:

ENGINEERING DESIGN + DISINFECTION AND DECONTAMINATION + PERSONNEL BEHAVIOR = DYNAMIC ISO CLASSIFICATION Therefore to ensure success and the maintenance of a clean room’s required parameters the following requirements apply:

1. Educate personnel on principles of airflow. 2. Educate personnel on purposes on each ISO class environment; ISO class 8, 7, and 5. 3. Draft a detailed facility design plan from functional, operational and structural perspectives . 4. Identify number of SECs, C-SECs, PECs, and C-PECs required. 5. Ensure required SEC HEPA or ULPA filtration coverage. 6. Ensure facility air handling system can generate sufficient force for required air flow velocity. 7. Ensure HVAC systems can meet temperature and humidity requirements. 8. Select PECs and C-PECs based on the type of compounding being performed. 9. Ensure optimal placement of PECs and C-PECs in relation to SEC or C-SEC HEPA or ULPA filter placement. 10. Place PECs or C-PECs a minimum of six (6) feet from any air disturbances. 11. Evaluate facility floor plans for risks and make appropriate adjustments, if required. 12. Re-certify all environmental controls at least every six (6) months. 13. Monitor for non-viable and viable particulate on a regular basis. 14. Validate that facility design plans meets ISO standards, USP requirements and federal law.



Compounding-specific ISO Class Clean Room Requirements for Non-Hazardous Drug Compounding Compounding-specific ISO class clean room requirements include:

1. ISO Class 8 environment (SEC) for hand washing, garbing and gowning. 2. ISO Class 7 environment (SEC) in the presence of a Containment Ventilated Enclosure (CVE) often referred to as a Vented

Balance Safety Enclosure (VBSE) for weighing and wetting powders. 3. ISO Class 5 environment (PEC), often in the form of a Biological Safety Cabinet (BSC) in which compounded sterile

preparations would be completed up to the point of the dispensing container being sealed. It is the relative position of the HEPA or ULPA filters of SECs and PECs that create specific and dynamic airflow patterns required to optimize efficiencies and assist in maintaining sterility of CSPs while protecting personnel.

Compounding-specific ISO Class Clean Room Requirements for Hazardous Drug Compounding Compounding-specific ISO class clean room requirements for hazardous drug compounding include:

1. Hazardous drug compounding must be performed in a designated externally vented ISO class 7 containment secondary engineering control (C-SEC), with at least 30 air exchanges per hour (ACPH) and a negative pressure between 0.01 and 0.03 inches of water column, in which there is an externally vented ISO class 5 containment primary engineering control (C-PEC) that serves as the direct compounding area (DCA).

2. Hazardous drugs must be stored in a negative-pressure room with at least 12 air changes per hour (ACPH).

3. Antineoplastic agents requiring refrigeration must be stored in a dedicated refrigerator in a negative pressure area with at least 12 ACPH.

Additional ISO Class Clean Room Requirements Additional ISO class clean room parameters that require constant attention in support of the maintenance of the environment include:

1. Temperature and humidity. 2. Neutralization of chemicals prior to disinfection. 3. Disinfection and decontamination of surfaces. 4. Non-viable particulate count monitoring. 5. Viable (Microbial) particulate count monitoring. 6. Certification and re-certification of all ISO class environments by a Controlled Environment Testing Association (CETA)

certified inspector.



Effect of Turbulent Air Turbulent air can be caused by two main sources. Turbulence caused by air flow from filtered air, any equipment using laminar air flow and the return air flow can be controlled or minimized by facility design. Again, the most appropriate source of filtered air should be from the ceiling down towards the floor. This serves to push particles out of the work zone and breathing space of the employee. Care should be taken to prevent having high flow units. The high velocity air will impact the floor and create turbulence that will pick particles off the floor and deposit them on critical areas within the facility. Having an uneven spread or too few sources can lead to “dead air” zones within the facility that are also a source of particulate and turbulent air. A dead zone will allow particulate to be taken up from the floor into critical areas. This dead zone also leads to diminished ability to recover when particulate contamination is present. Remember that an engineering control must have the ability to attain, maintain and recover in order to meet the “controlled environment” aspect of an engineering control. The second and most problematic source of turbulent air is the movement of personnel, equipment and materials throughout the facility in order to prepare the compounded preparations. This movement is necessary. However, minimization of movement should be an important principal especially when approaching the DCA or sterile workspace. Turbulence caused by the placement of materials within the DCA or sterile workspace is also a necessary “evil” but this should be done with an awareness of creating turbulent zones downwind of the object. These may also become a source of contamination. The major source of turbulent and unclean air within a clean room is, of course, the personnel within the clean room. Almost everyone remembers the character in “Charlie Brown”, “Pigpen”, and his cloud of dust that followed every movement. This, sadly, is an effect which has the greatest impact upon the cleanliness of a sterile compounding facility. Whether through breathing, talking, coughing or sneezing, even a masked individual can spread microbes. The mask should be properly affixed and provide filtration of the air coming from the employee. A surgical mask does not filter out microbes particularly when it becomes saturated. Surgical masks should be changed regularly (about every 2 hours) or after coughing or sneezing. Talking should be minimized and when talking the employee should turn his face away from the critical site. The selection of gowning material types also has an effect on the amount of particles present. Any particles sloughed off an employee will generally drop down and if the person is wearing a bunny suit, they will be trapped within the garment. However, an individual with an open bottomed gown will tend to drop particles onto the floor at an alarming rate. When individuals walk through the areas where they shed, particles accumulate and a plume of turbulent air 30 feet behind the individual will pick these particles up where they can reach critical areas.



Air Filter Systems There are two main classes of filter media used in clean room design. High-Efficiency Particulate Air (HEPA) filters remove 99.97% of particles 0.3 microns or larger. These are the most commonly used filters. However, the Ultra-Low Penetration Air (ULPA) filter removes 99.9995% of particles 0.3 microns or larger which means they are significantly more effective at providing particulate free air and the attendant microbes. These filters are usually preceded by a pre-filter which removes larger particles and often contains activated charcoal. These relatively inexpensive, larger pored filters serve to extend the life of the more expensive particulate reducing filters. The ULPA filters have a smaller pore size, about 90 microns, and are required to obtain a classification of ISO Class 4 or better. The lifespan of these filters is the same as the HEPA filter so the amortized cost over the life of the more efficient filter is rather insignificant. The ULPA filters often cost about 10 - 20% more than the HEPA filters, but in the grander scheme of overall cost of a facility that comes to about 0.5 - 1% of the cost of the facility. The daily cost of the more efficient filter can be from $ 1.64 - $ 4.566 / day for each filter unit; or $ 6.00 - $ 16.68 / year. This is a rather insignificant cost for a fairly significant better outcome. An important concept to remember is that engineering and personnel behavior work together to provide the cleanliness and decreased particle counts necessary for a sterile facility. It is often seen as a multiplicative association; small changes in one side of the equation cause a multiplicative change in the requirements of the other side of the equation. A facility minimally designed to meet requirements will greatly increase the work that the personnel need to perform to maintain the clean room. This can be seen as a “pay me now or pay me later” scenario. Maintaining a sterile compounding facility in the best of circumstances requires a significant amount of labor. This includes the disinfecting of the facility and also the increase in personnel behavior in order to get stock into the clean room. A figure often used is a 40% increase in staff to maintain a clean room. This includes about 30 minutes of time per 100 square feet per day to maintain the facility. There are three frequencies of disinfecting required: Daily, Weekly and Monthly. The weekly disinfecting is slightly more involved than the daily and the monthly disinfecting includes much more involvement than the others. To move supplies into the clean room requires about a 15% to 20% increase in FTE’s in excess of normal operation. There are two basic filtration designs: The classic “central” supply and the peripheral supply of filtered air provided by local “Fan Filter Units”. There are advantages and disadvantages to both systems. It is important to understand these differences when deciding on a design concept for a clean room. The classic version is a “central” supply of filtered air provided by one large unit. This filtered air is then distributed by solid or flexible ducting to one or more areas. This concept places all of the pre-filtration, filtration and HVAC supply in one area which should decrease original costs and maintenance costs. This “centralized concept” tends to put “all the eggs in one basket”. If there is a problem with the main unit or filter array it impacts the entire facility negatively. Also, there are issues with the ducting. While filtration provides reduced particulate and microbes; some may inevitably get through the filters. These ducts may harbour these microbes and provide a place for spores to become viable and grow. This may lead to contamination of the facility with spores and microbes from this source. Having ultraviolet lighting in these ducts may inhibit this growth but these ducts will need to be cleaned periodically with sporicidal agents leading to a significant downtime and cost. An offshoot of this design is the placement of a central air supply providing pressurized air via ducting to filter units placed peripherally. One of the issues to be addressed with this system is the uneven pressure delivered to the individual filters. Air flow does face resistance from flowing through ducting and this resistance will decrease the velocity and pressure of the air flow arriving at the filter. This could lead to decreased air flow past the filter into the clean room thus jeopardizing the quality and effectiveness of the clean room. The ducting will also face the same disinfecting issues as discussed previously. A more novel approach is the use of individualized local Fan Filter Units (FFUs). The local FFU is comprised of a pre-filter, a fan unit and the main particulate reducing filter (either HEPA or ULPA). The local FFU is usually standardized to fit into a 2’ x 2’ or a 2’ x 4’ ceiling or wall grid. The cooled and conditioned air can be delivered via individualized ducting or through a plenum (large opening). The return air would be delivered either back to the plenum or to the return ducting of the central HVAC system that provides the cooled and conditioned air. The speed of the fans on these local Fan Filter Units can usually be adjusted to balance air flow if necessary.



The local active filtration FFU’s have many advantages. There is terminal filtration directly at the site where one provides the clean air. By arranging an array of filters over a workspace; a designer can accomplish two major effects. The first is that with 100% ceiling coverage over a workspace, the workspace itself becomes an incredibly clean area and can be utilized for compounding without the need for additional equipment such as laminar flow hoods. This is the overriding principle behind the open architecture design. Whole walls can in effect become workspaces thus increasing the efficiency of the design. The second effect pertains to occupational exposure. When an employee is gowned, gloved and masked they are susceptible to two major routes of occupational exposure: Physical contact with the chemical through permeation of the protective equipment or by hand delivery to the face. The latter is a relatively minor concern if appropriate techniques are applied, the Fan Filter Unit array will provide a supply of charcoal and particulate filtered air to the employees main route of exposure, the breathing zone. By arranging the FFU’s throughout the facility, each room becomes an independently operational unit. The failure of one unit will not significantly affect the operational status of the facility. Usually there is enough “spare” filtration in the other regions to maintain the operational status of the facility.

The "Funnel Effect" The “Funnel Effect” concept is an extremely important part of the design and workflow layout of the entire facility from receiving material through to end-stage preparation and delivery of a sterile preparation. Material receiving should be done away from the sterile compounding facility. Open doors to the outside are huge sources of particulate contamination and these should be separated from the internal rooms of the facility. Materials should be unpackaged as far away from the entry to the sterile compounding facility as possible, as cardboard is a major source of particulate contamination. The exterior of the sterile compounding facility is a place where the materials can be brought. This area should be cleaned and disinfected on a regular basis. As previously stated, this is a two-step process – cleaning to remove residue and particulates and disinfecting to remove microbial contamination. This area should be kept as clean as possible. The pouched and unpackaged materials can be brought into the anteroom on a conveyance for further processing. This further processing consists of wiping materials as they are moved from the conveyance and placed on a clean conveyance on the clean side of the Line of Demarcation within the garbing room. Pouched materials can be either wiped or opened onto the clean conveyance. Remember that un-pouched materials are then subject to expiration date shortening due to the loss of water through the plastic material. The garbing room is subject to daily mopping of the floors and a monthly disinfection of every surface and material stored within it. This is in essence the first defence of the sterile compounding facility against unclean materials and air currents. The ISO Class 7 area within the facility receives the cleaned materials on a clean conveyance. Traffic within this area is restricted to necessary personnel to enhance safety by decreasing turbulence. This is a cleaner area than the garbing room with only properly gowned and attired personnel. Storage sites within the ISO Class 7 rooms are subject to stringent disinfecting requirements. Storage sites near the critical work areas (DCA) must be cleaned and disinfected weekly. Floors must be cleaned and disinfected at the beginning of each shift while ceilings and walls must be cleaned monthly. The DCA must be cleaned and disinfected after each activity in order to prevent contamination and cross contamination of end preparations. The movement of materials, personnel and other supplies goes from least clean to cleanest; the area surrounding the DCA being the cleanest. This entire process is referred to as the “funnel effect” and should infuse every aspect of every behavior that is incorporated into the SOP’s that govern a facility.



General Principles of Air Flow

An important aspect of an engineering control is laminar airflow. Laminar airflow is produced when air is introduced uniformly at low velocities so that the air flow is stratified. This will minimize cross-stream contamination. This stratified air stream will tend to push any particulates in a direction away from critical workspaces. Conventional secondary engineering controls have very limited laminar flow characteristics and thus have a very limited self-cleanup capability. This is the ability to remove contamination brought into the room and contamination generated by processes within the room. Another important principle involves the continuity of the flow of air; maintaining clean air in the workspace and pulling dirty air out of the facility. This can be assisted by mounting all of the return air features low along a wall or column. This will tend to draw the air off the floor where particles end up, and draw them out of the facility. A ceiling mounted return will tend to cause turbulent air that pulls these particles up into the air where they will potentially reach the breathing zone of the employee, and more importantly, the DCA or sterile workspace. “Down and away” is the mantra one should use when describing the flow of air throughout a facility and when considering occupational exposure to personnel. Placing air returns strategically along specific walls can lead to an arrangement whereby airflow in the entire facility can be controlled so that a general airflow pattern will emerge and can facilitate your overall design. In addition; appropriate location in areas where bioactive drugs may be prepared can lead to enhanced protection of your employees. There are several clean room design characteristics. Two important air flow requirements are:

Number of air exchanges per hour

Suggested filter coverage

General Principles of Containment of Hazardous or Bioengineered Drugs

An important aspect of engineering control operation is the containment of hazardous or bioengineered drugs to prevent cross contamination of preparations as well as occupational exposures. While behavior is paramount in preventing these exposures, engineering can also be used to minimize this risk. Hazardous drugs may only be compounded in engineering controls contained under negative pressure (called containment secondary engineering controls and containment primary engineering controls) that are segregated from non-hazardous rooms. In some setups, secondary engineering controls and containment secondary engineering controls for compounding may share a single garbing room, in which case secondary hazardous garb must be removed before re-entering the common garbing room to avoid spreading contamination. Having externally ventilated cabinets is another technique that will help control contamination. Hazardous drugs have been shown to aerosolize and escape through HEPA filters so it is imperative that if external ventilation is not available another engineering technique must be utilized. This technique is commonly called “bag-in bag-out” filters. This consists of having the exhaust air go through a series of charcoal and HEPA filters that are engineered to remove these hazardous materials. These systems are designed so that these can be removed and replaced within an enclosing bag to prevent exposure to the hazardous agents in the filter system. With the use of some of the viral vectors in the bioengineered class, use of ULPA filters and UV lights might be considered. The pore size of the ULPA filters would be more likely to trap these viral vectors. Up until now you have been instructed on what to do to design a more than adequate sterile compounding facility. It is equally important to understand what not to do. Work through the following table placing check marks beside those statements you feel you fully comprehend.



Airborne Particulate Count Particulate counts are utilized as a method of approximating viable microbial particles in the air. Viable microbial particles are often associated physically with particulate matter. The size of particles measured and counted depends upon the classification desired. Most counters will measure the 0.3 and 0.5 micron particles needed for classification of ISO 5 (Class 100) that is the standard for sterile compounding. Environments over ISO Class 5 will also measure 5 micron particles. For anything under an ISO class 4 (Class 10) it would be necessary to measure the 0.1 micron particles. The “not to exceed” numbers below are for a single cubic foot of air. If any of the numbers are above those listed levels, then the area tested does not meet standards for classification. It is important to note that it is not the average number but a consistent number one looks for. An engineering control is a controlled environment able to maintain particulate counts below those listed levels at all times. Measuring constantly gives a better view of the facility’s ability to maintain this control. If intermittent measurement is used it is important to measure at a time of peak use or a time most likely to produce problematic results.

Particulate Counts per Cubic Foot for ISO Class Environments

Clean room class Class Limits "not to exceed" particle per cubic foot for particle sizes shown

0.1 Micron 0.2 Micron 0.3 Micron 0.5 Micron 5 Micron

ISO 5 – – 750 300 100 – –

ISO 6 – – – – – – 1000 7.0

ISO 7 – – – – – – 10000 70.0

ISO 8 – – – – – – 100000 700

Microbial Counts The true test of an aseptic work environment is the number of viable microbes in the work site and surrounding areas. Surfaces are sampled on the DCA, the surrounding worktables, employee fingertips, and strategic areas throughout the clean facility by capturing viable microbes on growth plates. The plates are incubated and the number of colonies formed is counted. These counts are called “Colony Forming Units” and are then entered into a database. Since this process takes several days it is important to note that this process is best for identifying trends. To identify trends it is best to establish a baseline by testing daily for ten days to establish an expected acceptable count. Using this data, and taking into account the complexity of the sterile compounding processes performed, as well as the intended storage and use of the preparations, an action level is established. This action level will trigger a reaction among the staff to reduce the number of viable particles found within the facility on subsequent testing. ISO 14644-4:2001 Clean Rooms and associated controlled environments Part 4: Design, construction, and start-up will also define what these action levels should be for the typical compounding facility.



Humidity Control Highly humid air is more resistant to filtration and thus disinfection. However, air conditioning and heating systems tend to remove humidity so it is often necessary to add water vapor in order to maintain the comfort of the personnel within the faci lity. While humid air favors bacterial growth, working in extremely low humidity may lead to discomfort.

Clean Air Exchange Clean air exchange is an important concept in attainment, maintenance and recovery of controlled environments. When first operational; most clean rooms can attain necessary cleanliness given the appropriate behavior of the personnel. However, over time an under engineered facility can cause an undue burden on the personnel in order to maintain this level of cleanliness. When particulate incursions occur due to maintenance, power outages, or personnel behavior failures, the facility must be able to recover the cleanliness necessary through appropriate clean air exchanges.

Frequency per Hour The frequency per hour of total air changes, or exchanges, serves to provide the clean (particulate and microbe free) air that is necessary for an appropriate environment. Below are the suggested ranges for the average airflow velocity and more importantly the number of air changes per hour for a clean room facility. The air changes per hour are the number of times the entire volume of air within a room should be filtered per hour.

Frequency per Hour of Total Air Changes

Class Average Airflow Velocity Air Changes per Hour

100,000 (ISO 8) 0.005-0.041 m/sec (1-8 ft/min) 5 – 48

10,000 (ISO 7) 0.051-0.076 m/sec (10-15 ft/min) 60 – 90

1,000 (ISO 6) 0.127-0.203 m/sec (25-40 ft/min) 150 – 240

100 (ISO 5) 0.203-0.406 m/sec (40-80 ft/min) 240 – 480

Note that in the cleaner environments there is much overlap. A high class 1000 room (ISO 6) can also be a Class 100 (ISO 5). A mid-range class 100 (ISO 5) at 360 air changes per hour can also meet the requirements of a class 10 (ISO 4) or a class 1 (ISO 3). The main requirement of a class 10 or 1 is the necessity of using ULPA (Ultra Low Particulate Air) filters instead of HEPA filters.



Filter Coverage

The importance of suggested ceiling coverage—the proportion of the ceiling covered by HEPA filters—can be visualized easily. A high volume fan/filter unit could provide the number of air exchanges but would produce other problems as well. A high velocity plume of air will create a disturbance that will tend to sweep particles off the floor and back into the air; thus the importance of maintaining this flow by placing returns along the floors. The placement of air returns along the floor prevents particulate matter and the attendant microbes from being pulled high into the air from the floor, where they tend to settle, by the ambient currents within the room. Moreover, since unclean air pools in areas that are far from filters, it is best to have filters placed throughout the facility to provide a gentle flow of clean air from the ceiling to the floor.

Ceiling Coverage per ISO Classification

Class Ceiling Coverage

ISO 8 (Class 100,000) 5 - 15%

ISO 7 (Class 10,000) 15 - 20%

ISO 6 (Class 1,000) 25 - 40%

ISO 5 (Class 100) 35 - 70%

In order to maintain the purity of the clean filtered air it is important to maintain a pressure differential between a clean room and the surrounding ambient air. This pressure gradient, from the cleanest air to less clean air, will serve to keep contamination at bay. A pressure differential (negative) can also be utilized to keep hazardous drug contaminants within specialized compounding areas within a clean room.



Facility Design Characteristics General characteristics of facility floors, walls and ceiling are described in the table below.

Characteristics and Function of the Principal Physical Structures of a Sterile Compounding Facility

Structure Characteristics Function

Floors

Seamless, heat welded flooring Resistant to wear Resistant to chemicals Coved up the walls, if possible

To limit the space spores and microbes that can be harbored and stay viable Easily cleaned and disinfected

Walls

Smooth design Resistant to chemicals Caulked Easily reached

Ceiling Smooth design Resistant to chemicals Caulked

Shelving Solid shelving Removable and/or movable to easily clean behind and under

Lighting Fixtures

Sealed Smooth Easily maintained Doesn’t interfere with ceiling air filters Resistant to chemicals

Carts / Worktops

Solid shelving Removable and/or movable to easily clean behind and under Stainless steel



Common Errors in Facility Design Perhaps the two most important aspects of what not to do when designing a facility include:

1. Designing to meet standards of practice as opposed to how to best provide a sterile preparation; both perspectives should be given significant attention and address.

2. Designing with a minimalist concept; what is the least I can do? Additional errors in facility design are outlined in the table below.

Common Errors in Facility Design

Designing with…

Insufficient air and air conditioning supply

Insufficient electrical supply

Insufficient access to external venting

Insufficient incoming and outgoing of materials

Lack of sufficient facilities size; enough to separate tasks (in-process and set-up)

Lack of an adequately sized garbing room

Office grade instead of clean room materials

"Dependent" air flow technology

Potential for leaks and floods into clean room

Permanent cabinetry and other hard to clean areas

Immovable objects within facility

No consideration for the handling of hazardous materials

Low number of ceiling filters and high flow rate of filters

Ceiling returns

Painted surfaces not resistant to disinfecting processes

Many dust collecting devices in design; example: Ledges, overhangs and boxes

Too little material storage and handling capability

All storage inside clean room

Drains inside clean room instead of garbing room



Facility Design Diagram The following facility design is for a moderately sized practice and considers not only the minimal requirements, but the practical day-to-day activities that take place within the facility. Facilities can be smaller or larger than the example provided. It is recommended that it be studied for its design from a workflow dynamics-related perspective, i.e., how would compounding personnel move through the facility while performing all sterile compounding-related functions. It features non-hazardous and hazardous drug compounding in completely separate clean rooms.



Functional and Operational Considerations in Facility Design The following table illustrates the activities that occur when moving into and between ISO class environments. It should be compared to the facility design diagram on the previous page. Note that not all stepwise procedures match the facility design; procedures may sometimes be facility design dependent.

Stepwise Processes and Procedures moving into and between ISO Class Environments

Ambient (Receiving Area)-to-ISO Class 8 Room Activities

Ensure jewelry, makeup, perfumes, unnecessary clothing and the like, are removed.

Tie hair back, if applicable.

Don non-sterile personal protective equipment during inventory control management and inspection.

Assemble required reusable and disposable devices, and chemicals needed for transfer to ISO class 8 room.

Clean and disinfect outer surfaces of all inventory containers.

Don designated shoes prior to crossing tacky mat or don shoe covers, outside ISO class 8 room door.

Slowly walk across tacky mat with designated shoes prior to entering anteroom or enter anteroom with shoes covers.

Slowly enter anteroom with inventory.

ISO Class 8 Room Activities (Garbing and Gowning Room)

Don hair net; beard cover if necessary.

Don face mask.

Scrub forearms from finger nails-to-fingers-to-hands-to-elbows for at least 30 seconds, and then dry with lint free wipes.

Don coveralls that fit to neck, wrists (thumb loops preferred) and ankles; additional apron or sleeve covers, if required.

Don appropriate protective eye wear; additional face shield, if required.

Don a hood, and then pull draw strings to secure in place.

Don boot covers as you cross over line of demarcation from clean-to-cleaner side.

Apply waterless alcohol-based surgical hand scrub; allow hands to dry.

Don sterile gloves.

Disinfect gloves, with Sterile Isopropyl Alcohol (SIPA).

Disinfect external surfaces of all pre-sterile sealed reusable and disposable devices and chemical containers.

Place inventory in pass-through or in designated conveyances on the clean side of the line of demarcation slated for immediate use.

Store any other inventory in their respective and designated sites discriminating hazardous from non-hazardous chemicals.

Remove gloves, and then don a new pair of sterile gloves.


Don a second level of personal protective equipment if entering a designated hazardous drug compounding room.

Transition to the ISO class 7 room.

ISO Class 7 Room Activities (Weighing and Wetting Room)

Retrieve inventory from pass-through, if applicable.

Disinfect a second time, external surfaces of all pre-sterile sealed reusable and disposable devices and chemical containers.

Store hazardous drugs in their designated sites, if applicable.

Disinfect gloves, a second time, with Sterile Isopropyl Alcohol (SIPA).

Perform aseptic manipulations related to the weighing and wetting of powders, if applicable.

ISO Class 5 Primary Engineering Control-related (PEC) Activities

Disinfect Direct Compounding Area (DCA).

Disinfect all materials upon transfer from ISO class 7 SEC or C-SEC into ISO class 5 PEC.

Prepare Compounded Sterile Preparation (CSP); includes end-stage filtration, if possible.

Perform an inspection of final CSP for particulate and fill volume.

Partially or completely seal final dispensing containers.

Remove all materials from, and then disinfect, direct compounding area.

Prepare samples for testing of the CSP.

Continued on next page…



Functional and Operational Considerations in Facility Design

Stepwise Processes and Procedures moving out of and between ISO Class Environments

Inspection Station Activities

Disinfect the outer surface of all sealed dispensing containers prior to exiting ISO class environment.

Sterilize finished CSP, if possible.

Quarantine finished CSP.

Perform a complete inspection of each finished CSP dispensing container.

Label finished dispensing containers of CSP.

Determine if immediate dispensing is permissible.

Ensure appropriate testing is performed on finished CSP; external, internal if permissible.

Exiting the ISO Class Environment for Non-Hazardous Drug Compounding

Remove disposable garb when exiting the ISO class room and discard appropriately.

Decontaminate reusable garb, as appropriate.

Exiting the ISO Class Environment for Hazardous Drug Compounding

Remove outer layer gloves and place in hazardous waste container located in the containment primary engineering control

Remove all other disposable garb when exiting the ISO class room and discard in appropriate hazardous waste bag.




Verification of Facility Design Plans As a final review of facility design parameters; review this verification of facility design plans to ensure your comprehension of functional and operational parameters of performance.

Verification Parameters for Facility Design Plans

Criterion Description of Potential Challenge Verification

Air changes per hour ISO Class 6 or worse environments typically feature turbulent airflow and reduce contamination by supplying a minimum number of air changes per hour.

An air change per hour is calculated based on airflow rate, and the volume of the room. The airflow rate is measured using a specialized instrument.

Air velocity ISO Class 5 and better environments control contamination by providing a minimum air velocity.

Air velocity is verified by placing a specialized instrument (anemometer) in the stream of airflow.

Laminar (unidirectional) airflow

Non-unidirectional (turbulent) airflow in critical areas is conducive to particle collection, and subsequent build-up of contamination.

Laminar airflow is verified by use of a device that generates smoke that reveals air turbulence.

Room pressurization Positive air pressurization of a clean room is required to prevent entry of particles through doors or pass-throughs.

Differential pressure across two environments can be verified using a differential pressure gauge.

HEPA filter integrity Leaks in HEPA filters can lead to unfiltered air reaching critical areas.

A HEPA-filter leak test involves introducing an aerosol upstream of the filter and measuring the percentage of aerosol that penetrates downstream of the filter.

Temperature Uncontrolled temperature can make personnel uncomfortable leading to poor habits. Temperature also affects the rate of growth of microorganisms.

A temperature probe is used to validate temperature. Plotting temperature over time ensures consistency in the HVAC system.

Humidity Relative humidity affects the rate of growth of microorganisms.

Humidity control is verified by recording readings from a humidity sensor and plotting on a graph over time to ensure consistency in the HVAC system.

Non-viable particulate count

ISO class environments must meet specifications for non-viable particulate counts.

A non-viable particulate counter measures the number of non-viable particles per 1000 L (m

3).

Microbial Counts Microbial presence in air and surface must be within specific limits according to ISO class environment.

Air and surface microbial samples are collected in-house by compounding personnel, and can be processed internally or externally.



Primary Engineering Controls Now that we have reviewed secondary engineering controls, we can now review primary engineering controls.

Suggested Characteristics of a Laminar Airflow Workstation for Compounding

ISO Class 5 required

Corrosion-resistant type 304 stainless steel work surfaces and IV bar for hanging bags and bottles

Filter system is 99.99% efficient in capturing 0.3 micrometer particulate

Controlled airflow volumes and velocity

Average air velocity at 100 FPM

Fluorescent lighting at 200 foot candles over work surface

Particulate, dust count and leak test can be performed by single particle monitor or cold DOP photometer

Manufacturer provided verification documentation performed by independent laboratory



Compounding Aseptic Isolator / Compounding Aseptic Containment Isolator

Compliant with current NIOSH and CETA standards, and ISO Class 5 environment or better Negative pressure within work area as compared to C-SEC if compounding hazardous materials External ventilation may be required if compounding hazardous materials Fluorescent lighting to minimize heat and improve eye comfort Ability to load instrumentation and equipment Inter-connected negative pressure pass-through chamber Easy access and separate HEPA filter systems; supply and exhaust Stainless steel type 316



Biological Safety Cabinets

Biological Safety Cabinets are sub-divided into three classes; I, II, and III. Class II is further divided into four types; A1, A2, B1, and B2.

Protection Airflow Exhaust Particularities Use

Cla

ss I

Protects personnel and environment.

75 ft. /min of unfiltered room air travels horizontally

across the work surface.

Passed through a HEPA filter into the room or

outdoors.

Does not protect preparations.

When minimal preparation protection

required.

Cla

ss II

; Ty

pe

A1

Protects personnel,

environment, and

preparations.

75 ft. /min inflow; down-flow air is

HEPA-filtered from a common plenum containing down-

flow and inflow air.

Non-recirculated portion of down-flow and inflow air are released through a common HEPA-filtered exhaust into the room or

outdoors.

May have positive pressure

contaminated ducts and plenums not

surrounded by negative pressure

plenums.

Not suitable for volatile toxic chemicals and

volatile radionucleotides.

Cas

s II

; T

ype

A2

Protects personnel,

environment, and

preparations.

100 ft. /min. inflow; down-flow air is

HEPA-filtered from a common plenum

containing recirculated and

inflow air.

Non-recirculated portion of down-flow and inflow air are released through a common HEPA-filtered exhaust into the room or

outdoors.

All ducts and plenums under

negative pressure or surrounded by

negative pressure ducts and plenums.

When minute quantities of volatile toxic chemicals and trace amounts of radionucleotides are produced and if air is

directly exhausted outdoors.

Cla

ss II

; Ty

pe

B1

Protects personnel,

environment, and

preparations.

100 ft. /min. inflow; down-flow HEPA-

filtered air is mostly inflow air with

minimally recirculated air.

The majority of collected down-flow air is HEPA-filtered and exhausted

into the room or outdoors.




When minute quantities of volatile toxic chemicals and trace amounts of radionucleotides are

produced and air must be directly exhausted

outdoors.

Cla

ss II

; Ty

pe

B2

Protects personnel,

environment, and

preparations.

100 ft. /min inflow; down-flow air is

completely HEPA-filtered inflow air

with no recirculation.

All down-flow air is collected and HEPA-

filtered before release into outdoors with no

recirculation within cabinet.




Volatile toxic chemicals and radionucleotides.

Cla

ss II

I Maximum protection for environment and worker

Down-flow air is completely HEPA-filtered inflow air

with no recirculation.

All down-flow air is collected and passed

through 2 HEPA filters before discharge to

outdoors.

Gas-tight enclosure with a viewing

window secured with locks.

Highly infectious microbiological agents and

hazardous operations.



Containment Ventilated Enclosure or Vented Balance Safety Enclosure The Containment Ventilated Enclosure (CVE) or Vented Balance Safety Enclosure (VBSE) is a HEPA or ULPA filtered containment device intended to prevent exposure to non-hazardous or hazardous drugs. It can be vented to the outside. The enclosure is designed so that the balances are not interfered with by vibration and / or air currents. In contract to a biological safety cabinet, the CVE or VBSE is not designed for sterile compounding; it is not considered an ISO class 5 PEC.

Used in pharmaceutical compounding to provide containment of powders during weighing and wetting, and to prevent cross contamination HEPA filter system 99.99% efficient in capturing 0.3 micrometer particulate Must have turbulent-free airflow to prevent fluctuations in balance readings during weighing Must have a chemically resistant base able to withstand disinfection and decontamination agents Must have a color surface able to show spills most easily; black or grey being best to show white powder Must be verified and within ASHRAE standards



Automated Compounding Devices The use of automated compounding devices (ACDs) for delivering and administering compounded sterile preparations is becoming increasingly more popular. However, consistency in operations within acceptable limits is equally important. An ACD is intended to accurately transfer volumes of fluid from one container to another. There are five types of pumps used to transfer liquids.

1. The peristaltic pump squeezes, and as such occludes, tubing in the direction of flow of its content. During the momentary occlusion a vacuum is created drawing fluid forward. The internal diameter of the tubing and size of the occluding mechanism determines flow rate.

2. The diaphragm pump pulses a flexible diaphragm to displace liquid by applying pressure against a plate. 3. The linear flow pump is more commonly used to deliver a predefined volume of liquid intermittently and regardless of

the liquid’s viscosity. It is not commonly used in the preparation of parenteral nutrition or other compounded sterile preparations.

4. The volumetric pump conducts high-speed filling by calculating the volume of liquid to be pumped, and considers the length and internal diameter of the attached tubing, as well as the viscosity of the liquid to be pumped. Often based on peristaltic pump technology, these devices must be both calibrated before use and periodically adjusted for accuracy during their operation.

5. The gravimetric pump operates by calculating the weight of the liquid to be delivered. The fluid’s weight is estimated by multiplying the expected volume of liquid by the specific gravity of the liquid.



Automated Compounding Devices

Requirements of… and when using… Automated Compounding Devices

Accuracy to within ± 5 %

Multiple source tubing should be pre-sterilized

Technology should have bar code reading capabilities (FDA specification)

Items requiring bar codes include: patient prescription, ingredient and final containers

Items requiring tracking include: ingredient lot numbers, expiration dates and volume usage.

The ACD for TPN should incorporate these parameters:

Ingredient name

Product ID / NDC Number

Barcode ID

Source container volume

Ingredient family; Ex: Amino acid, dextrose, fat emulsion, calcium

Ingredient specific gravity

Compounding sequence algorithm

User-friendly interface with touch-screen operations

Warning indicator system to report over or under delivery of ingredients

Recording of system’s functional operations

Interface capable of minimizing errors associated with duplicate entries

The ACD should exceed the level of accuracy achieved with manual compounding and be accurate to within 5% of the amount programmed, with verification of the amount pumped versus the programmed amount for each ingredient. The ACD should have inherent safeguards, including the ability to detect inadvertent source-solution mix-ups, i.e., the ability to detect situations that could result in inaccurate deliveries, such as occluded transfer-set tubing and empty source containers, and the ability to keep incompatible source solutions separate. This later function requires the pump to be programmed with a built in system that alerts the user when formulation issues such as incompatibilities arise. The ACD software should have the ability to assist the compounding pharmacist in producing parenteral nutrition formulations that are of physicochemical compatibility. The ACD software should provide the compounding pharmacist with useful clinical information. The ACD software should integrate with existing pharmacy programs wherever possible to optimize patient care and avoid therapeutic duplications. The contractual agreement with the manufacturer should provide continuous support of the compounding pharmacist and software, including information updates, problem solving, and emergency coverage.



Sterilization Equipment

Wet Heat Sterilizer (Autoclave)

Dry Heat Sterilizer

Creates a uniform high pressure environment (15 psi) in the presence of water vapor at a specified temperature (121

○C) and for a designated period of

time (20 - 60 min) resulting in the sterilization of a water-based CSP.

Provides a uniform source of dry heat used for sterilization of non-heat labile active agents and non-aqueous liquids. Sterilization can usually be accomplished by heating the materials at 160

○C -

180○C for periods of 30 – 120 minutes.



Material Types of Reusable and Disposable Devices Prior to describing a wide variety of reusable and disposable devices, it is important to consider the types of materials these devices are made of and whether or not they are compatible with the chemicals used in sterile compounding. Below is a table of materials for which devices are often made. Active Pharmaceutical Ingredients (APIs) and excipients should always be evaluated for their compatibility with material types.

Material Types of Select Devices Used in Sterile Compounding

Material Type Device or Device Part

Type 1 Glass Borosilicate, Clear Beakers, Cylinders, Flasks, Vials, Bottles

Type 1 Glass Borosilicate, Amber Vials, Bottles

Ethyl Vinyl Acetate (ETA) IV Bags

Polyethylene Terephthalate with Glycolised Polyester (PETG) Flasks

Polycarbonates Flasks

High Density Polyethylene (HDPE) Beakers

Low Density Polyethylene ( LDPE) Droppers

Polymethylpentene Beakers, Cylinders

Polypropylene Beakers, Cylinders, Flasks, Syringes

PVC Plasticized IV Bags, tubing

PVC Non-plasticized (DEHP free) IV bags, tubing

Teflon Resin. PFA Beakers

Stainless Steel Beakers

Aluminum Vial Seals

Bromobutyl Vial Septa

Chlorobutyl Vial Septa

Rubber Vial Septa

Silicone Vial Septa

Teflon-faced Vial Septa

Polyvinyl Chloride (PVC) with silicone section Tubing from Transfer Tube Sets

Acrylonitrile Butadiene Styrene (ABS) Connectors from Transfer Tube Sets

Homopolymer Clamp from Transfer Tube Sets

Polyethylene (PE) Tubing

PVC, Ethyl Vinyl Acetate, Polyethylene Triple layered extension tubing



Filtration Systems for Large and Small Volumes

Large Volume Filtration System

Mini Capsule Filter

Filters are used to remove particulates from liquid solutions. Large volume filtration filters made of Polyvinylidene Fluoride (PVDF) membrane provide low protein binding, high flow rates and high throughputs. The membrane material should have a broad chemical compatibility. These types of filters are suited for many parenteral or ophthalmic preparations.

Provides accurate fills, uniform flow, and maximum throughput Houses a 0.22 µm filter Built-in air vent allows elimination of trapped air bubbles Sterilized by gamma irradiation Used for filtration of batches ranging from 1 to 10 liters



Large Disc Filter

Small Volume Filtration Systems

Moderate to Large Volume Filter Systems

This filter is designed for point-of-use filtration at the filling head. They may be used for either final sterilization (0.22 µm units) or particle removal (5.0 µm units). The stacked disc design allows minimal hold-up volume and particle shedding.

These filters have two sterile connecting ports, one on either side of the disc. These ports are available in an assortment of types; luer, slip, male, female. The disc membrane also comes in a variety of materials so as to permit filtering of varied chemical substances.

Hydrophilic filter (left) for large-volume sterilization applications. Its housing is made of polypropylene. The filter is a 0.2 µm polyethersulfone membrane.



Compatibility Characteristics between Filters and Chemicals

Chart of Compatibility between Filter Material and Chemical Agent

Silv

er

Cel

lulo

se A

ceta

te

Gla

ss

Nit

roce

llulo

se (

MC

E)

Nyl

on

Po

lyca

rbo

nat

e

Po

lyet

her

sulf

on

e (P

ES)

Po

lyes

ter

Po

lyp

rop

ylen

e

PTF

E (L

amin

ate

d)

PTF

E (U

nla

min

ate

d)

Typ

e 3

16

Sta

inle

ss S

teel

Acetic Acid, 10% R N R N L R R R R R R L

Acetic Acid, 5% R R R R R R R R R R R -

Acetic Acid, Glacial R N R N N L R R R R R L

Boric Acid R R R R L R T R R R R -

Hydrochloric, 6N R L R N N R R L R R R R

Hydrochloric, Conc. R N R N N R R N R R R L

Hydrofluoric, 10% R N T N N R T R R R R -

Hydrofluoric, 35% R N N N N R T R R T R -

Nitric Acid, 6N N L R R N R N R R L R R

Nitric Acid, Conc. N N R N N R N N R N R L

Sulfuric Acid, 6N N L L R N R T R R L R L

Sulfuric Acid, Conc. N N R N N N N N R N R N

Ammonium Hydroxide, 6N R N N N N N R L R R R R

Potassium Hydroxide, 6N R N T N R N T N R R R -

Sodium Hydroxide, 6N R N N N N N R L R R R R

Benzyl Alcohol R L R R L L N R R R R R

Legend: R – Recommended; L – Limited (verification studies should be performed prior to use); N – Not recommended; T - Test Small Reusable and Disposable Devices



Transferring Devices

Fluid Dispensing System This Fluid Dispensing System is a spring-loaded syringe system with tubing to attach to a larger volume bag or bottle. It is used during repetitive tasks in the preparation of moderate sized batches when consistent volume is desired.

Used for reconstitution, medication dispensing, IV syringe pre-filling, unit dose medication transfer, and oral medication transfer. Used for doses from 10 mL to 30 mL.



Disposable Syringes and Needles

Parts of a Needle

Example of Transfer Spike

Parts of a Needle

Used as a connector between a vial, bottle or bag to luer syringe or tubing with a luer connection.



Needles 1-½ “ Needle is long enough to penetrate the double layer of the port of a bag 16 gauge is typically used to draw from a bottle or vial 18 or 19 gauge is typically used to draw from a bag

Vented Spike

Disposable Tubing and Transfer Sets

Transfer Tube Set

Used as a connector between a vial, bottle or bag to luer syringe or tubing with a luer connection

Fluid transfer set with male luer lock fitting on one end and dispensing pin on the other end. Also houses a tube clamp to stop the flow of fluid.



Luer-to-Luer Connector

Luer-to-Slip Connector

Luer Tip Dispensing Cap

A luer-to-luer connector with platforms for thumb and index finger

A luer-to-slip connector with platforms for thumb and index finger

A tamper resistant dispensing cap for a luer tip syringe



Luer Syringe Tip Cap

Dispensing Pin with Vent

Fluid-Filled Bag

Luer syringe tip cap used during procedures to protect critical site.

Dispensing pin with vent used to facilitate transfer of fluids from luer syringe or tubing to vial, bottle or bag.

Fluid-filled bag used in conjunction with other liquids or powders to make up a CSP.



Empty Bag

Belly Port of Bag

Sharps Container

Empty bag used to make up a CSP.

Sharps container used to discard needles and other dangerous disposable devices.

Belly port of bag used to inject additional fluids or to draw fluids out of a bag.



Packaging Devices and Materials When determining container types, review standard references for incompatibilities between chemicals and packaging material. Syringes Syringes may be pre-filled as part of the unit-dose distribution system or to enhance efficiency.

Example: Buffered Lidocaine solution for Emergency Room rapid administration.

Example: Injection into IV or irrigation bag for administration.

Example: Cardioplegic concentrates for rapid dilution in Operating Room.

Example: Bacitracin concentrated solutions for immediate dilution in irrigations.

Vials Vials can contain single or multiple doses of parenteral administrations.

Light sensitive active agents should be packaged in amber glass vials.

Colorless or clear glass vials are suitable for all others. Vials are available in 1 mL - 100 mL sizes.

Smaller sizes of 1 - 5 mL are selected for single-dose applications.

The required dose should always be packaged in the smallest vial possible.

Larger sizes are used to package multiple doses. The actual size is dependent on:

Dose

Rate of use

In consultation with the user

Vials can be acquired sterile empty and sealed available for filling.

Example: Concentrates of sodium, potassium, calcium, and magnesium ions may be added in 20 mL increments to liter bags of Dextrose and Saline when preparing cardioplegia solutions in an operating room pharmacy.

Septums (Stoppers) Septums or seals are selected on the basis of chemical compatibility and are available as:

Rubber caps Butyl rubber caps Butyl rubber caps with Teflon coating Silicon caps



Glass Containers Glass containers for sterilization are occasionally used when other standard sterile containers may not be appropriate. Example: Topical preparations, such as a lidocaine – epinephrine – tetracaine topical solution, may be dispensed in glass sample vials that allow opening and pouring onto a wound. IV Bags IV Bags, sterile and empty are appropriate for large and small volume intravenous drug administration. They are available in 50 mL - 1000 mL sizes and are ideal for transferring / pumping large volumes to single-unit dose fluids through sterilizing filters. Eye Dropper Bottles Eye dropper bottles, sterile and empty are used for ophthalmic solutions.



Closed System Transfer Devices Closed System Transfer Devices (CSTDs) protect compounding personnel form exposure to hazardous drugs during their manipulation and administration. The use of a CSTD is in compliance with the USP Chapter <800>.

Protector

Injector

Infusion Adapter

Syringe-to-Injector

Injector-to-Protector Syringe-to-Injector-to-

Protector-to-vial

Infusion Injector

spiked to Bag

Syringe-to-Injector-to-

Infusion Adaptor

(Syringe full)


Infusion Adaptor

(Syringe Empty)



Personal Protective Equipment Personal Protective Equipment (PPE) serves to protect compounded sterile preparations from contamination from non-viable and viable particulate, and protect personnel from harm. The table below outlines PPE required for non-hazardous drug sterile compounding. The following PPE must be donned in the ISO class 8 environment of a sterile compounding facility: Head cover and shoe covers; donned prior to entry to ISO class 8 environment. Coveralls; finishes at the neck, wrists and ankles. Boots; double elastic bands (ankle high and at top just below the knee). Hood; draw string in the back to secure position so vision is not obstructed. Face mask; sealed to face to prevent passage of air between mask and face / N-95 NIOSH approved. Goggles; sealed to face to prevent powder from getting in contact with eyes. Gloves; sterile and covers over the wrists and lower forearm.

All PPE must be made of lint-free fabric. Personal Protective Equipment Specific to Hazardous Drug Compounding The following PPE must be donned in the ISO class 8 environment of a hazardous drug sterile compounding facility: Hair cover as well as beard and/or moustache cover, if applicable. Appropriate gown material based on permeability data; if no permeation information is available, gowns must be changed every 2–3 hours or immediately after a spill or splash. The gown must close in the back. Disposable sleeve covers must be made of coated material. Double shoe covers required. Respiratory protection; N-95 NIOSH or multi-gas cartridge or P100-filter or chemical cartridge-type respirator. A full-facepiece respirator provides eye and face protection. Goggles and face shield; required outside of BSC/CACI. Safety glasses are not adequate. Face shields in combination with goggles provides adequate protection, but face shields alone do not provide full eye and face protection. A full-facepiece respirator can also be used to provide eye and face protection. Chemotherapy gloves; must be tested to American Society for Testing and Materials (ASTM) standard D6978 (or its successor).



Testing Technology A variety of technologies exist for monitoring the environment. They include:

Non-viable particulate air sampler

Viable (Microbial) air sampler

Swabs to capture viable particulate for surfaces

Growth media and growth plates to culture captured particulate In addition, a similar set of technologies exist to assess sterility and endotoxin levels in CSPs. They include:

Membrane filters to capture, hold and culture viable microbes.

Growth media to inoculate CSP test samples

Endotoxin testing technology that looks for the presence of pyrogens in CSPs



Non-viable Particulate Monitoring Technology Non-viable particles are monitored using particle counters which, in fact, do not discriminate between viable and non-viable particles. A calibrated laser particle counter is used to sample a defined volume of air that is sucked into a sample chamber by a pump. The basic components for the device include a laser diode as an illumination source and a photo detector that receives the light scattering signal. Light scattered by a single particle has a unique signature that relates to the size, shape, and material of the particle. Routine particle counting under dynamic conditions provides immediate realization of particle levels when sterile formulations are being prepared. The location of the particle counter should include all critical areas in which the sterilized preparation, containers and closures are exposed to environmental conditions. Measurements should also be taken in the work area around air flow workbenches and in areas around doors or pass-throughs, where contamination might be a concern. The device is programmed to sample the appropriate particle size over 400 L to 1000 L of air. If the number of non-viable particulate is greater than USP requirements for an ISO class environment, remedial action should be taken.

Recommended Action Levels for Non-viable Airborne Particulate Contamination: 0.5 micron or larger particles per cubic meter (1000 Liters) of air sampled per site

Classification Air Sample

ISO class 5 environment > 3520

ISO class 7 environment > 352,000

ISO class 8 environment or less > 3,520,000



Viable Particulate Monitoring Technology A viable particle sampling device serves as a microbial air sampler by collecting air and passing it over a petri dish to which microorganisms will adhere. This allows the user to quantify microbial presence in the air. In order to obtain a realistic measurement, viable air quality testing is performed under dynamic conditions. The flow rate of the device should be calibrated to 100 liters/minutes for 1000 liters of air, or according to manufacturer specifications in order to obtain an adequate sample size. The appropriate culture plate is inserted and then run for a 10 minute sampling cycle. It’s important to diligently document the precise location of sampling, date, time, culture media used, sample volume and operator, along with the outcome of each run. Multiple cycles should be run in strategic locations with new culture plates. The tested culture plates are then incubated in order to measure microbial growth. It is important to include negative and positive controls. If the resulting number of Colony Forming Units (CFUs) is greater than USP requirements for ISO class, begin remedial action plan to correct. Sample plates that show CFUs must be sent to a laboratory for speciation so as to rule out the presence of pathogens.



Sterility Testing Technology for Compounded Sterile Preparations There are two (2) types of sterility test methods for CSPs:

1. Membrane Filtration 2. Direct Inoculation

a. Inoculation b. Inoculation; Oil

Membrane filtration is preferred over direct inoculation as this method will filter the total volume, capture all microorganisms present and remove the product components that could cause the growth medium to appear turbid or that could inhibit microbial growth. Membrane filtration is ideal for small volume and large volume parenterals, emulsions, suspensions and antibiotics. Because a filter may capture some of the drug in a preparation being tested, testing must be performed to ensure there is no interference between the drug any a microbe in the mix.

Membrane Filtration Membrane filtration consists of filtering percent volumes of a CSP through a sterile 0.22 μm filter. Following filtration, membranes are washed with a sterile fluid to remove bacteriostatic compounds. Membranes are then incubated in the presence of one of three growth mediums; Soybean Casein Digest Media (SCDM), Fluid Thioglycollate Media (FTM), or Sabouraud Dextrose Broth (SDB).

Detection through Incubation

Growth Media Intended Growth Incubation Parameters

Soybean Casein Digest Aerobic bacteria and some fungi 22oC for 14 days

Fluid Thioglycollate Aerobic and anaerobic bacteria 32oC for 14 days

Sabouraud Dextrose Fungi (yeasts and molds) 28oC for 14-days

Along with the test samples, positive controls (intentionally contaminated samples with known organisms) and negative controls (no contamination) are also prepared and incubated. Turbidity during the 14-day incubation period indicates a positive test. Filtration is used to remove the possible microbial contamination from a preparation by passing the preparation through a 0.2 micron filter. Any microbes will be left on the anterior side of the filter. With the use of special technologies, a growth medium is added to the chamber on the anterior side of the filter and the media is incubated to test for growth for 14 days at an appropriate temperature range. This procedure is used when the desire is to remove a possibly microbial growth inhibitory solution from the equation and test for microbial presence. The process of filtration and removal of solution with the addition of growth media gives an increased risk of contamination during the sterility testing process. For this reason, the negative control must simulate the filtration procedure.



Membrane Filtration Method for Sterility Testing Technology

Cap: Non-vented Male Luer [white]

Outlet: Female Luer Lock Fitting

Filter Membrane [0.2 micron]

Media Chamber [5 mL]

Inlet: Female Luer Lock Fitting

Cap: Vented Male Luer [red]

1. Remove and discard RED Vented Male Luer cap on INLET Female Luer Lock fitting on chamber.

2. Attach syringe containing solution to be tested to the INLET Female Luer Lock fitting.

3. Remove and save WHITE Non-vented Male Luer cap from OUTLET Female Luer Lock fitting. Carefully position in laminar air flow to avoid contamination of inner surface of Male Luer cap.

4. Firmly attach a sterile, empty (receiving) syringe to the OUTLET Female Luer Lock. The empty syringe must have a capacity equal to or

greater than the volume of solution in the syringe being tested.

5. Press plunger on syringe containing solution to be tested to transfer solution through chamber into the receiving syringe. Pull back syringe plunger slightly and press again to transfer any solution remaining in the filter housing.

6. Carefully remove and cap receiving syringe.

7. Replace WHITE cap on OUTLET Female Luer Lock fitting.

8. Remove empty syringe from INLET Female Luer Lock fitting.

9. Attach syringe containing TSB growth media to the INLET Female Luer Lock fitting.

10. Point syringe DOWN while pressing plunger. This will remove air from filter chamber. Press plunger on growth media syringe to fill

chamber.

11. Leave growth media syringe attached to the chamber.

12. Complete, then attach gummed label to attached syringe.

13. Incubate at 22.5+/- 2.5°C for not less than 14 days.

14. Remove "piggy back" gummed label from chamber and record results.



Direct Inoculation A sample from the batch solution is collected and added to Soybean Casein Digest Medium (SCDM), Fluid Thioglycollate Medium (FTM), or Sabouraud Dextrose Broth (SDB) media at 22

oC, 32

oC, and 28

oC respectively for 14-days. Along with the test samples,

positive controls (intentionally contaminated samples with known organisms) and negative controls (no contamination) are also prepared and incubated. During the incubation period, samples showing turbidity indicate contamination. One disadvantage of direct inoculation is the difficulty in detecting microorganism growth from milky or cloudy products due to initial turbidity. Inoculation Inoculation is performed by adding a growth media to the final container or adding a significant portion of the solution in the final container to a container of growth media. This tests the effectiveness of the process and/or solution for the lack of microbes or the inability of the microbes to grow in the diluted media. The presence of the diluted form of the solution might in and of itself inhibit microbial growth. Theoretically, this test method might not result in the detection of infinitesimal microbial contamination or proliferation of microbes if the solution interferes with the growth of the microbes. Inoculation-oil This procedure is carried out by addition of the oil based substance to a growth media and the mechanical mixing of the oil with the growth media; microbial contamination will be able to be detected by the growth of microbial colonies in the growth media. This procedure is used for substances that cannot be filtered. The media container must be shaken regularly to be sure that microbes can reach the liquid growth medium. The process of injecting the oil into the growth media might lead to a solution that is hazy and which might mask microbial growth.



Inoculation-Oil Test Technology

Remove the loose fitting protective cap covering the rubber diaphragm on the top of the bottle. Do NOT unscrew the large blue cap with the knurled rim. This will cause a loss of vacuum and may introduce contaminates into the sterile media area.

Swab the rubber diaphragm with an appropriate antiseptic.

Inject up to 17mL of test sample into the bottle. Mix contents using

gentle inversion.

Label bottle with piggyback label.

Incubate at 22.5° +/- 2.5° C for not less than 14 days.

Inspect daily for signs of growth.

Slowly and gently invert every other day, making certain paddle surfaces are coated with broth.

If growth occurs, colonies can be removed for further testing by

twisting off the cap paddles and lifting out of the bottle.

Remove piggyback gummed label and attach to log. Fill out remaining information in log.

Discard used bottle in a safe manner.



Endotoxin Testing Technology There are three (3) types of endotoxin tests:

Gel Clot

Chromogenic

Turbidometric Gel Clot This procedure is used to test for pyrogens. The LAL gel clot test is an enzymatic test that is sensitive to temperature, time and vibration. Once mixed, the reaction solution must be stored in a dry block incubator or non-circulating water bath at 37°C ± 1°C for 60 ± 2 minutes. If a gel is formed and remains intact after inverting 180° then the test is positive. The positive test indicates that the endotoxin concentration in the tube is greater than or equal to the sensitivity of the test. This is often thought of as the most accurate and sensitive test for pyrogens. The problem arises in the temperature, time and vibration sensitivity of this test. It can be difficult to meet these requirements and variation will give a false negative. This test is economical if small numbers of tests must be run and cannot be grouped in large numbers. There are no automated gel clot systems available. Chromogenic This procedure is used to test for pyrogens. The chromogenic LAL test uses an enzymatic reaction similar to the gel clot test which produces p-nitroaniline in the presence of endotoxins. The yellow color of this chemical has an absorbance of 405 nm and this is what is measured to give the endotoxin concentration. There are two variations of this test. The kinetic method uses time to reach a particular absorbance level to determine the endotoxin level while the chomogenic endpoint method uses the levels of p-nitroaniline after a set incubation period to determine the level of endotoxins present in the sample. Both methods require using a standard curve in order to determine the final endotoxin levels in the sample. The advantages of the chromogenic method are the availability of automated methods that will decrease personnel costs associated with these tests. These methods are significantly more expensive than gel clot tests. Turbidometric This procedure is used to test for pyrogens. The turbidometric method is similar to the chromogenic method but uses the turbidity of the solution after incubation rather than the absorbance to measure endotoxin levels. There are also two different ways that this test is performed. One uses the rate of change in turbidity as measured by optical density over time while the other method uses the turbidity at a set endpoint to determine the endotoxin level. These methods compare the sample to known standards to determine the standard curve. This method also can have interference problems but the automated systems available can be more cost effective in the long run, especially if the testing of several preparations can be performed at the same time. The start-up cost of this test is significantly higher while the cost per test can be significantly lower.



Indicator and Integrator Test Technology In every sterile compounding practice there is wet and dry heat sterilization procedures performed. Biological indicators and thermal integrators serve to determine whether or not the conditions of wet and dry heat sterilization were met. Thermal indicators can also be used to assess the efficacy of the depyrogenation process. A chemical integrator is used to determine whether the sterilization process conditions of an autoclave were met inside the chamber during each run. These strips can be used in all 121°C/250°F sterilization cycles. The moving front ink technology provides a clear-cut ‘accept or reject’ result. The biological indicator monitors the effectiveness of the steam sterilization process at 121°C/250°F. It does not provide information about what conditions were met inside the chamber, other than if they were sufficient to kill spores or not. The biological indicator is a self-contained, sealed, glass ampule with growth medium and a bromocresol pH indicator system. The brown color-coded cap contains holes for sterilant penetration, and a hydrophobic filer as a bacterial barrier. After sterilization, the vial is crushed such that the growth media joins the processed spore strip containing geobacillus stearothermophilus. The biological indicator must be incubated for 48 hours before a response can be obtained. A visual color change to yellow indicates surviving spores, and thus a positive result. The selection of biological indicators depends on the process being verified. For wet heat sterilization, heat-resistant spore-forming microorganisms are employed. Different spores are recommended for different sterilization processes.

Biological Indicator (left) and Thermal Integrator (right)



Growth Media Technology

Microorganisms in a clean room environment are monitored in order to ensure adequate maintenance of the level of microbes in the air and on surfaces of a clean room. All surfaces should be disinfected on a regular basis and verified by microbial surface testing. Additionally, fingertips of personnel are tested for verification of aseptic techniques. Microbial organisms to be tested include aerobic bacteria, anaerobic bacteria, fungus, mold, and yeast. The type of media used to perform testing should reflect the comprehensive array of microbes being tested. The direct cultivation plates are coated with agar which allows for direct inoculation. With this particular plate, the person being fingertip tested simply presses onto the surface with their fingertips; the plate is then covered, labeled and incubated. These plates can also be directly pressed onto surfaces in the clean room. Plates are available with Trypticase Soy Agar, Sabouraud Dextrose Agar, and Potato Dextrose Agar. Plates can also be purchased with agents to neutralize disinfecting chemicals, in order to prevent test interference. For hard to reach places, swabs contained in a neutralizing saline solution are used. The solution neutralizes a broad spectrum of commonly used antiseptics and disinfectants. The media does not promote growth, but simply facilitates survival of organisms during transport to a lab before being transferred to a petri dish. This is ideal for external testing. Swab B is recommended for use in critical areas due to its reliability in the ability to recover 3X more organisms from surfaces and release more than 4X the organisms onto a plate when compared with a series of traditional swabs.

Microbial Type to be Tested Growth Media

Aerobic Bacteria, Yeast, Mold, Fungus Trypticase Soy Agar

Yeast, Mold, Fungus Sabouraud Dextrose Agar

Yeast, Mold, Fungus Maltose Extract Agar



Section 4: P3 - Procedure

Procedure Quality Management

Environmental Monitoring, Maintenance, and Control

Inventory Control Management and Storage

Technology Maintenance and Calibration

Chemical Quality Control

Deactivation/Decontamination and Disinfection

Glassware Cleaning & Depyrogenation

Recall Enabled and Traceability

Hazardous Drug Compounding Requirements

Verification

Documentation

Definition of Procedure Quality Management

Procedure, in the context of System P are all tasks, once removed, and in support of a compounded sterile preparation. It includes the general operation and verification of a compounding facility, and its maintenance, monitoring, control, cleaning and disinfecting, both internal and external to ISO class environments. It also includes the maintenance, cleaning and disinfecting, monitoring, control and calibration of technology. Finally, Procedure involves selection, inventory control, safe handling, and the recall capability of active pharmaceutical ingredients and excipients, hazardous drugs, and controlled substances.



Equipment and Technology Management All equipment and technology must be calibrated, maintained, monitored and inspected on a regular basis as per regulatory requirement and/or manufacturer specification. Equipment must be cleaned after each use and disinfected in between preparations to ensure that cross contamination or microbial contamination does not occur.

Durable Medical Equipment and Automated Compounding Devices Durable Medical Equipment (DME) and Automated Compounding Devices (ACD) require special consideration as they necessitate calibration and monitoring, verification and documentation.

Calibration and Monitoring Calibration and monitoring of equipment and technology is done on a regular basis as per standards of practice or manufacturer’s specifications. Each time a piece of equipment or technology is used, the user shall monitor the automated device’s ability to perform; to fulfill its necessary tasks and ensure an efficacious and safe preparation. Volumetric pumps must be calibrated prior to the filling process and regularly during an extended process. Balances should be leveled and calibrated prior to use. All equipment must be verified to be working properly prior to use as per established Standard Operating Procedures.

Sampling and Testing As part of everyday operations, ongoing sampling and testing for non-viable and viable particulate must be performed to ensure that all PECs, C-PECs, SECs, and C-SECs are performing appropriately.

Environmental Monitoring There must be a specific environmental monitoring action plan put in place for a sterile compounding facility. All areas of a facility that may impact safety and effective preparation need to be monitored. Environmental monitoring is a means to validate cleaning and disinfection procedures in the sterile facility.

Considerations for Environmental Air Monitoring

Method of sampling

Location of samplers

Volume of air sampled

Frequency of sampling

Time of day related to activity level

Action level threshold per sample type



Chemical Safety Standards OSHA follows the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) published by the United Nations. There are nine hazard pictograms in the GHS which represent the physical, health and environmental hazards:

GHS Hazard Pictograms

Explosive

Flammable

Oxidizing

Gases under pressure

Acute Toxicity

Irritant

Corrosive

Health Hazards

Environmental



Canada Only Health Canada mandates that hazardous substances be labeled according to the Workplace Hazardous Materials Information System. Many of the symbols are similar to those of the Globally Harmonized System.

Workplace Hazardous Materials Information System

Dangerous Reactive

Materials

Flammable and Combustible

Materials

Oxidizing Materials

Compressed Gases

Materials Causing

Immediate and Serious Toxic Effects

Poisonous and Infectious

Materials

Corrosive Materials

Materials Causing Other

Toxic Effects



Chemical Safety and Storage Requirements General storage requirements include:

1. Room temperature storage: 20° C to 25° C (68° F to 77° F). 2. Refrigerated storage: 2° C to 8° C (36° F to 46° F) 3. Frozen storage: - 20° C to -10° C (-4° F to 14° F) 4. Humidity range: 35-60%. 5. Dry storage: Note that these chemical storage areas’ humidity must never exceed 40%. 6. ISO Class 8 environment or better. 7. Chemicals should not be exposed to sun light. 8. Shelving units should be impermeable and noncorrosive.

Hazardous Drug Storage Requirements Additional hazardous drug storage requirements include:

Hazardous drugs must be stored separately from other inventory.

Negative pressure room externally vented with at least 12 air changes per hour.

Antineoplastic agents must be stored in a designated refrigerator in a negative pressure room with 12 ACPH.

Acids and bases should be stored separately from each other and preferably in secondary containment/containers.

Acids and bases should be stored close to the floor.



Environmental Management - Sterile Rooms and Work Area The procedures to maintain and operate a clean room facility are a vital component of the process that ends in a safe and efficacious CSP. These procedures must ensure that the refuse levels, gross contaminant levels, particulate levels, and microbial load within the most critical areas of the facility are at a negligible level. The level of attention paid to these processes should be comprehensive and meticulous. Deactivation/Decontamination and disinfection imply multiple step processes; therefore:

Materials entering the clean room must be wiped with a disinfecting agent to remove gross and microscopic particulate, and kill any microbes remaining on their surfaces. In the case of a sterile pouched item, it can be opened onto a clean conveyance.

Refuse from the compounding area and/or from general facility maintenance processes should be removed regularly. In order to prevent the dispersal of particulates, they should be moved with little agitation.

The floors, walls, ceiling, shelving, storage areas and work surfaces must be decontaminated to remove hazardous drug residue, disinfected to decrease microbial load in a fashion to reduce the risk of microbial resistance. The residue from the decontamination and disinfecting agents is removed using sterile isopropyl alcohol.

Surfaces and critical sites of the items used in the compounding process within the ISO class 5 Direct Compounding Area (DCA) must always be disinfected immediately prior to use, and every 30 minutes thereafter. The DCA must also be either decontaminated and then disinfected (hazardous drug compounding) or disinfected (non-hazardous drug compounding) immediately following their use.



General Principles of Deactivation/Decontamination and Disinfection Deactivation/Decontamination and disinfection are essential to preparing a safe and efficacious CSP. Deactivation/Decontamination is the destruction or chemical decomposition of hazardous material or hazardous drug substances. Disinfection is the reduction of the microbial presence to a level considered safe for compounding processes to be performed and is defined by viable and non-viable particulate levels in controlled ISO class environments. Oftentimes, a disinfecting agent will be able to remove particulate contamination and soiled areas, but will often leave residue which must also be removed. The combination of disinfecting agent followed by the use of sterile isopropyl alcohol will ensure the removal of disinfecting agent residue and the reduction of both non-viable particulate and viable particulate in the form of microbial contamination. Deactivation/Decontamination and disinfecting processes are rather time consuming and expensive. As such they need be determined to be effective in their ability to prevent microbial accommodation and thus resistance to the chosen process. The rotation of disinfecting agents with differing mechanisms of action is recommended as is the use of a broad spectrum sporicidal agents between disinfecting agents to “reset the microbial clock to zero”, as bacteria and fungi periodically release spores. This approach is recommended to ensure effectiveness. Another important factor is the need for appropriate contact (dwell) time for the various agents to exert their microbial effect; oftentimes indicated in manufacturer specification literature as 10 minutes. A table has been provided, listing characteristics of disinfecting agents and their respective efficacy. Another consideration is the ability for these agents to actually exert effectiveness on various types of organisms. Using these characteristics to choose the agents to be used within a facility is one way to improve disinfecting agent efficacy.



Efficacy of Disinfecting Agents

Application of Cleaning and Disinfecting Agents

Target Soaps and Detergents

Hydrogen peroxide

Isopropyl alcohol, 70%

Phenolics Quaternary ammonium

Chlorine compounds

Paracetic acid Aldehydes

Particulate Excellent - - Excellent Good - - - - - - Good

Lipid-coated viruses - - Very Good Excellent Very Good Good Excellent Very Good Very Good

Gram-positive, facultative anaerobic (Staphylococcus aureus)

Very Good Excellent Excellent Excellent Excellent Excellent Excellent Very Good

Gram-negative, facultative anerobic (Escherichia coli)

Very Good Excellent Very Good Excellent Excellent Very Good Excellent Very Good

Spore-forming bacteria (Bacilli subtilis)

Very Good Good - - - - Excellent Very Good Very Good Very Good

Yeasts (Candida albicans) - - Very Good Very Good Excellent Good Good Excellent Good

Molds (Aspergillus Niger) - - Very Good Good Very Good Good Good Good Good

Non-lipid coated viruses - - Very Good Very Good - - - - Excellent Good Very Good

Mycobacteria (Mycobacterium tuberculosis)

2 Very Good Very Good Excellent - - Good Good Excellent

Spores - - - - - - - - - - Good 1 Very Good Good

Protazoa - - - - - - - - Good Good Very Good Very Good

1. Good at > 1000 ppm sodium hypochlorite 2. Unclear in literature.



Some General Characteristics of Disinfecting Agents The table below shows disinfecting agents and their generally accepted uses, based on how harsh or corrosive they are. There are many agents with differing efficacies, as well as advantages and disadvantages. When considering which agent(s) to utilize, it is imperative to consider their mechanisms of action. This will help with the rotation of agents. The rotation of disinfecting agents helps to prevent microbial resistance to the agent. It is equally important to consider whether or not a particular agent has the ability to kill spores and molds.

Surface-specific Disinfecting Agents

Gloves and Varying Technology

Isopropyl Alcohol

Walls, Ceilings, Floors and Varying Technology

Glutaraldehyde

Paracetic Acid

Hydrogen Peroxide

Iodine

Sodium Hypochlorite

Phenol

Skin

Hexachlorophene

Povidone Iodine

Isopropyl Alcohol



Schedules for Disinfection Cleaning and disinfecting a clean room is a critical process in ensuring the safety and efficacy of a preparation made in a given facility. The purpose of this activity is to reduce the particulate and microbial burden so as to reduce the risk or likelihood of its introduction into the compounding process. It takes a 0.5-micron particle approximately five minutes to fall to the ground through Brownian motion. Therefore, it is important to reduce the number of microbes and particulate levels as much as possible. It is recommended that facility cleaning and disinfecting take place every four weeks. There are several important concepts that should be considered when deciding on the processes and procedures for cleaning and disinfection.

Concepts Applicable to Disinfection

Utilize and duplicate a process that does not require repeat verification; that is, employ an approved process already peer reviewed in a reputable journal publication. Use a sporicidal agent monthly to reset microbial adaptation. Change the agent used every four weeks period to another agent with a different mechanism of action. Whenever particulate or microbial monitoring levels reach action levels, a thorough disinfecting is immediately required. In the presence of a positive microbial count; speciation is required to rule out the presence of pathogens. Processes and procedures should be performed in accordance to written Standard Operating Procedures.

The cleaning and disinfecting process must be robust enough to ensure a safe and effective compounding environment. The processes and procedures employed need be verified and/or documented in a peer reviewed article, and must be based on sound scientific principles. The monitoring of a facility for particulate and microbes is an equally important step in the cleaning and disinfection process. If the facility reaches a level of microbial growth designated as an action level, then an appropriate action such as a thorough cleaning and disinfecting, should be conducted immediately. The rotation of two disinfecting agents with different mechanisms of action within a monthly schedule coupled with a sporicidal agent is considered an effective process in reducing microbial adaptation. Employ one of the rotated agents with a 10-minute dwell time to ensure efficacy. The treatment of the facility with a sporicidal agent would ensure the removal of any resistant microbes. During the next four weeks the other rotated agent should be used until the sporicidal agent is used again.



Daily versus Monthly Cleaning and Disinfection

Cleaning and Disinfecting Performance

Frequency What to Clean and Disinfect & How to Perform the Task

Shift or After Spill

Clean Direct Compounding Area. Use disinfecting agent with 10-minute dwell time, and then remove residue with SIPA.

Daily

Clean floors in buffer and anteroom, work surfaces around DCA and counters. Use disinfecting agent with 10-minute dwell time, and then remove residue with SIPA.

Monthly

Clean work surfaces around DCA, counters, floors in buffer and anteroom, walls, ceilings, storage and shelving units as well as all equipment and devices located on these shelving units Use sporicidal agent with 10-minute dwell time. Remove just prior to next compounding activity. Rotate disinfecting agent after every monthly cleaning with one that has a different mode of action.



Sample of Weekly Disinfection Schedule

Weekly Cleaning Form for One Room within Facility

DATE: <DAY>; <MMM DD, YYYY>

Disinfecting Agent Used:

Main Room

Direct Compounding Area (Controlled Substance Wall - Plenum Wall - Wall to Breakaway Door)

Move all rolling work stations

Wipe walls with disinfecting agent

Wait 10 minutes for effect

Wipe walls with sterile Isopropyl alcohol 70%

Floor

Move all shelving units and rolling work stations

Clean corners along wall using disinfecting agent and scrub pad where needed

Wipe floor using designated floor mop using disinfecting agent


Wipe floor using designated floor mop with sterile Isopropyl alcohol 70%

Shelving Unit

Remove bins on shelving unit

Clean shelving unit with disinfecting agent

Wipe top of shelving with disinfecting agent

Wipe bottom of shelving with disinfecting agent

Wipe support rods with disinfecting agent


Clean shelving unit with sterile Isopropyl alcohol 70%

Wipe top of shelving with sterile Isopropyl alcohol 70%

Wipe bottom of shelving with sterile Isopropyl alcohol 70%

Wipe support rods with sterile Isopropyl alcohol 70%

Clean bins with disinfecting agent

Wipe outside of bin with disinfecting agent

Wipe Interior of bin with disinfecting agent


Clean bins with sterile Isopropyl alcohol 70

Wipe outside of bin with sterile Isopropyl alcohol 70%

Wipe Interior of bin with sterile Isopropyl alcohol 70%



Procedures for Deactivation/Decontamination and Disinfection for Hazardous Drug Compounding Subsequent to hazardous drug compounding, there need be a deactivation/decontamination process followed by disinfection. There is limited research into the appropriateness of deactivation/decontamination agents. Nonetheless, decontaminating and disinfecting agents should be pre-qualified for use by reviewing product specifications, literature, safety data sheets, and by performing surface testing protocols. Decontaminating agents, much like disinfecting agents, must be compatible with all surfaces and technology. They must also be EPA registered. Decontamination of hazardous drug substances is typically performed using aqueous alkaline detergent; pH between 8 and 9. Commonly used deactivation agents include sodium hypochlorite and sodium thiosulfate.

Spill Control Pharmacy personnel must take spills very seriously. A spill can have a number of negative consequences if not properly managed. Depending on the type of spill, these hazards can include:

Immediate injury, damage or irritation of skin, eyes and other tissue, for example, from strong acids or bases and other irritating substances.

Respiratory damage from inhalation of toxic fumes.

Systemic effects or chromosome damage from transdermal, respiratory or other absorption of chemicals, such as hormones and chemotherapeutic agents.

Long-term effects from chronic exposure to chemicals that may have been left in the environment from spills which are not cleaned up or improperly cleaned up.

Exposure to communicable diseases such as hepatitis from blood/body fluids. Pharmacies that work with hazardous drugs must have appropriate spill kits available in case of accidents. A pharmacy may require several different spill kits depending on the hazardous drugs it handles. Hazardous material spill kits are designed to clean up a specific type of spill. The proper spill kit must be chosen to clean up a particular spill:

Chemotherapy spill kits include materials for cleaning up and disposing of solid and liquid hazardous drugs.

Acid spill kits include materials for solidifying the spill and for cleaning up and disposing of the acid.

Base spill kits include materials for solidifying the spill and for cleaning up and disposing of the base. If a spill does occur, all personnel involved must take appropriate actions to protect themselves. The first priority is to address any injuries, tissue damage or personal contamination as a result of the spill and an incident/accident report must be completed after the event. If necessary, other personnel can manage the spill while any affected personnel seek first aid and medical treatment. The risk due to a particular spill is based not only on the quantity, but on the potency and the particular hazard posed by the spilled substance. Even if the amount of chemical spill is very small, it can still pose a hazard.



Procedures for Handling Hazardous Drugs Procedures for handling hazardous drugs and related materials must begin immediately upon receipt of these supplies, as there have been confirmed reports documenting contamination of the outside of vials with detectable amounts of hazardous drugs. Personnel handling the receiving of hazardous drugs and materials must wear appropriate gloves and work in a well-ventilated area. Hazardous drug vials are placed in plastic bags and then stored in a negative pressure area isolated from other drugs and supplies. Any surface that might be contaminated by the receiving process must be wiped down with sodium hypochlorite, while allowing for sufficient contact time to bring about the desired effect. Gloves and any other disposable protective wear must be properly discarded to prevent further contamination. Hazardous drug compounding must be performed inside a negative pressure ISO class 7 room connected to an ISO class 8 room. The ISO class 7 room and any areas designated for hazardous drug storage must have a negative pressure differential as compared to all other compounding areas. This will inhibit the flow of hazardous materials back into the main compounding area and maintain any hazardous materials within the hazardous drug compounding area. The face is the most vulnerable area for contamination. Therefore, filtered air coming from the ceiling over the work area, and then being pulled out via baseboard returns will give a net flow down and away from sensitive areas of the body. This latter flow of air must be filtered prior to its removal to reduce hazardous residue from being vented to the outdoors. Working with either a barrier isolator or an appropriately classified biological safety cabinet within a negative pressure room is a requirement to isolate personnel from hazardous drug residue. The air from these workbenches must also be filtered to remove residue, and then vented outdoors through HEPA filters. Personal protective equipment is an important part of the process. Putting on shoe covers that will only be used within the hazardous drug room is recommended and a second pair of dissimilar gloves is mandatory, as is a chemotherapy gown. Another consideration is using an N95 mask that is impregnated with charcoal. This type of mask will absorb noxious organics and is a prudent safety precaution. All personal protective equipment that might be contaminated with hazardous materials must be removed in the hazardous drug negative pressure room and placed in appropriate disposal containers. If the ISO class 8 room, preceding the ISO class 7 hazardous drug compounding room also has an entry to a non-hazardous compounding room, then the hazardous personal protective equipment must be removed in the negative pressure ISO class 7 room. The rest of the garb is removed in the ISO class 8 room. The decontamination of a chemotherapy room is required on a daily basis. Walls and floor must be wiped with sodium hypochlorite. The solution must be left in contact with the surface for an appropriate amount of time to ensure decontamination, and then removed with sterile Isopropyl alcohol. The DCA or critical workspace must be decontaminated after each preparation, since cross contamination is a major concern. You should use your professional knowledge, experience, and testing data on hazardous drug contamination levels in your compounding practice to decide on the appropriateness of the timing of the decontamination of the compounding area. The decontaminating agent must be left for a time sufficient to ensure the deactivation of any residual hazardous material. It must be done at a minimum with the changeover of each shift. Every surface must be wiped with sodium hypochlorite, or a specific decontaminating agent, if known. The caustic decontaminating agent must be removed with sterile Isopropyl alcohol when the decontamination time is finished.



Discriminating between Disinfection, Sterilization, and Depyrogenation

IMPORTANT NOTICE

EACH OF THE PROCESSES, DISINFECTION, STERILIZATION OR DEPYROGENATION, INFERS A LEVEL OF

ASSURANCE AND SHOULD NOT BE TAKEN AS A GUARANTEE.

Sterilization is the process of complete destruction and/or removal of all viable microbes within a statistically reliable certainty. A sterile surface is assured to be microbe free. Disinfection is a less than specific term which is most often used to mean the reduction of viable microbes to a level which is not harmful to humans. No assurance is implied. Sterilization with a solution is most notably a process which implies an assurance of the presence of no viable microbes. For a solution to sterilize a surface it must be in contact with the entire surface for a dwell time to ensure complete microbial death or removal. Most sterilization procedures are defined as a probability of complete microbial death or removal. Sterilization does not imply that these surfaces are pyrogen free. Disinfection for pharmaceutical processes is often accomplished with a 10-minute contact time. Wiping a surface with a saturated cloth containing the disinfecting agent with a 10-minute dwell time does not give the same level of probability as implied by sterilization. Disinfection does not imply that these surfaces are pyrogen free. Endotoxins are lipopolysaccharides are found on the outer membrane of various gram-negative bacteria. Endotoxins are a type of pyrogen, and you will note that some sterile products specifically say sterile and pyrogen free on the label. Injected endotoxins/pyrogens can cause adverse reactions in humans. This reaction can range from fever and chills to irreversible and fatal septic shock. The severity of the reaction depends on the level of endotoxins/pyrogens in the injected product and the route of administration. Pyrogen free is a term that implies no pyrogen causing agents are present. While the levels may be decreased by washing and rinsing with pyrogen free water, this is not the implied guarantee of pyrogen free. Glass, metal and heat resistant objects can be rendered pyrogen free by heating these objects to 250°C for at least 2 hours. While a device might be considered to be free of pyrogens, most CSPs will have an “acceptable limit” of pyrogens present; this is usually expressed as endotoxin units per milligram of active agent or EU/mg.

TWO CRITICAL PRINCIPLES

DISINFECTION DOES NOT MEAN THE DESTRUCTION OR REMOVAL OF ALL ORGANISMS.

DISINFECTION MAY NOT NECESSARILY RESULT IN STERILIZATION.



Section 5: P4 - Process

Process Quality Management

Process Development

Risk Assessment

Preparatory Procedure

Technology Selection

Aseptic Techniques

Filtration Method

Sterilization Methods

Test Method Selection

Verification Protocol

Personnel Rehearsal

Documentation

Definition of Process Quality Management

Process, in the context of System P is synonymous with Process Development (PD) during the establishment and refinement of a Master Formulation Record. It includes the verification of the formulation, its procedure, and all pre-, in-, and post- qualification related protocols. It includes the selection of appropriate aseptic techniques, equipment and devices, mathematical calculations, packaging, filtration and sterilization methods, and the establishment of a Beyond-Use Date (BUD). A major component of Process is the internal and external testing of protocols associated with a MFR and is conducted during PD leading toward the establishment of the MFR.



Process Development Process Development (PD) is the establishment and rehearsal of a Master Formulation Record. Process development allows you to pre-qualify a vast majority of requirements leading to the finalization of a MFR. If process development is the establishment of a MFR, and a MFR must be documented, then it stands to reason that there is a document or template for process development. The same document for process development serves as a MFR. If we go the distance, then it also stands to reason that a MFR serves as the template for a Compounding Record (CR). To fully understand process development, please refer to the MFR template in this manual. You may identify its location by looking it up in the Table of Contents. It is the last sub-section in this manual just prior to your learning assessment.

Master Formulation Record Template

PLEASE REVIEW THE PROCESS DEVELOPMENT

MASTER FORMULATION RECORD COMPOUNDING RECORD

TEMPLATE.



Excipients Used in Compounded Sterile Preparations The table below contains a list of common excipient types used to prepare CSPs.

Excipient Used to Prepare CSPs

pH Adjuster

Buffer

Antioxidant

Preservative

Osmolarity Adjusting Agent

Solvent

Co-solvent

Solubilizing Agent

Emulsifying Agent

Wetting Agent

Surfactant

Chelating Agent



Antioxidants The table below lists antioxidants used to prepare CSPs.

Antioxidants Used in Parenteral Preparations

Name Concentration [%] Soluble in Water Soluble in Oil

Ascorbic acid 0.01 - 0.5 Y N

Cysteine 0.1 - 0.5 Y N

Sodium bisulfate 0.05 - 1.0 Y N

Sodium formaldehyde sulfoxylate 0.005 - 0.15 Y -

Sodium metabisulfite 0.1 - 1.0 Y -

Thiourea 0.005 Y N

Butyl hydroxyanisole 0.005 - 0.02 N Y

Tocopherol 0.05 - 0.5 - Y

Monothioglycerol 0.1 - 1.0 Y -



Preservatives Preservatives are typically not used in single unit dose Large Volume Parenterals (LVPs) or Small Volume Parenterals (SVPs) that can be sterilized. However, when they are needed, the selection process, in the case of multiple-dose vials, is dependent upon:

The pH requirement for a CSP

Physiological function-related considerations in a newborn

Preservatives Used in Parenteral Preparations

Name Concentration [%]

Benzalkonium chloride 0.01

Benzethonium chloride 0.01

Benzyl Alcohol 1.0 – 2.0

Chlorobutanol 0.25 – 0.5

Chlorocresol 0.1 – 0.3

Cresol 0.3 – 0.5

Thimerosal 0.01

Osmolarity The most commonly used osmolarity adjusting agent is Sodium chloride for SVP, ophthalmic drops, Intramuscular (IM) injections, Subcutaneous (SQ) injections, and intrathecal injections. Dextrose and/or Sodium chloride may be used with LVP intravenous administration.

Efficacy Enhancers Specific excipients may bring about an enhanced effect for other excipients. The addition of either Sodium edetate or Benzyl alcohol can result in an increased efficacy of the preservative Benzalkonium chloride. Propylene Glycol, which acts as a co-solvent for a paraben may also enhance the efficacy of Benzalkonium chloride at concentrations of 2 - 5% of the total volume of a CSP.

Solvents and Co-Solvents In the case of a chemical solution, a single liquid used to prepare a preparation is referred to as a solvent. When several liquids are used, they are referred to as co-solvents. .



Selection of Solvents and Co-solvents:

Route of Administration: The default solvents for all routes of administration are water for injection and sodium chloride for injection. Only water or water-soluble liquids are used to prepare intravenous injections. If a longer acting intramuscular injection is desired for an oil-soluble drug, then peanut oil, sesame oil or another appropriate vegetable oil may be selected.

Drug Solubility: While Nitroglycerin’s water solubility is adequate for the dose and method of administration in large volume intravenous solutions, it is far too low to use water as the solvent in its multiple dose vial form. In this later case, Nitroglycerin for injection is dissolved in Propylene glycol and Alcohol.

Drug Stability: Active pharmaceutical ingredient (API) stability in solution, and whether or not it will hydrolyze, are important considerations in selecting solvents and co-solvents.

Special Needs: An example of a special need is Anhydrous glycerin used as a solvent for Phenol; the crystals and not liquefied for spinal injections in certain neurological conditions.

Osmolarity: Adjusting the osmolarity of large volume parenterals and small volume intramuscular injections are performed by calculating Sodium chloride equivalents or the osmolarity of the components, and then using the appropriate amounts of Water for injection or Saline for injection.

A co-solvent can be used for several purposes.

Co-solvents enhance the solubility of an API. When preparing an injection of Progesterone 200 mg / mL in Sesame oil, dissolve the Progesterone in Benzyl alcohol to 20% of the final volume, and then add this mixture to Sesame oil. This allows for a more rapid solubility of the API, while the Benzyl alcohol acts as a local anesthetic upon injection.

Co-solvents enhance the stability of other excipients. Phenobarbital sodium hydrolyzes relatively quickly in water. By dissolving the phenobarbital sodium in a minimal amount of water, its solubility is about 1 g / mL. By diluting this concentrated mixture to the desired strength with Propylene glycol, Glycerin, or Alcohol, the stability of the Phenobarbital is greatly enhanced and hydrolysis is very minimal.

Co-solvents allow the rapid dissolution of other components in the mixture A paraben acting as a preservative slowly dissolves in an aqueous solution. If the parabens are first dissolved in propylene glycol, then this mixture can be added to an aqueous medium. In this instance the paraben would rapidly and completely dissolve.

Propylene glycol used as a solvent for parabens also enhances their efficacy with its own antibacterial properties.



Parenteral Solutions Used in Sterile Compounding The table below identifies parenteral solutions used to prepare CSPs as well as their corresponding tonicity and pH.

IV Solutions and their respective Tonicity and pH

Solution Tonicity pH

0.45% NaCl Hypotonic 4.5 - 7.0

0.9% NaCl Isotonic 4.5 - 7.0

5% Dextrose Isotonic 3.5 - 6.5

10% Dextrose Hypertonic 3.5 - 6.5

5% Dextrose + 0.9% NaCl Hypertonic 3.5 - 6.5

5% Dextrose + 0.45% NaCl Hypertonic 3.5 - 6.5

5% Dextrose + 0.2% NaCl Isotonic 3.5 - 6.5

Ringer's Solution Isotonic 5.0 - 7.5

Lactated Ringer's Solution Isotonic 6.0 - 7.5

Lactated Ringer's Solution + 5% Dextrose Hypertonic 4.0 - 6.5

When faced with an isotonicity problem you will need to know: a) the amount of drug in whatever amount of solution you’re making b) the sodium chloride equivalent [E] for that drug* c) the concentration of NaCl nearest to blood concentration; this is called “normal saline” and is 0.9% NaCl.



Base Solutions and Components of Parenteral Admixtures The table below identifies parenteral solutions and their respective acronyms.

Base Solutions and Components of Parenteral Admixtures

Acronym Common Base Solutions and Components of Parenteral Solutions

UNSP Unspecified

BWFI Bacteriostatic Water For Injection

SWFI Sterile Water For Injection

D5W Dextrose 5% in Water (5% Dextrose Injection)



D5LR Dextrose in Lactate Ringer’s Solution (5% Dextrose in Lactated Ringer’s Injection)

D5¼S Dextrose 5% in 1/4 Strength Saline (5% Dextrose and 0.22% Sodium Chloride Injection)

D5½S Dextrose 5% in 1/2 Strength Saline (5% Dextrose and 0.45 % Sodium Chloride Injection)

D5NS Dextrose 5% in Normal Saline (5% Dextrose and 0.9% Sodium Chloride Injection)

D5R Dextrose 5% in Ringer’s Injection (5% Dextrose in Ringer’s Injection)

D10NS Dextrose 10% in Normal Saline (10% Dextrose and 0.9% Sodium Chloride Injection)

IS10W Invert Sugar 10% in Saline (10% Invert Sugar in 0.9% Sodium Chloride Injection)

LR Lactated Ringer’s Injection

Pr Protein Hydrolysate (Protein Hydrolysate Injection)

R Ringer’s Injection

NS Sodium Chloride 0.9% (Normal Saline) (0.9% Sodium Chloride Injection)

SOD CL 5 Sodium Chloride 5% (5% Sodium Chloride Injection)

Sod Lac Sodium Lactate, 1/6 Molar (M/6 Sodium Lactate Injection)



pH Adjusters and Compounded Sterile Preparations The pH of a preparation is adjusted for one of three reasons:

Stability

Solubility

Tolerability to administration site It may not be possible to optimize the pH for all three of these reasons at one time resulting in the need for appropriate compromise. The selection of a pH adjusting agent and their concentrations depends on the specific components of the formulation and the buffering capacity of the solution. Often the adjusting agents are either strong acids or bases, such as hydrochloric acid or sodium hydroxide, respectively. The pH value is determined using a calibrated pH meter. After the pH is adjusted the preparation is brought to its final and full volume. If the buffer capacity of the preparation is small there might be a dramatic change in the pH of the CSP, should a large quantity of water be added to the mixture. It is possible to take a solution initially adjusted to one pH for stability, and then later adjust the solution pH for patient tolerability for short periods of time with refrigeration.

A pH Testing and Adjusting Procedure The below procedure is a practical method for pH adjustment:

1. Draw an appropriate amount of the mixture needed to test pH levels.

2. Test the pH of the sample. It should lie between an established [minimum] and [maximum].

3. If the pH < the [minimum], carefully add sodium hydroxide solution to the mixture:

a. Draw and transfer one or two drops of the sodium hydroxide solution to the mixture. b. Stir for at least five minutes to evenly disperse the Sodium hydroxide. c. Re-test the pH. d. Continue to add the sodium hydroxide solution until the pH of [minimum] to [maximum] is obtained.

IMPORTANT: Do not allow the pH to rise above [maximum].

4. If the pH > [maximum], carefully add the hydrochloric acid solution to the mixture:

a. Draw and transfer one or two drops of the hydrochloric acid solution to the mixture. b. Stir for at least five minutes to evenly disperse the hydrochloric acid. c. Re-test the pH. d. Continue to add the hydrochloric acid solution until the pH of [minimum] to [maximum] is obtained.

IMPORTANT: Do not allow the pH to fall below [minimum].



Balancing Physiological pH with required pH of a CSP A carefully thought out process is required when balancing the pH between physiological requirements and that of a CSP. In the case of a non-parenteral preparation (example: Ophthalmic solution), the pH of the solution should be between 4.5 and 9 so as to avoid irritation. Fortunately, most ophthalmic agents are stable within this range. In the case of a single application of an ophthalmic solution, if used early enough, it may not need to be buffered and the focus of attention can now be placed on the API. However, if an ophthalmic solution is to be used repeatedly over a period of days, an appropriate compromise between preparation stability and patient comfort may need to be considered. The buffering action of tears will bring an ophthalmic solution to neutrality or a slight alkalinity. Generally, a single drop is adequate for most doses so the eye is not overwhelmed by a large amount of acidic or alkaline solution. If the drug is acidic, the eye’s buffering action will form the free base and result in more rapid absorption. A solution with a pH of 5 administered several times daily should not be cause for concern. However, a more heavily buffered solution will interfere with this natural protection. Generally speaking, there is more tissue irritation and damage from a high pH than from a low pH. In the case of a parenteral preparation (example: Intramuscular solution), the pH is adjusted for drug stability and solubility. The volume for an injection is usually small and adjustments are not made to meet physiological pH.

Commonly Used pH Adjusters

Commonly Used pH Adjusters

Acidic Adjusters Hydrochloric Acid (used most often) Acetic Acid (used often with amino acids) Citric Acid Sodium phosphate, monobasic Basic Adjusters Sodium Citrate Sodium hydroxide Sodium bicarbonate Sodium phosphate, dibasic Tromethamine Used in the presence of calcium and magnesium ions which will precipitate in the presence of hydroxide, bicarbonate or phosphate ions

When validating a preparation, record the amount of acid or base needed for a given preparation that brings a solution to its required pH level. Should you be creating an actual formula, the quantity for a given pH adjuster would be unknown to you during the verification process. After learning how much pH adjuster is needed, a slightly lesser quantity should be recorded in your documented and verified formulation for subsequent preparations. Then, when adjusting for pH, relatively small amounts will be needed to attain the final desired pH. This will increase your efficiency and assist you in identifying any gross discrepancies should a significantly different quantity of pH adjuster suddenly be required. Your documented and verified formula will specify the quantity of acid or base required to bring the solution to the desired pH.



Buffering a Preparation A preparation is often pH adjusted to maintain its solubility and stability. While buffering agents, such as phosphate salts, acids or bases, are used to make this pH adjustment, the preparation is not buffered to withstand exposure to future acidic or alkaline conditions. Therefore, when adjusting the pH or buffering a solution, you must determine whether or not there are chemical or efficacy-related incompatibilities; an example being citrate and phosphate buffers that decrease the efficacy of benzalkonium chloride solutions while borate buffers do not. Benzalkonium is more effective at an alkaline pH. Citrates and phosphate buffers decrease its efficacy but borates do not. In the case of physical incompatibilities, sodium phosphate buffers may cause precipitation in the presence of calcium or magnesium salts.

Active Pharmaceutical Ingredient Characteristics in a Compounded Sterile Preparation It is equally important to know the characteristics and function of an API as it is the excipients of a CSP. The table below lists some important API characteristics that must be identified when preparing a CSP.

Important Characteristics of Active Pharmaceutical Ingredients

1. Solubility of active agent 2. Stability of active agent in a given medium 3. Necessity for refrigeration / freezing of CSP 4. Susceptibility of active agent to oxidation, reduction, hydrolysis 5. Sensitivity of active agent to light 6. pH requirement of medium to maintain stability 7. pH requirement related to CSP tolerability 8. Excipient compatibility / interaction with active agent



Chemical Sensitivities Associated with Sterile Preparations Chemical sensitivities that should be considered when preparing a CSP are listing in the table below.

Chemical Sensitivities

Sensitivities

Photosensitive

Oxygen reactive

Hygroscopic

Metal reactive

Glass reactive / adsorbent

Plastic reactive / adsorbent

Rubber reactive



Heating, Freezing, and Thawing of a Sterile Preparation Determining whether to heat a solution in order to speed up the solubilisation of ingredients of a preparation is governed by the ingredient’s stability in the presence of heat. Generally speaking, refrigerating or freezing will increase the stability of a preparation, and decrease the solubility of the APIs and/or excipients in the mixture. If any component of the preparation is close to the upper limit of solubility at room temperature, refrigerating or freezing may result in precipitation. If a precipitate forms, you must be absolutely certain that all components go quickly back into solution at room temperature. The injection of a precipitate is not an acceptable practice.

Rule Regarding Refrigeration and Freezing of a Preparation

THE PHYSICAL INSPECTION OF A THAWED PREPARATION IS AN ABSOLUTE NECESSITY IF THAT PREPARATION

WAS FIRST REFRIGERATED OR FROZEN.

Example 1: Lidocaine hydrochloride for injection Lidocaine hydrochloride for injection is stable at RT and at a pH of 4.0. However, this acidity induces pain upon injection when injected at multiple wound sites. Stability studies show that if the pH is raised to 7.3 by adding sodium bicarbonate to the mixture, the solution remains stable for a period of up to four weeks with refrigeration. Therefore, raising the pH, filtering and dispensing the preparation in syringes, and refrigerating the preparation will provide both a suitable and stable preparation. More so, there is relatively no pain upon injection. While studies have shown Lidocaine to be stable at RT and a pH of 7.3, the unionized form absorbs into various plastics; loss of strength (potency) ensues not because of hydrolysis, but because of the absorption of Lidocaine into the plastic container. Refrigeration will slow down this process. Example 2: Bacitracin sulfate Bacitracin sulfate solution is stable for only a few days at RT and approximately one week with refrigeration. As a result, commercially packaged Bacitracin sulfate powders are diluted on a daily basis as it is prepared for use in irrigation. When research indicated Bacitracin solution maintained its strength (potency) for up to five months at -20°C, it became feasible to purchase 2 Kg containers of sterile Bacitracin sulfate powder; approximately 135 - 140 million units from which you can prepare 13.5 - 14 L of solution containing 10,000 Units/mL. The solution is pumped through sterilizing filters into syringes in 5 and 10 mL increments and immediately frozen at -20°C. On demand, syringes would be removed from the freezer, stability-labeled for two weeks when refrigerated, and sent to an operating room.



Section 6: P5 - Preparation

Preparation Quality Management

Prescription Processing

Aseptic Techniques

In-Process Testing

End-Stage Filtration

Sterilization

CSP Quarantine and Inspection

Preparation Packaging

Preparation Labeling

Definition of Preparation Quality Management

Preparation, in the context of System P is defined as all tasks performed in support of the development of a sterile preparation. All that is necessary to follow a MFR is included in Preparation. It includes such elements of a MFR as personnel selection, ISO class environment assignment, aseptic technique selection, filtration, sterilization, inspection, packaging, labeling, of the CSP.



Verification of Preparations The verification of a CSP is synonymous with the successful completion of a Compounding Record. If process development was the pre-qualification phase leading to the establishment of a MFR, then a CR is the post-qualification phase of a MFR. It is a MFR being prepared for an actual patient as opposed to a rehearsal. It is also that aspect of a MFR template that couldn’t have been completed as there was no physician prescription or patient. The correlation of patient information and MFR brings finality to the template. All that remains are the results of end-stage filtration filter integrity tests, sterility and endotoxin tests related to the finished CSP. Physician communications, patient monitoring, and recording of patient outcome measures is a factor of P6: Patient. The finished CSP must be delivered to a patient in a safe and efficacious state, and it must contain the appropriate strength and purity of the API and any other ingredient for that matter. The dispensing container must be properly labelled. The content of the final dispensing container(s), the label, and the MFR must be congruent. In order to accomplish this, the activities that take place before, during and after the preparing of a CSP must be verified.

End-Stage Filtration of Compounded Sterile Preparations IMPORTANT: End-stage filtration is not a means of sterilization. Filtration methods used in sterile compounding do not block all microbes. Certain types of bacteria have been shown to be able to penetrate 0.45 µm filters. To maximize bacterial, fungal and yeast retention, a 0.2 µm filter membrane is required. Equally important is the fact that endotoxins are not readily removed by 0.2 µm filters. It is for this reason a preparation must be promptly filtered to avoid gram-negative bacteria from undergoing proliferation and their immediate release of endotoxins. Even if wet or dry heat sterilization is an option, end-stage filtration must still be performed, if possible. End-stage filtration reduces the pyro-burden by first removing bacteria from the preparation. Otherwise, the endotoxin levels may be too high after sterilization. In addition, end-stage filtration does not remove endotoxins from the mixture. Upon completion of end-stage filtration, each filter must undergo a filter integrity test whereby the used filter is subjected to a specific air pressure for an extended period of time and not demonstrate a breach in its integrity to withstand that pressure over time. The illustration to the right shows a syringe applying pressure up against a filter. If the filter’s integrity is not breached, then the pressure gauge reading will increase to the desired level. If the filter‘s integrity is breached, then air will pass through the filter, through a tube and into the water situated in an Erlenmeyer flask where it will emit bubbles.



Wet and Dry Heat Sterilization of Compounded Sterile Preparations Assuming no ingredients in a formulation are heat labile and the mixture is water-based, then the finished preparation must undergo wet heat sterilization. Wet heat sterilization in an autoclave is best achieved at 121.5

○ C with 15 psi of vapor pressure for 20 to 60 minutes. While the

temperatures, pressures and times listed are recognized as a guideline; the actual process must be verified as having achieved sterility.

Wet Heat Sterilization

Temperature Pressure Exposure Time

121.5° C 15 psi 20-60 Min.

Dry heat sterilization should be utilized for anhydrous oils and powders that cannot be easily permeated by steam. Dry heat sterilization is less efficient than wet heat sterilization. It requires a longer time or higher temperature. Dry heat sterilization is not suitable for aqueous solutions. This will result in either the water boiling away or exploding if in a sealed container. Dry heat is only used for stable active agents and non-aqueous liquids such as dry powders or oleaginous bases such as Peanut oil or Sesame oil, respectively. A specific time and temperature must be determined for each preparation before its being sterilized. Dry heat sterilization can usually be accomplished between 160

○ C - 180

○ C for periods of 30 to 120 minutes. The table below

illustrates the temperature and time conditions for dry heat sterilization; however, while the temperatures and times listed are recognized as a guideline; the actual process must be verified as having achieved sterility.

Dry Heat Sterilization

Temperature Exposure Time

180° C 30 Min.

170° C 60 Min.

160° C 120 Min.



Evidence that a wet or dry heat sterilization cycle has achieved its respective conditions does not insure sterilization. Each sterilization cycle must be itself, verified. Integrators are used to determine that parameters have be met (temperature, pressure and time for wet heat sterilization and temperature and time for dry heat sterilization) and biological indicators are utilized to ensure the actual destruction of their micro-organisms. The reason for the use of biological indicators is illustrated by the following facts.

Sterilization cannot be achieved in oleaginous vehicles or closed containers without moisture.

When the autoclave reaches the set temperature, not everything inside the autoclave is at that temperature, and it does not signify sterilization.

It takes longer to achieve sterilization conditions in a 1000 mL bottle than in a 1 mL vial.

When the contents of a container reach the set temperature, sterilization is not yet achieved; there is still a time factor involved in this process.

The use of autoclave tape as a verification process, generally speaking, does not assure sterility; the tape indicates only that the proper temperature had been achieved and is not dependent on time. Therefore, time requires independent recording. Different bacteria die at different rates in a fluid, and the rate of death can vary with the fluid. The “D” value of a bacterial strain is the time it takes to kill 90% of that particular bacterium during the wet heat sterilization process. If the “D” value is two minutes, then 90% of that strain is killed in two minutes. In another two minutes, 90% of the remainder of the bacteria is ki lled. The conditions of pressure and temperature must be maintained long enough during wet heat sterilization process to kill all bacteria.

Quarantine Inspection of Compounded Sterile Preparation Compounded sterile preparation must undergo visual inspection for:

Precipitate

Non-dissolved particles

Non-viable particulate

Viable particulate

Small rubber cores

Crystals The solvent of a solution must be inspected for:

Transparency

Clarity

Color

Absence of turbidity Dispensing container closures must be inspected for:

Ability to maintain its integrity, stability, and sterility

Ability to protect a handler (personnel, caregiver, or patient) from exposure

Ability to protect from damage, leakage, contamination, and degradation

Finally, dispensing containers must be inspected for appropriate labelling. Hazardous drug label identifiers must be clearly visible. Hazardous handling precautions must also be clearly legible and accessible.



Section 7: P6 - Patient

Patient Quality Management

Patient and Caregiver Instruction

Patient Counselling

Patient Monitoring

Adverse Events Reporting

Statistical Outcome Measures

Definition of Patient Quality Management

Patient, in the context of System P is defined as all health care related activities that take place upon issuing a CSP to a patient or caregiver focusing on initial counselling. Instructions, oral and written include administration, indications, cautions, and possible explanations of contraindications. It will also include patient care monitoring practices; patient outcome, adverse event reporting, statistical recording and applicable reporting.



Patient and Caregiver Instruction and Counselling Patient and caregiver instruction is an important aspect and often overlooked responsibility of the compounding pharmacist. Ensuring appropriate utilization of compounded sterile preparations is important to the efficacy of treatment. Another important aspect of this is ensuring strength (potency) of the preparation is maintained during shipping, handling and storage. Patient and caregiver instruction should include information about the effects and side effects of the CSP along with directions to report the outcomes of treatment to their physician as well as the compounding pharmacist.

Patient Monitoring Patient monitoring can be performed in conjunction with the primary caregiver or depending on your service portfolio and abilities as an added service to the primary caregiver. Clinical report writing can serve as a wonderful tool for expanding your ability to care for patients as it will serve as a database of patient outcomes. Many guidelines describe the responsibility of the compounding pharmacist as comprehensive throughout the continuum of care. Being able to document successes as well as less than desirable outcomes is important.

Event Recording and Reporting Noting important events throughout the course of therapy is imperative. Being able to recall data when needed is also an important aspect of patient monitoring. Whether the pharmacy uses electronic records or manual patient records, being able to document the events throughout the course of therapy will give one the ability to show a comprehensive approach towards patient care.



Clinical Considerations related to Sterile Compounding Much has been spoken and written about the “health care team” being a unit. Working together, members of the healthcare care team produce the highest quality patient care. An example of this team might include (depending on the clinical situation) the physician, nurse, pharmacist, dietician, physical therapist, occupational therapist, speech therapist, social worker, and respiratory therapist. In order for a team to function efficiently and productively, whether that team consists of three people or eight people, all members of that team need to understand the function of every other member of the team. As pharmacists, we need to appreciate the “big picture”, rather than understanding only the pharmaceutical services portion of patient care. A thorough understanding of the breadth of the various considerations and the potential complications associated with IV therapies makes us a much more respected and productive member of the team. Complications of Parenterals Complications of parenteral administration arise from the injection process itself (phlebitis) and include vein spasms, arterial punctures and even air embolisms. Complications can also arise from the physiochemical properties of the preparation itself. However, the most irritating injections result from physiological conditions at the site of administration. There are numerous factors impacting the parenteral dosage form itself, such as pH and tonicity. Age, disease state, sex and Body Mass Index (BMI) also effect the administration of parenteral injections. The site of injection can lead to particular complications and is often dependent of the condition of the body. These complications can range from difficulty in obtaining venous access in malnourished patients to sciatic nerve damage in gluteus (IM) injections with infants. In some disease states such as neutropenia or thrombocytopenia, an intramuscular injection can be contraindicated. Besides administration complications, there can be major differences in drug absorption between routes of administration, for example, between IM and SC administrations. This later point is an important consideration for the compounding pharmacist. Pyrogen Response A pyrogen response is defined as the presence of a fever caused by the presence of endotoxins and/or exotoxins in the body resulting in a febrile response in the patient. Possible sources could be phlebitis at the catheter site, infusion equipment or the parenteral solution itself. In a severe case, patients may even go into “pyrogen shock”. Interestingly, the management of patients in pyrogen shock includes the administration of parenteral fluids; hopefully non-pyrogenic. Signs and symptoms of pyrogen shock include:

Fever

Chills

Aching

Malaise Pyrogen contamination in sterile preparations is prevented by:

Performing comprehensive pyrogen screening tests

Maintaining proper storage and handling

Depyrogenation of glassware Bactericidal procedures such as heating, filtration, or adsorption techniques do not eliminate pyrogens from parenteral solutions.



Infection-Catheter Site to Sepsis Infection is defined as the presence of pathogenic organisms in the body. An infection related to IV infusion therapy may range in severity from a catheter site infection to sepsis; the presence of bacteria in the blood or tissue. When an infusion-related infection is suspected, the IV catheter is first removed, and then the catheter tip, the access site and the infusate, if it is suspected as a source of sepsis, should be cultured using aseptic technique and observing universal precautions. Signs and symptoms of sepsis include:

Fever

Chills

Tachycardia

Fatigue

Muscle aches

Weakness

Hypotension

Erythema

Swelling at insertion site

Induration

Purulent drainage at site

Elevated white blood cell count Methods for the prevention of sepsis:

Use of strict aseptic technique

Frequent observation of access site for potential problems

Change of the IV access site at least every 72 hours Nociceptive Response A nociceptive pain response occurs when specific nerve endings become irritated. Nociceptive pain is that type of pain you feel when you burn your hand, twist your ankle, or feel pain at an injection site. Often a nociceptive pain response is pH sensitive and is activated by acidic injections. Signs and symptoms of a nociceptive pain include:

Dull or sharp aching pain; ranging in severity from mild or severe

Shooting "electric shock sensation" of pain during IV insertion; can result in numbness, tingling, weakness, or paralysis

Methods for the prevention of nociceptive pain responses include:

Removal of the cause of the response, or otherwise medically treated. Nociceptive pain usually responds well to mild pain medications, anti-inflammatory agents, or other drug therapies.

The addition of sodium bicarbonate to an injection; as is done with KCl and erythromycin.

The dilution of the injection; nociceptive pain response can be concentration dependent. Too much volume of injection can lead to triggering pain responses. In the case of an IM injection, Lidocaine can be mixed with another API to reduce or eliminate pain on administration, as long as the two APIs are compatible.

The control the pH to avoid acidic solutions; maximize dilution of fluids, and slow the infusion rate of the IV fluid.



Allergic Reaction; local or systemic An allergic reaction in this instance is a bonafide antigen-antibody reaction normally. This reaction is typical to the drug being infused or injected, although equipment reactions can also occur. Signs and symptoms of an allergic response, in order of severity, include:

Rash

Hives

Itching

Tachycardia

Increased blood pressure

Bronchi constriction

Labored breathing

Cardiac or respiratory arrest Methods for the prevention of allergic responses include:

The discontinuance of the IV immediately.

The close monitoring and administrative supportive treatment; steroids, antihistamines, or other appropriate medication therapy.

Researching the patient medical history for evidence of drug or equipment allergies.

Making additional inquiries with patient and family for complete and updated information.



Section 8: Master Formulation Record Template The following pages represent a sample Master Formulation Record template. It can be utilized in any one of three (3) phases of development of a formulation for a compounded sterile preparation:

1. Process Development (PD)

2. Master Formulation Record (MFR) establishment

3. Compounding Record (CR) establishment An in-depth review of this template is in itself an important source of learning as it relates to the preparation of a CSP.



MASTER FORMULATION RECORD AND COMPOUNDING RECORD TEMPLATE

<PHARMACY LOGO> <PHARMACY NAME>

FORM CODE: STRL - 0000

MFR APPROVAL DATE: DD-MMM-YYYY

MFR IMPLEMENTATION DATE: DD-MMM-YYYY

MFR TERMINATION DATE: N/A

Formulary ID: F 000 000 v0 MFR ID : MFR 000 v0 CR ID : CR 000 000 Prescription ID :

Formulary Name: API1 00 g/mL; API2 00 g/mL; (00 x 00 mL in Dispensing Container; Route of Delivery and Dosage Form) (Composition) (Expression of Unit Metered Dose) (Expression of Frequency) (Expression of Duration)

☐ MASTER FORMULATION RECORD ☐ COMPOUNDING RECORD Page 1 of 10

Master Formulation Record Signatories

MFR Prepared by: SIGNATORY:

TITLE: SIGNATURE

DATE

MFR Reviewed and approved for use by:

SIGNATORY:

TITLE: SIGNATURE

DATE

Master Formulation Record Signatories 1

Preparation Testing Requirements 2

Sterilization Method Requirements 2

Pharmaceutical Calculations 2

Technological Requirements 3

Environmental Requirements 3

Electromechanical Equipment 3

Reusable Devices 3

Disposable Devices 3

Dispensing Container and Packaging Materials 3

CSP Labelling 4

MFR Label 4

CR Label 4

Auxiliary Labels 4

Physicochemical Characteristics 4

Chemical Sensitivities Assessment 5

Ingredient Tracking 5

Ingredient Identification 5

Ingredient Quantification 5

Preparatory Procedure 6

Beyond-Use Dating and Storage Requirements 7

Filter Integrity Test Results 7

Sterilization Cycle Completed 7

Visual Inspection 8

Criteria and Approval for Release; Pre-Testing 8

CSP Shipping Requirements 8

Packaging Details 8

Shipping Details 8

CSP Test Results Summary 9

Criteria and Approval for Release; Post-Testing 9

Quality Control or Adverse Event Reported 9

References in Support of Master Formulation Record 10












Preparation Testing Requirements

☐ N/A ☐ Sterility Testing Requirement (TSB): Units Required: Volume/Unit:

☐ N/A ☐ Sterility Testing Requirement (FTG): Units Required: Volume/Unit:

☐ N/A ☐ Endotoxin Testing Requirements: Units Required: Volume/Unit:

☐ N/A ☐ Stability Testing Requirements: Units Required: Volume/Unit:

☐ N/A ☐ Strength / Identity Testing Requirements: Units Required: Volume/Unit:

TOTAL ADDITIONAL VOLUME REQUIRED TO PREPARE THIS BATCH EXPRESSED AS A MULTIPLICATION FACTOR: <1.00>

Sterilization Method Requirements

☐ N/A ☐ Wet Heat Sterilization Specifications: ☐ 121C at 15 PSI for… ☐ 20 minutes ☐ ______ minutes

☐ N/A ☐ Dry Heat Sterilization Specifications: ☐ 160C ≥120 minutes ☐ 170C ≥ 60 minutes ☐ 180C ≥ 30 minutes

Pharmaceutical Calculations

☐ N/A












Technological Requirements

Environmental Requirements

☐ Primary and Secondary Engineering Controls for Non-Hazardous Drug Compounding Required

☐ Containment Primary and Secondary Engineering Controls for Hazardous Drug Compounding Required

Electromechanical Equipment

ID Technology Name Technology Specifications

Reusable Devices

ID Technology Name Technology Specifications Expiration Date

Disposable Devices

LOT QTY Technology Name Supplier Manufacturer Technology Specification Expiration Date

End-Stage Filtration Filters

LOT QTY Technology Name Supplier Manufacturer Technology Specification Expiration Date

Dispensing Container and Packaging Materials

LOT QTY Dispensing Container Name Supplier Manufacturer Technology Specification Expiration Date












CSP Labelling

MFR Label

Place sample label here. Include information, which shall contain, in addition to legally required information;

generic name and quantity or concentration of each active ingredient, assigned beyond-use date, storage conditions, and prescription or control number, whichever is applicable

CR Label

Place duplicate compounded prescription label here

Auxiliary Labels

Physicochemical Characteristics

Document specific physicochemical characteristics here, example, pH requirement for formulation












Chemical Sensitivities Assessment

Chemical Listing Light

Sensitive Heat

Sensitive Oxygen

Sensitive Hygroscopic

Metal Reactive

Glass Reactive

Plastic Reactive

Rubber Reactive

Ingredient Tracking

Ingredient Identification

Ingredient NDC CAS Supplier Lot Number Expiry Date

Ingredient Quantification

Ingredient QTY UOM Multiplication

Factor % Additive

Volume FINAL QTY TO

MEASURE UOM

INGREDIENT IDENTIFICATION AND QUANTIFICATION VERIFIED BY:

<Special Circumstance Signature Requirement> DATE:












Preparatory Procedure

Prepared on: Date Start Time: Time End Time: Time

Step Preparatory Procedure Instruction

1

PERFORMED BY: VERIFIED BY:

2


3


4


5













Beyond-Use Dating and Storage Requirements

BUD and Storage Requirements:

☐ Days @ Room Temperature [ 20 to 25 ⁰C ] ☐ Extended or… ☐ N/A

☐ Days @ Refrigerated [ 2 to 8 ⁰C ] ☐ Extended or… ☐ N/A

☐ Days @ Frozen [ - 10 to - 20 ⁰C ] ☐ Extended or… ☐ N/A

Date Compound Prepared: Actual BUD:

Filter Integrity Test Results

Filters Used PSI Held Duration of PSI Held (sec) Pass or Fail

☐ N/A Pre-Filter [0.45 m] ☐ Pass ☐ Fail



☐ N/A 1st Filter [0.22 m] ☐ Pass ☐ Fail



☐ N/A 2nd Filter [0.22 m] ☐ Pass ☐ Fail



Sterilization Cycle Completed

☐ N/A ☐ Wet Heat Sterilization ☐ Successfully Completed ☐ N/A ☐ Dry Heat Sterilization ☐ Successfully Completed












Visual Inspection

☐ Appropriate Color ☐ Pass ☐ Fail ☐ Accurate Volumes / Unit ☐ Pass ☐ Fail

☐ Appropriate Transparency ☐ Pass ☐ Fail ☐ Appropriate Labeling ☐ Pass ☐ Fail

☐ Appropriate Clarity ☐ Pass ☐ Fail ☐ Appropriate Packaging ☐ Pass ☐ Fail

☐ Absence of Visible Particulate ☐ Pass ☐ Fail ☐ Correct Number of Units ☐ Pass ☐ Fail

☐ Homogeneous, if Suspension ☐ Pass ☐ Fail ☐ Resuspendable, if Suspension ☐ Pass ☐ Fail

☐ Outer Surfaces Decontaminated ☐ Pass ☐ Fail ☐ Units Sealed ☐ Pass ☐ Fail

VISUAL INSPECTION PERFORMED BY:

DATE:

Criteria and Approval for Release; Pre-Testing

☐ Approved for release for immediate use due to clinical necessity. Compounding Record has been reviewed.

☐ Approved for release for general use. Compounding Record has been reviewed.

☐ Approved for release for general use. Test results pending. Compounding Record requires further review once testing is complete.

☐ Approved for release due to clinical necessity. Patient monitoring required. Test results pending. Compounding Record requires further review once testing is complete.

☐ Not approved for release until all required testing is complete. Retain under quarantine until required testing is successfully completed. Compounding Record requires further review once testing is complete.

☐ Not approved for release. Discard formulation.

SIGNATURE OF PHARMACIST-IN-CHARGE:

DATE:

If <not approved for release until all required testing is complete> has been selected, then PIC signature for release defaults to next page.

CSP Shipping Requirements

Packaging Details

Special Packaging for Shipping: ☐ N/A Details:

Shipping Details Shipping Co.: Date Shipped: Tracking No.:

Date Received: Received by Patient: ☐ Yes












CSP Test Results Summary

Primary Lab Selected: ☐ <Lab Name> Secondary Lab Selected: ☐ <Lab Name>

☐ N/A TSB Sterility

Results: ☐ Passed ☐ Failed ☐ (+) Control Positive ☐ () Control Negative Sterility Test Log ID:

☐ N/A FTG Sterility

Results: ☐ Passed ☐ Failed ☐ (+) Control Positive ☐ () Control Negative Sterility Test Log ID:

☐ N/A Endotoxin Results: ☐ Passed ☐ Failed Endotoxin Log ID:

☐ N/A Stability Results: ☐ Passed ☐ Failed Stability Log ID:

☐ N/A Strength Results: ☐ Passed ☐ Failed Strength Log ID:

Required Range for Strength Test:

☐ 90% - 110% [USP 10% range] ☐ Other:

☐ N/A Identity Results: ☐ Passed ☐ Failed Identity Log ID:

Laboratory Reference ID: Date Performed: Time at Completion:

Notes:

CSP TEST RESULTS REVIEWED BY PHARMACIST-IN-CHARGE:

DATE:

Criteria and Approval for Release; Post-Testing

☐ Approved for release. Required testing has been successfully completed. Compounding Record has been reviewed.

☐ Not approved for release. Testing failed; discard formulation.

SIGNATURE OF PHARMACIST-IN-CHARGE:

DATE:

Quality Control or Adverse Event Reported

☐ Patient Reported ☐ Caregiver Reported Adverse Event Log ID:












References in Support of Master Formulation Record

Subject No. Reference

<Compatibility> 1

2

3

<Stability> 4

5

6

7

8

9

10



Section 9: Pharmaceutical Calculations for Compounded Sterile Preparations Calculation Method – Percent Concentration Percent concentrations (percent strength) are one of the most common expressions of concentration used in pharmacy. They are defined as follows:

Expressions of Percent Concentration

Expression Meaning

Percent weight-in-volume (w/v) The number of g of substance in 100 mL of solution or other liquid preparation

Percent volume-in-volume (v/v) The number of mL of a substance in 100 mL of solution or other liquid preparation

Percent weight-in-weight (w/w) The number of g of a substance in 100 g of preparation.

Additionally, concentrations are sometimes expressed as mg %, which means mg of substance in 100 mL of the preparation. Sterile compounding often involves the dilution of a solution with its solvent to alter the concentration of the solute. The formula used for this calculation is: Whereby C is a measure of Concentration, V is a measure of Volume. Subscript 1 signifies the initial value and subscript 2 signifies the final value.

C1V1 = C2V2



Question 1:

What is the percent concentration of Sodium chloride in a 50 mL epidural morphine sulfate solution that also contains 35 mL of a 0.9 % Sodium chloride solution for Injection? Answer 1: The calculation in this case would then read:

The concentration of Sodium chloride in a 50 mL Morphine sulfate solution is 0.63%.

Question 2: How much 23.4% NaCl is needed to make 1000 mL of a 3% NaCl inhalation therapy solution for the treatment of Cystic Fibrosis? Answer 2: Using the formula: The calculation in this case would then read:

128.2 mL of a 23.4% NaCl solution is needed to make up 1000 mL of a 3% NaCl solution.

31.5 𝑚𝐿 %

50 𝑚𝐿= 𝐶2

0.9% x 35 mL = C2 x 50mL

31.5 mL % = C2 x 50 mL

C2 = 0.63%

C1V1 = C2V2

3000 𝑚𝐿 %

23.4 %= 𝑉1

23.4% x V1 = 3% x 1000 mL

23.4% x V1 = 3000 mL %

V1 = 128.2 mL



Calculation Method – Ratio Strength For very dilute preparations, ratio strength is more useful or convenient than percentage strength. Ratio Strength is expressed as: Ratio Strength of 1:1000, according to the formulation type, can be described as:

Expressions of Ratio Strength

Formulation Type Description

Solids in liquids 1 g solute or constituent in 1,000 mL of solution or liquid preparation

Liquids in liquids 1 mL of constituent in 1,000 mL of solution or liquid preparation

Solids in solids 1 g of constituent in 1,000 g of mixture

Example: Epinephrine is available in 1 mL ampules as a 1:1000 solution and is administered IM or SQ. How many milligrams of Epinephrine would be administered if 0.6 mL of the product was injected SQ? Answer: This question can be solved by applying Simple Ratio equation: Whereby V is a measure of Volume and Wt is a measure of Weight.

0.6 mg Epinephrine would be administered if 0.6 mL of the product where to be injected SQ.

IU:Volume

1:1000 is 1 g in 1000 mL

or

1000 mg/1000 mL 1 mg/mL

𝑉1

𝑊𝑡 1=

𝑉2

𝑊𝑡 2



Salts, Ester, and Bases In compounding it is important to represent the active ingredient in the form in which it will be incorporated in the preparation. The label should indicate the active agent strength in terms of the salt, ester or base form, whichever is appropriate. Prescriptions on the other hand are often presented in the base form when a salt or ester is required for the preparation. Depending on how the preparation is made, a conversion may be required. Often, the conversion factor from base to salt is supplied in the literature or by the USP database. When this is not provided one must be able to utilize the formula weight (also known as molecular weight) to make these calculations.

Question: Prepare Prochlorperazine 5 mg/mL for injection (600 mL) using Prochlorperazine Edisylate. How much of Prochlorperazine edisylate would you need to use? Answer: Step 1: Calculate the Prochlorperazine base requirement.

Step 2: Calculate the Prochlorperazine edisylate equivalent to 3000 mg Prochlorperazine base. Step 3: Set up a simple ratio of amounts and calculate.

𝟔𝟎𝟎 𝒎𝑳 𝒙 𝟓 𝒎𝒈/𝒎𝑳 = 𝟑𝟎𝟎𝟎 𝒎𝒈 𝑷𝒓𝒐𝒄𝒉𝒍𝒐𝒓𝒑𝒆𝒓𝒂𝒛𝒊𝒏𝒆

𝑼𝑺𝑷 𝒔𝒕𝒂𝒕𝒆𝒔: 𝟏.𝟓𝟎𝟖 𝒈 𝑷𝒓𝒐𝒄𝒉𝒍𝒐𝒓𝒑𝒆𝒓𝒂𝒛𝒊𝒏𝒆 𝒆𝒅𝒊𝒔𝒚𝒍𝒂𝒕𝒆 ≡ 𝟏 𝒈 𝑷𝒓𝒐𝒄𝒉𝒍𝒐𝒓𝒑𝒆𝒓𝒂𝒛𝒊𝒏𝒆 𝒃𝒂𝒔𝒆

𝟏 𝒈 𝑷𝒓𝒐𝒄𝒉𝒍𝒐𝒓𝒑𝒆𝒓𝒂𝒛𝒊𝒏𝒆 𝒆𝒅𝒊𝒔𝒚𝒍𝒂𝒕𝒆 ≡ 𝟔𝟔𝟑 𝒎𝒈 𝑷𝒓𝒐𝒄𝒉𝒍𝒐𝒓𝒑𝒆𝒓𝒂𝒛𝒊𝒏𝒆 𝒃𝒂𝒔𝒆

or

𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑃𝑟𝑜𝑐ℎ𝑙𝑜𝑟𝑝𝑒𝑟𝑎𝑧𝑖𝑛𝑒 𝑒𝑑𝑖𝑠𝑦𝑙𝑎𝑡𝑒 = 1.508 𝑥 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑃𝑟𝑜𝑐ℎ𝑙𝑜𝑟𝑝𝑒𝑟𝑎𝑧𝑖𝑛𝑒 𝑏𝑎𝑠𝑒 1.508 𝑥 3000 = 4524 𝑚𝑔 𝑃𝑟𝑜𝑐ℎ𝑙𝑜𝑟𝑝𝑒𝑟𝑎𝑧𝑖𝑛𝑒 𝑒𝑑𝑖𝑠𝑦𝑙𝑎𝑡𝑒



Question:

How do you make 100mL of a solution with a Lidocaine 2% as the base from the Anhydrous Hydrochloride? Answer:

Lidocaine base C14H22N2O MW 234.34 CAS# 137-58-6

Lidocaine HCl, Anhydrous C14H22N2O· HCl MW 270.80 CAS# 73-78-9

Formula A

Formula B

2 % = 2 g / 100 mL

𝐴𝑚𝑜𝑢𝑛𝑡 𝐵𝑎𝑠𝑒

𝑀𝑊 𝐵𝑎𝑠𝑒=

𝐴𝑚𝑜𝑢𝑛𝑡 𝑆𝑎𝑙𝑡

𝑀𝑊 𝑆𝑎𝑙𝑡

𝑀𝑊 𝐵𝑎𝑠𝑒

𝑀𝑊 𝑆𝑎𝑙𝑡=

𝑊𝑒𝑖𝑔ℎ𝑡 𝐵𝑎𝑠𝑒

𝑊𝑒𝑖𝑔ℎ𝑡 𝑆𝑎𝑙𝑡

𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑏𝑎𝑠𝑒

𝑀𝑊 𝐵𝑎𝑠𝑒=

𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐻𝐶𝑙

𝑀𝑊 𝐻𝐶𝑙

2000 𝑚𝑔 𝐵𝑎𝑠𝑒

234.34=

𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐻𝐶𝑙

270.80

𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐻𝐶𝑙 = 2311.17 𝑚𝑔 𝑜𝑓 𝐿𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝐻𝐶𝑙 𝐴𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠



Waters of Hydration Waters of hydration must be considered in determining ingredient quantities. The compounding pharmacist should refer to the USP/NF or other appropriate source for such questions. For instance, does the USP specify the dextrose content is the anhydrous or the hydrous form and the appropriate ratios of molecular weights? Case in Point: Dextrose 5% in Water contains 5 g Dextrose anhydrous per 100 mL solution The two main forms of Dextrose are:

Dextrose anhydrous C6H1206 MW 180.20 CAS# 50-99-7

Dextrose monohydrate C6H1206· H20 MW 198.17 CAS# 5996-10-1 To prepare Dextrose 5% in Water using the hydrous form of Dextrose, set the ratio as: Subsequently, the calculation for the required quantity of Dextrose, monohydrate would read:

𝑋

5𝑔=

𝐹𝑊 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒 𝑚𝑜𝑛𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒

𝐹𝑊 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠

𝑋

5𝑔=

198.12

180.20

𝑋

5𝑔= 1.099

𝑋 = 1.099 𝑥 5𝑔

𝑋 = 5.4986

𝑊𝑒𝑖𝑔ℎ𝑡 𝑚𝑜𝑛𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒

𝑊𝑒𝑖𝑔ℎ𝑡 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠 =

𝑀𝑊 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒, 𝑚𝑜𝑛ℎ𝑦𝑑𝑟𝑎𝑡𝑒

𝑀𝑊 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒, 𝑎𝑛ℎ𝑦𝑑𝑟𝑜𝑢𝑠



Loss on Drying / Waters of Association Waters of association is similar to water of hydration in that it alters the weight required to reach a certain concentration. Lidocaine hydrochloride anhydrous has a water of association of 5% to 7% due to its propensity to associate with water molecules in the atmosphere. As a result, waters of association must be checked on the certificate of analysis for each batch used in order to obtain the formula for adjustment. Question: Your formula calls for 5 grams of Lidocaine hydrochloride and your certificate of analysis reports a water of association of 6.2%. Answer: A water of association of 6.2% means that for every 1 g of raw lidocaine hydrochloride powder, there is actually 0.938 g (1 - 0.062) of lidocaine hydrochloride. Therefore, you need to weight 5.33 g of the raw powder instead of 5 g to account for waters of association.

𝑊𝑒𝑖𝑔ℎ𝑡 𝑟𝑎𝑤 𝑝𝑜𝑤𝑑𝑒𝑟

5 𝑔 =

1

0.938

𝑊𝑒𝑖𝑔ℎ𝑡 𝑟𝑎𝑤 𝑝𝑜𝑤𝑑𝑒𝑟

𝑊𝑒𝑖𝑔ℎ𝑡 𝑏𝑎𝑠𝑒 =

𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝑚𝑜𝑖𝑠𝑡 𝑤𝑒𝑖𝑔ℎ𝑡

𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑦 𝑤𝑒𝑖𝑔ℎ𝑡



International Units of Potency Ingredient quantities and concentrations can be expressed in several ways. It is important that the compounding pharmacist be aware of these variations. The expressions reviewed here are units of potency, percent concentration, and ratio strength. This section will familiarize you with calculations involving “units” of potency. In the United States, potency is written in endotoxin units (EU) whereas elsewhere it’s usually written in international units (IU).

𝑂𝑛𝑒 𝐼𝑛𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑜𝑛𝑎𝑙 𝑈𝑛𝑖𝑡 (𝐼𝑈) 𝑜𝑓 𝐸𝑛𝑑𝑜𝑡𝑜𝑥𝑖𝑛 = 𝑂𝑛𝑒 𝐸𝑛𝑑𝑜𝑡𝑜𝑥𝑖𝑛 𝑈𝑛𝑖𝑡 (𝐸𝑈)

Calculation Method – Units of Potency Some naturally produced chemicals (such as biologicals; example: Proteins or antibodies) cannot be expressed the same way as a chemical concentration. As such, they have their potency expressed in IU, and their official strength is given as a minimum number of units/mg or units/μg. It is important to know the exact number of units/mg in order to fill a prescription correctly. Example: You want to make an irrigating solution containing 100 mL of: It is important to recognize the potency in units/mg of all biological agents. The actual potency of each batch for each antibiotic is listed on the container label. More correctly they would read:

Neomycin sulfate 66.7 mg/mL Polymixin B sulfate 200,000 IU/mL Bacitracin sulfate 10,000 IU/mL (Irrigation solution)

Neomycin sulfate 66.7 mg Polymixin B sulfate 6,549 IU/mg Bacitracin sulfate 54.1 IU/mg



To prepare a 100 mL total volume, you require: Neomycin sulfate calculation:

6670 mg of Neomycin sulfate is required to make up a 100 mL batch

Polymixin B sulfate calculation:

3,053.9 mg of Polymixin B sulfate is required to make up a 100 mL batch

Bacitracin sulfate calculation:

18,484.288 mg of Bacitracin sulfate is required to make up a 100 mL batch

66.7 𝑚𝑔/𝑚𝐿 𝑥 100𝑚𝐿 = 6670 𝑚𝑔

200,000 𝐼𝑈/𝑚𝐿 𝑥 100𝑚𝐿 = 20,000,000 𝐼𝑈

20,000,000 𝐼𝑈

6,549 𝐼𝑈/𝑚𝑔= 3,053.9 𝑚𝑔

10,000 𝐼𝑈/𝑚𝐿 𝑥 100𝑚𝐿 = 1,000,000 𝐼𝑈

1,000,000 𝐼𝑈

54.1 𝐼𝑈/𝑚𝑔= 18,484.288 𝑚𝑔



Molar Amounts and Concentrations: Molarity and Osmolarity Colligative properties are those properties that depend on the number of particles in solution. Increasing the number of particles in solution will raise the osmotic pressure, raise the boiling point, lower the freezing point, and decrease the vapor pressure. Our concern here is with osmotic pressure and its effects on the body’s semi-permeable cellular membranes. Cellular membranes are semi-permeable, allowing the solvent, but not the solute, to pass in and out of the cell. If the solute is too concentrated, fluid will be drawn from the cell and if the fluid is too dilute, fluid will be drawn into the cell. This can result in either swelling or contractions from dehydration of the cells and, subsequently, cellular damage. Preparations for application to body membranes, for IM injection or for ophthalmic use need be prepared with the same osmotic pressure as that of body fluids. Blood serum and tears contain the physiological equivalent of 284 mOsm/L. The relationship between millimoles and milliosmoles depends on whether the solute is an electrolyte or non-electrolyte. For the non-electrolyte, such as dextrose, the 1 mOsmol equals 1 mmol. For the electrolyte, the number of osmotically active particles in solution depends on the degree of dissociation of the chemical. A molecule of Dextrose is one particle. A molecule of NaCl (because it’s a salt joined by an ionic bond) will dissociate into a Na+ cation and a Cl- anion and as such contribute two particles. A molecule of calcium chloride will dissociate into three particles; one calcium and two chloride ions. This leads to a relationship between millimoles and milliOsmoles. The unit of measure for colligative properties is the Osmole, or more appropriately for our calculations, “MilliOsmoles/Liter” or mOsm/L. Electrolytes and Electrolyte Concentrations

Electrolytes are molecules that can dissociate in solution to charged species; either anions or cations. They comprise 95% of the total solutes in the body. The major physiological electrolytes are listed below.

Physiological Electrolytes

Ion Name

Na+ Sodium ion

K+ Potassium ion

Ca2+

Calcium ion

Mg2+

Magnesium ion

Cl Chloride ion

HCO3 Bicarbonate ion

H2PO4 Di-hydrogen phosphate

HPO42 Hydrogen phosphate



The physiological functions of electrolytes are listed below.

Physiological Functions of Electrolytes

Function

Maintains distribution of fluid between compartments

Maintains physiological pH

Maintains myocardial rhythm and contractility

Functions as an enzymatic co-factor

Participates in blood coagulation

Maintains neuromuscular excitability

Electrolyte imbalance can result from a variety of processes and can lead to a variety of disorders that reflect their physiological functions. A co-factor is anything necessary for another item to function. So these elements are necessary for enzymes to function.



Calculation Method – Osmolarity Labels of solutions used for the intravenous replacement of fluid, nutrients, electrolytes, and Mannitol are required to state their osmotic concentration. The osmolarity of a solution is reported as mOsmol/L (mOsM) of solution. Question: What is the osmolarity in (mOsmol/L) of half-normal saline [0.9% NaCl (MW = 58.5)]?

0.45% NaCl in solution dissociates into equal parts of Na+ and Cl- making up 76.9 mM of each part or 153.8 mOsm/L The above calculation assumes complete dissociation of Sodium and Chloride ions. However this complete dissociation does not occur except in very dilute solutions. Hence, the measured osmolarity is usually less than calculated. Normal saline, 0.9% NaCl in Water has a calculated 308 mOsm/L but the experimentally determined, and accurate, osmolarity for this solution is 286 mOsm/L.

The actual osmolarity depends on the degree of dissociation of NaCl

𝑁𝑜𝑟𝑚𝑎𝑙 𝑠𝑎𝑙𝑖𝑛𝑒 𝑖𝑠 0.9% 𝑁𝑎𝐶𝑙 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑖𝑛 𝑊𝑎𝑡𝑒𝑟

𝐻𝑎𝑙𝑓 𝑛𝑜𝑟𝑚𝑎𝑙 𝑠𝑎𝑙𝑖𝑛𝑒 𝑖𝑠 0.45% 𝑁𝑎𝐶𝑙 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑖𝑛 𝑊𝑎𝑡𝑒𝑟

0.45 % = 0.45 𝑔 𝑖𝑛 100 𝑚𝐿 𝑊𝑎𝑡𝑒𝑟 = 4.5 𝑔 / 𝐿 = 4500 𝑚𝑔 / 𝐿

𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑂𝑆𝑚/𝐿 = 𝑚𝑔/𝐿 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙

𝑀𝑊 𝑥 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑜𝑛𝑠 𝑜𝑓 𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛

𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓𝑚𝑂𝑠𝑚

𝐿=

4500 𝑚𝑔/𝐿 𝑁𝑎𝐶𝑙

58.5 𝑔/𝑚𝑜𝑙 𝑥 2 𝑖𝑜𝑛𝑠 𝑜𝑓 𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛

Number of mOsm/L = 76.9 mM NaCl x 2 ions of dissociation

Number of mOsm/L = 153.8 mOsM

𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑂𝑆𝑚/𝐿 = 𝑚𝑔/𝐿 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙

𝑀𝑊 𝑥 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑜𝑛𝑠 𝑜𝑓 𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛



Calculation Method – Electrolytes and Electrolyte Concentrations Treatment of electrolyte imbalance is usually provided by oral or intravenous solutions. They are expressed as milliequivalents per liter or mEq/L. One equivalent equals the molecular or atomic weight of the ion in grams multiplied by the number of electrical charges that it carries—valence. Question: Use the stepwise approach to the following question. What is the Na

+ content in mEq/L of a solution of normal saline; 0.9% w/v NaCl?

Answer: The molecular weight or MW of NaCl = 58.5 g/mol. A liter of 0.9% NaCl solution contains 9 grams NaCl per liter water ≡ 9000 mg/L NaCl

153.8 mEq of Sodium is contained in 1 L of a 0.9% w/v NaCl Solution.

NOTE: Since there is one Cl ion associated with each Na ion, there will be 153.8 mEq Cl/L as well. Question: How many mL of a 20% w/v Magnesium chloride hexahydrate solution or MgCl2•6H2O solution are needed to obtain 14 mEq of Mg

2+?

Answer: MW of MgCl2•6H2O = 203 g/mol

A 20% solution contains 20 g of MgCl2•6H2O in 100 mL of Water ≡ 20,000 mg in 100 mL = 200 mg/mL. Divided into a step wise approach; the number of mmol/L is derived by the following calculation:

9000 𝑚𝑔/𝐿

58.5 𝑔/𝑚𝑜𝑙= 153.8 𝑚𝐸𝑞 𝑁𝑎/𝐿

𝑚𝑔/𝐿 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙

𝑀𝑊 𝑥 𝑉𝑎𝑙𝑒𝑛𝑐𝑒 = 𝑚𝐸𝑞 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙

200 𝑚𝑔/𝑚𝐿

203 𝑔/𝑚𝑜𝑙= 0.9852 𝑚𝑀/𝑚𝐿



Due to the fact that Magnesium is divalent, the following calculation is required: Then, the following calculation is required to determine the actual quantity of MgCl2•6H2O needed to obtain 14 mEq of Mg

2+:

Sodium Chloride Equivalents or E-values

Sodium chloride equivalents or E-values, express the amount of sodium chloride equivalent in osmolarity to 1 gram of a drug. The E-values, found in published tables, consider contributions of the drug's molecular weight, the number of particles that the drug produces in solution, and the degree of dissociation of those particles. The purpose and intent of using sodium chloride equivalents is to determine the amount of tonicity-adjusting agent (ex: NaCl) needed to adjust a solution to a desired tonicity; usually isotonicity. The calculation can be used for any aqueous solution, but is most often used for ophthalmic solutions. Calculation Method: Step 1: Calculate the grams of NaCl alone that would be needed to prepare an isotonic solution of a given volume. Step 2: Calculate the grams of chemical needed in the prescription.

Step 3: Calculate the grams of NaCl equivalent to the ingredients in the prescription.

0.9852 𝑚𝑀/𝑚𝐿 𝑥 2 = 1.97 𝑚𝐸𝑞/𝑚𝐿

𝑚𝐸𝑞 𝑛𝑒𝑒𝑑𝑒𝑑

𝑚𝐸𝑞/𝑚𝐿=

14 𝑚𝐸𝑞 𝑀𝑔2+

1.97 𝑚𝐸𝑞/𝑚𝐿= 7.1 𝑚𝐿

𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙 𝑔

100 𝑚𝐿𝑥 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) 𝑛𝑒𝑒𝑑𝑒𝑑 = 𝑔 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙

𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙 𝑁𝑎𝐶𝑙 𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 (𝐸 − 𝑣𝑎𝑙𝑢𝑒) 𝑥 𝑔 𝐶ℎ𝑒𝑚𝑖𝑐𝑎𝑙 = 𝑁𝑎𝐶𝑙 𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡𝑙

0.9 𝑔

100 𝑚𝐿𝑥 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) 𝑛𝑒𝑒𝑑𝑒𝑑 = 𝑔 𝑁𝑎𝐶𝑙 𝑛𝑒𝑒𝑑𝑒𝑑



Step 4: Calculate the grams of sodium chloride needed to include in the preparation to create an isotonic fluid by subtracting the grams of NaCl equivalent [Step 3] from the grams of NaCl needed if alone [Step 1]. Step 5: If necessary, in the case where another agent is used for adjusting isotonicity, ex: Glucose or Boric acid, one must calculate the E value of the other substance and subtract it from the value obtained in step 3 as well.

Question: A formula calls for 200 mL of a 1.0 % Atropine sulfate solution. How many grams of Sodium chloride should be included in the formulation to make it isotonic with tears? Answer: The E-value for Atropine sulfate is 0.13

Step 1:

Step 2:

Step 3:

Step 4:

1.54 g NaCl is needed in this formulation. Step 5 is not necessary in this instance.

1 𝑔 𝐴𝑡𝑟𝑜𝑝𝑖𝑛𝑒

100 𝑚𝐿𝑥 200 𝑚𝐿 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 = 2 𝑔 𝐴𝑡𝑟𝑜𝑝𝑖𝑛𝑒

0.13 𝑔𝑙 𝑁𝑎𝐶𝑙 𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑥 2 𝐴𝑡𝑟𝑜𝑝𝑖𝑛𝑒 = 0.26 𝑔 𝑁𝑎𝐶𝑙 𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡𝑙

0.9 𝑔

100 𝑚𝐿𝑥 200 𝑚𝐿 = 1.80 𝑔 𝑁𝑎𝐶𝑙

1.80 𝑔 𝑁𝑎𝐶𝑙 − 0.26 𝑔 𝑁𝑎𝐶𝑙 𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 = 1.54 𝑔 𝑁𝑎𝐶𝑙



HIGHER CONCENTRATION

LOWER CONCENTRATION

PARTS OF HIGHER CONCENTRATION

PARTS OF LOWER CONCENTRATION

DIFFERENCE

DIFFERENCE

EQUALS

EQUALS

DESIRED CONCENTRATION

Dilutions – Alligation Occasionally two strengths of a product must be mixed to prepare an intermediate strength. Performing an alligation is one approach to making a dilution. This section shows how to quickly calculate the quantity of these components of different strengths to make that intermediate strength compound. Calculation Method: Alligation requires setting up an X-pattern of the values with the higher concentration formulation in the upper left, the lower concentration formulation in the lower left, and the intermediate (desired) concentration in the middle. Proceed as follows:

𝑃𝑎𝑟𝑡𝑠 𝑜𝑓 𝐻𝑖𝑔ℎ𝑒𝑟 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

𝑇𝑜𝑡𝑎𝑙 𝑃𝑎𝑟𝑡𝑠𝑥 𝑇𝑜𝑡𝑎𝑙 𝐴𝑚𝑜𝑢𝑛𝑡 = 𝐴𝑚𝑜𝑢𝑛𝑡 𝐻𝑖𝑔ℎ𝑒𝑟 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

𝑃𝑎𝑟𝑡𝑠 𝑜𝑓 𝐿𝑜𝑤𝑒𝑟 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

𝑇𝑜𝑡𝑎𝑙 𝑃𝑎𝑟𝑡𝑠𝑥 𝑇𝑜𝑡𝑎𝑙 𝐴𝑚𝑜𝑢𝑛𝑡 = 𝐴𝑚𝑜𝑢𝑛𝑡 𝐿𝑜𝑤𝑒𝑟 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛



Question: A prescription is written for 2 L of 7% dextrose solution. You will make the solution using D5W and D10W. Using alligation, determine the volumes of each solution to use.

Answer:

The difference of 10% from the desired 7%, 3 is assigned to the lower concentration, and the difference of 5% from the desired 7%, 2 is assigned alternately to the higher concentration.

2 parts of 10% Dextrose and 3 parts of the 5% Dextrose amounts to 5 total parts Dextrose.

2/5 th

of the total volume is Dextrose 10% ≡ 2/5 th

x 2,000 mL = 0.4 x 2,000 mL = 800 mL

and

3/5 th

of the total volume is Dextrose 5% ≡ 3/5 th

x 2000 mL= 0.6 x 2,000 mL = 1,200 mL

10% Dextrose

5% Dextrose

2 PARTS OF 10% Dextrose

3 PARTS OF 5% Dextrose

DIFFERENCE

DIFFERENCE

EQUALS

EQUALS

7% Dextrose



Dosing by Body Weight

Because of physiological differences between normal adults, geriatric and pediatric patients, dosages must be adjusted for children and sometimes for the elderly. When age is an important factor in drug dosage it is often combined with another factor, weight, to give recommendations specific for the drug. This section will review calculations for drug dosage regimens based on a patient’s body weight and drug-specific dosing requirements. Calculation Method: From patient information and a reliable reference source, acquire the appropriate information needed to calculate a weight-specific dose for the patient. Question: A prescription for congestive heart failure calls for Lanoxin (Digoxin) 18 mcg po bid. The child is two months of age and weighs 7 lbs 4 oz. Calculate the safe dosage range for this child. A safe dosage of Digoxin for children under two years of age is 10 - 12 mcg/kg/24hrs divided bid. Answer: Step 1: Convert the patient’s weight in kilograms. Step 2: Calculate the dosage range.

Lower Dose Range: 10 mcg/Kg day x 3.3 Kg = 33 mcg/day

2 doses / day: 33 mcg/day ÷ 2 doses/day = 16.5 mcg/dose

Upper Dose Range:

12 mcg/Kg day x 3.3 kg = 39.6 mcg/day 2 doses / day: 39.6 mcg/day ÷ 2 doses/day = 19.8 mcg/dose

The prescribed dose is within the safe range.

𝑃𝑎𝑡𝑖𝑒𝑛𝑡 𝑊𝑡 (𝑙𝑏𝑠)𝑥 1 𝐾𝑔

2.2 𝑙𝑏𝑠= 𝑃𝑎𝑡𝑖𝑒𝑛𝑡 𝑊𝑡 (𝑘𝑔)

7.25 𝑙𝑏𝑠 𝑥 1 𝐾𝑔

2.2 𝑙𝑏𝑠= 3.3 𝐾𝑔



Parenteral Delivery Amounts, Rates, and Duration Large volume IV fluids and piggybacks are either allowed to drip slowly into the vein by gravity or with the aid of different types of infusion pumps. In the case of an IV drip, different administration sets with different drip rates are available to deliver the required fluid. These administration sets are classified as ‘macro-drips’ or ‘micro-drips’ based on their drop factor or drops/mL. Macro-drips deliver a flow rate of 10 drops/mL, 12 drops/mL, and 15 drops/mL. Micro-drips deliver a flow rate of 60 drops/mL. An electronic infusions pump may also be used to control infusion rates. A typical range of delivery for an electronic infusion pumps is 1 - 999 mL/hr. Delivery rates can be expressed as mL/hr, mL/min, drops/min, mg/min, or as the total time of administration of the fluid. In this section we will practice calculations of infusion amounts, rates, and duration based on the method of infusion. Given the variability in infusion sets with different drip rates or infusion pumps with different programmable rates, calculate the desired values of amounts, rates, or duration. Question: A prescription is written for 2,500 mL of normal saline to be infused over 24 hours. Calculate the drip rate in drops / min if the fluid is infused by gravity using an administration set with a drop factor of 15. Answer:

Now, calculate the flow rate in mL / hr for an infusion pump.

𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)𝑖𝑛𝑓𝑢𝑠𝑒𝑑

𝑇𝑖𝑚𝑒𝑥

𝐷𝑟𝑜𝑝𝑠

𝑚𝐿= 𝐷𝑟𝑜𝑝𝑠/𝑇𝑖𝑚𝑒

2,500 𝑚𝐿

24 ℎ𝑜𝑢𝑟𝑠𝑥

15 𝐷𝑟𝑜𝑝𝑠

𝑚𝐿= 1,562 𝐷𝑟𝑜𝑝𝑠/ℎ𝑟

1,562 𝐷𝑟𝑜𝑝𝑠

ℎ𝑟𝑥

1 ℎ𝑟

60 𝑚𝑖𝑛= 26 𝐷𝑟𝑜𝑝𝑠/𝑚𝑖𝑛

𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)𝑖𝑛𝑓𝑢𝑠𝑒𝑑

𝑇𝑖𝑚𝑒 (ℎ𝑟)= 𝑚𝐿/ℎ𝑟

2,500 𝑚𝐿

24 ℎ𝑟= 104 𝑚𝐿/ℎ𝑟



Question: An ICU prescription reads:

KCl 40 mEq in 1 L of NS and infuse rate is 0.2 mEq / min How many minutes should the infusion last and what will be the flow rate mL/hr? Answer – Part A: Answer – Part B:

𝑚𝐸𝑞/𝑇𝑖𝑚𝑒

𝑚𝐸𝑞/𝑉𝑜𝑙𝑢𝑚𝑒= 𝑉𝑜𝑙𝑢𝑚𝑒/𝑇𝑖𝑚𝑒

0.2 𝑚𝐸𝑞/𝑚𝑖𝑛

40 𝑚𝐸𝑞 / 1000𝑚𝐿=

0.2 𝑚𝐸𝑞/𝑚𝑖𝑛

0.04 𝑚𝐸𝑞 /𝑚𝐿= 5 mL/ 𝑚𝑖𝑛

5 𝑚𝐿

𝑚𝑖𝑛𝑥

60 𝑚𝑖𝑛

1 ℎ𝑟= 300𝑚𝐿/ℎ𝑟

1000𝑚𝐿 𝑥 𝑚𝑖𝑛

5 𝑚𝐿𝑥 = 200 𝑚𝑖𝑛



Nutritional Requirements and Amounts of Nutritional Components Total Parenteral Nutrition (TPN) or hyper-alimentation will vary from patient-to-patient, but some standard calculations and formulas are fundamental in compounding these admixtures. The following patient specific data is essential to collect before attempting any calculations regarding caloric intake requirements:

Age

Sex

Height

Weight

Metabolic consideration: Renal insufficiency; Chronic disease states; Burns Most hyper-alimentation preparation rooms today are equipped with a computer enhanced ACD that will generate a patient’s:

Basal Energy Expenditure (BEE)

Ideal Body Weight (IBW)

Total caloric requirement range

Estimated daily requirements of dextrose and protein

Caloric intake needed from lipids The basic components of almost all TPN fluids are:

Water

Carbohydrates

Proteins

Fats

Electrolytes

Vitamins

Trace elements The typical fluid components are available in the following formats

Carbohydrates - Dextrose 20% or 50% or 70% solutions

Proteins - 5.5% or 8.5% or 10% concentrations

Fats – 10% or 20% of intravenous lipid concentrations Calculation Methods and Sample Exercise The calculation steps to prepare a TPN are:

Calculate target for the required fluid, calories and protein

Determine volumes for dextrose, protein (amino acids) and fat to meet target ranges

Calculate required amounts of Electrolytes

Determine the volumes of additives (based on concentrations of each) to add to the TPN fluid. The following calculations and ranges can be used to determine the standard fluid (water) and protein (amino acid) requirements as well as non-protein calories (dextrose / lipids).



Fluid Requirement: The standard fluid requirements for adults are considered to be between 30 – 35 mL / Kg / day. Exercise: What would be the lower range of fluid requirement for a 115 lb person/day? Convert weight to kilograms:

Patient Wt (Kg) ▪ 30 mL / Kg / day ≡ 52.27 Kg ▪ 30 mL / kg / day = 1,568 mL / day

The lower range fluid requirement is rounded out to 1,600 mL / day. If fluid intake is restricted, then round down to 1,500 mL

/ day.

Protein Requirement: The following are the protein requirements / day for adults and children:

Protein Requirements for Adults and Children

Adults (16 years of age and older): Normal; Unstressed: 0.8 g / kg / day Hospitalized Patient:1 - 1.2 g / kg / day Stressed* Patient: 1.5 - 2 g / kg / day

Children (under 16 years of age): Infant: 2 - 3 g / kg / day Older Children: 1.5 - 2 g / kg / day Adolescent: 1 - 1.5 g / kg / day

* Stressed implies serious infection, major surgery, organ system failure, serious burns, etc…

115 𝑙𝑏𝑠 𝑥 1 𝑘𝑔

2.2 𝑙𝑏𝑠= 52.27 𝐾𝑔



Question: What is the target protein range for a hospitalized, 178 lb man with viral hepatitis (stressed)? Answer:

Convert weight to kilograms:

Lower end of range (from above chart) = 1.5 g x weight in Kg / day = 122 g of protein / day

Upper end of range (from above chart) = 2 g x weight in Kg / day = 162 g of protein / day

The range is 122 - 162 g / day

Question: What is the target protein for a 16-year-old, 109 lb female patient recovering from a multiple trauma? Answer: Since the patient is stressed due to multiple trauma. The upper protein range factor must be used. Convert weight to kilograms: Protein requirement:

Upper end of range (from above chart)

1.5 g x weight in Kg / day ≡ 1.5 x 49.54 Kg / day = 74.3 g of protein / day (Round up to 75 g)

Non-Protein Requirement: The Non-Protein caloric requirement can be determined using the Harris-Benedict equation which calculates the BEE.

BEE (men) = 66.67 + 13.75 (W) + 5.0 (H) – 6.76 (A)

BEE (women) = 665.1 + 9.56(W) + 1.86 (H) – 4.68 (A)

[Where W= weight in kg, H= height in cms, and A= age in years]


2.2 𝑙𝑏𝑠= 81 𝐾𝑔


2.2 𝑙𝑏𝑠= 49.54 𝐾𝑔



Questions: Calculate the BEE for a 48-year-old male who is 67 kg and 6’ tall. Answer: Convert height from feet to cm:

6’ is 12” / 1 ft which is 2.54 cm / 1” = 183 cm Then, calculate using the equation for men: BEE (men)

= 66.67 + 13.75 (W) + 5.0 (H) – 6.76 (A) = 66.67 + 13.75 (67) + 5.0 (183) – 6.76(48) = 66.67 + 921.25 + 915 – 324.48 = 1,578.44 kcal / day (Round out to 1,579 kcal / day)

Total TPN Volume Total TPN volume is usually determined by an evaluation of numerous patient-related factors involving such things as fluid restriction; ex: heart failure-related or fluid overload and other fluids the patient might be receiving, and so on. The standard fluid requirements for adults are considered to be between 30 - 35 mL / kg / day. However, if the patient is receiving 1,000 mL of other fluids per day, the fluid volume may need to be adjusted down to avoid fluid overload. Examples where fluid volume would be adjusted down would include acute weight increase, edema, pneumonia, high blood pressure, etc. If none of these factors are at play, then the target fluid volume would be the total TPN volume calculated at 30 - 35mL / kg / day. Question: A patient is 71 kg and is only receiving 100 mL of additional fluids every 12 hours. The physician would like to limit the patient’s fluid volume to the lower end due to the patient’s past history of pedal edema. Answer: 30 mL /Kg / day x Patient Wt ≡ 30 mL / Kg / day x 71 Kg = 2,130 mL / day

The patient is taking 100 mL / day by mouth and this has to be accounted for as well. Total volume needed / day (all routes) – Volume taken / day (Oral) = Parenteral Volume needed

2130 mL total – 100mL (oral) = 2,030 mL needed parenterally So as to simplify electrolyte calculations this value could be rounded out to an even number such as 2,000 mL / day or 2 x 1 L bags / day.



Protein Volume Protein volume is calculated using the protein requirement equation in addition to other related factors.

Question:

What is the protein volume for a patient whose protein requirement is 120 g / day using an 8.5% Amino acid solution? (8.5% AA = 8.5 g / 100 mL or 0.085 g / mL) Answer: Note: This volume can be subtracted from the total fluid volume to determine the remaining volume that can be used for Dextrose, Fats, Free Water and Electrolytes. Dextrose Volume: Dextrose volume is calculated using two important facts:

The patient’s feed weight

The fact that the liver can handle a maximum of 4 mg / kg / min of sugar (conservatively) Use the following guidelines to determine a patient’s feed weight where ABW is actual body weight and IBW is ideal body weight:

Feed Weights

Criteria Feed Weight

ABW is < 120% of IBW and patient is not volume overloaded ABW

ABW is above the IBW and patient is fluid overloaded IBW

ABW is more than 120% of IBW Any weight between ABW and IBW

Patient is under IBW IBW

𝑉𝑜𝑙𝑢𝑚𝑒𝐴𝐴

𝑑𝑎𝑦=

𝑔 𝐴𝐴 𝑛𝑒𝑒𝑑𝑒𝑑/𝑑𝑎𝑦

𝑔 𝐴𝐴/𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)=

120 𝑔 𝐴𝐴/𝑑𝑎𝑦

0.085𝑔/𝑚𝐿= 1412 𝑚𝐿



Questions: Calculate the grams per day of dextrose to give a patient whose feed weight is 77 Kg. Use the conversion factor that there are 1,440 minutes in a day. Note: 4 mg Dextrose / Kg / min from chart. Answer:

First calculate the mg needed / minute or Kg / min:

Next calculate the g Dextrose / day: Use the g Dextrose / day calculation and the concentration of Dextrose solution being used to determine the volume of Dextrose / day. Calculate for a 70% Dextrose solution. Calculate the g / mL of Dextrose solution to be used:

Next calculate the volume of Dextrose / day for the patient:

𝐹𝑒𝑒𝑑 𝑊𝑡 (𝐾𝑔) 𝑥 4 𝑚𝑔 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒

𝐾𝑔/𝑚𝑖𝑛= 77 𝐾𝑔 𝑥

4 𝑚𝑔 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒

𝐾𝑔/𝑚𝑖𝑛= 308 𝑚𝑔/ min 𝑜𝑟 0.308 𝑔/𝑚𝑖𝑛

0.308 g/min x 1440 min/day = 444 g/day

70% = 70g/ 100mL = 0.7 g/mL

𝑔 /𝑑𝑎𝑦 𝑟𝑒𝑞𝑢𝑖𝑟𝑒𝑑

𝑔 /𝑚𝐿 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑢𝑠𝑒𝑑=

444 𝑔 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒 𝑟𝑒𝑞𝑢𝑖𝑟𝑒𝑑

0.7 𝑔/𝑚𝐿= 634 𝑚𝐿



Fat Volume: To determine the fat emulsion volume, subtract the Kcal provided by Dextrose from the target of non-protein calories. Then, using the available IV lipid emulsions, the volume for the required emulsion may be calculated. The choices for lipid emulsions are:

20% which provides 1,000 Kcal / 500 mL or 2 Kcal / mL

10% which provides 550 Kcal / 500 mL or 1.1 Kcal / mL Note: The Kcal of 20% is not double the Kcal of 10% as expected due to the concentration of Glycerin added to lipid solutions to maintain stability. Question: What would be the IV fat volume requirement for a TPN when using 600 mL of a 70% Dextrose solution and a 20% fat emulsion? The total non-protein requirement for the patient is 2,260 Kcal. Answer:

Calculate the amount of Dextrose / mL:

Calculate g / 600 mL:

Calculate the Kcal via Dextrose:

Calculate the amount of Kcal needed from fat: Calculate mL of 20% fat emulsion needed:

70g /100mL = 0.7 g/mL

0.7g /mL x 600 mL = 420g Dextrose

3.4Kcal /g x 420g = 1428 Kcal /day from Dextrose

2260 𝐾𝑐𝑎𝑙 𝑛𝑜𝑛 − 𝑝𝑟𝑜𝑡𝑒𝑖𝑛 𝑟𝑒𝑞𝑢𝑖𝑟𝑒𝑚𝑒𝑛𝑡 𝑚𝑖𝑛𝑢𝑠 1428 𝐾𝑐𝑎𝑙 𝑓𝑟𝑜𝑚 𝐷𝑒𝑥𝑡𝑟𝑜𝑠𝑒 = 832 𝐾𝑐𝑎𝑙 𝑓𝑟𝑜𝑚 𝑜𝑡ℎ𝑒𝑟 𝑛𝑜𝑛 − 𝑝𝑟𝑜𝑡𝑒𝑖𝑛

832 𝐾𝑐𝑎𝑙 𝑛𝑒𝑒𝑑𝑒𝑑

2 𝐾𝑐𝑎𝑙 /𝑚𝐿 𝑓𝑟𝑜𝑚 20% 𝐹𝑎𝑡 𝐸𝑚𝑢𝑙𝑠𝑖𝑜𝑛= 416 𝑚𝐿 𝑜𝑓 20% 𝐹𝑎𝑡 𝐸𝑚𝑢𝑙𝑠𝑖𝑜𝑛



Electrolyte Requirements: Most electrolyte combination requirements are calculated using a computer program or programmable worksheet providing results per liter, per calorie, per day, etc… The volumes of electrolytes are calculated based on the concentration of each electrolyte stocked in the pharmacy. The electrolyte needs may be based on caloric needs, fluid needs, or on general guidelines. Below is an example of an electrolyte range based on a patient’s caloric needs:

Adult Electrolyte Amount per 1000 cal:

Sodium 40-50 mEq

Note: The amount of Calcium and Phosphate must be less than or equal to 45 mEq / L to prevent CaPO4 precipitate

Potassium 40 mEq

Magnesium 8-12 mEq

Calcium 2-5 mEq

Phosphate 15 - 24 mMol (3 mEq/mMol) use this conversion to calculate mEq of phosphate



Section 10: Aseptic Manipulations in Sterile Compounding The Human Body - A Major Source of Contamination A clean room is a controlled environment. It is able to attain and maintain the environment necessary to produce a sterile preparation. It is an environment shielded from contaminated air currents whether they are from unfiltered air ducts or from open entrances. The controlled airflow from most laminar air flow systems can easily be disrupted by movement from personnel moving in and out of the room, air conditioning or open entrance air currents. A person walking creates a plume of disturbed air about 30 feet behind them. This disturbed air picks up contaminants from the floor and raises them to higher levels in the room. It takes about 8 minutes for a 0.5 micron particle to settle to the floor through Brownian motion from a height of 5 feet.

Particulate Measures Related to Air Flow Disruption

Activity Effect

Person sitting motionless 100,000 particles/cubic feet/minute

Person sitting down or standing up 2,500,000 particles/cubic feet/minute

Person walking 10,000,000 particles/cubic feet/minute

Open, non-air locked door Billions of particles/cubic feet/minute

The human body will shed particles from the skin; these particles are also usually impregnated with bacteria. This shedding can be enhanced by makeup, perfume, cologne, poor personal hygiene or conditions such as eczema or dandruff.



Aseptic Techniques: Personnel Preparation

Preparation for Entering the Garbing Room

In preparation for entering the garbing room, be sure that you have gathered all that you need with you to do your work and that it is clean room compatible. Make appropriate changes to your clothing by removing hats and outerwear such as jackets and loosely woven or fuzzy sweaters. Shoes must completely cover the foot; no sandals, open toed shoes, sling backs or open backed shoes. Remove all jewelry from hands, wrists, ears and other body parts. No chewing gum, candy, or food items may be brought into the ISO class environments.

Tips:

1. Objects that shed particles cannot be brought into ISO class environments; these include pencils, cardboard cartons,

paper towels and cotton items. Only lint free paper-related products can be brought into the clean room. Special pens are available for clean room use. Notwithstanding sterile compounding supplies, only the master formulation record and a special writing pen can be brought into the clean room.

2. Compounding personnel must remove personal outer garments; cosmetics; artificial nails; hand, wrist, and body jewelry which includes face piercings that can interfere with the fit of gowns, gloves and goggles.

3. The wearing of artificial nails or extenders is prohibited while working in the sterile compounding environment. Natural nails must also be kept neat and trimmed.



Aseptic Techniques: Moving into and between ISO Class Environments

Stepwise Processes and Procedures moving into and between ISO Class Environments

Ambient (Receiving Area)-to-ISO Class 8 Room Activities

Ensure jewelry, makeup, perfumes, unnecessary clothing and the like, are removed.

Tie hair back, if applicable.

Don non-sterile personal protective equipment during inventory control management and inspection.

Assemble required reusable and disposable devices, and chemicals needed for transfer to ISO class 8 room.

Clean and disinfect outer surfaces of all inventory containers.

Don designated shoes prior to crossing tacky mat or don shoe covers, outside ISO class 8 room door.

Slowly walk across tacky mat with designated shoes prior to entering anteroom or enter anteroom with shoes covers.

Slowly enter anteroom with inventory.

ISO Class 8 Room Activities

Don hair net; beard cover if necessary.

Don face mask.

Scrub forearms from finger nails-to-fingers-to-hands-to-elbows for at least 30 seconds, and then dry with lint free wipes.

Don coveralls that fit to neck, wrists (thumb loops preferred) and ankles; additional apron or sleeve covers, if required.

Don appropriate protective eye wear; additional face shield, if required.

Don a hood, and then pull draw strings to secure in place.

Don boot covers as you cross over line of demarcation from clean-to-cleaner side.

Apply waterless alcohol-based surgical hand scrub; allow hands to dry.

Don sterile gloves.


Disinfect external surfaces of all pre-sterile sealed reusable and disposable devices and chemical containers.

Place inventory in pass-through or in designated conveyances on the clean side of the line of demarcation slated for immediate use.

Store any other inventory in their respective and designated sites discriminating hazardous from non-hazardous chemicals.

Remove gloves, and then don a new pair of sterile gloves.


Don a second level of personal protective equipment if entering a designated hazardous drug compounding room.

Transition to the ISO class 7 room.

ISO Class 7 Room Activities

Retrieve inventory from pass-through, if applicable.

Disinfect a second time, external surfaces of all pre-sterile sealed reusable and disposable devices and chemical containers.

Store hazardous drugs in their designated sites, if applicable.

Disinfect gloves, a second time, with Sterile Isopropyl Alcohol (SIPA).

ISO Class 5 Primary Engineering Control-related (PEC) Activities

Disinfect Direct Compounding Area (DCA).

Disinfect all materials upon transfer from ISO class 7 room into ISO class 5 PEC.

Prepare Compounded Sterile Preparation (CSP); includes end-stage filtration, if possible.

Perform an inspection of final CSP for particulate and fill volume.

Partially or completely seal final dispensing containers.

Remove all materials from, and then disinfect, direct compounding area.

Prepare samples for testing of the CSP.



Aseptic Techniques: Moving out of and between ISO Class Environments

Stepwise Processes and Procedures moving out of and between ISO Class Environments

Inspection Station Activities

Disinfect the outer surface of all sealed dispensing containers prior to exiting ISO class environment.

Sterilize finished CSP, if possible.

Quarantine finished CSP.

Perform a complete inspection of each finished CSP dispensing container.

Label finished dispensing containers of CSP.

Determine if immediate dispensing is permissible.

Ensure appropriate testing is performed on finished CSP; external, internal if permissible.

Exiting the ISO Class Environment for Non-Hazardous Drug Compounding

Remove all disposable garb when exiting the ISO class room and discard appropriately.


Exiting the ISO Class Environment for Hazardous Drug Compounding

Remove outer layer gloves and place in hazardous waste container located in the containment primary engineering control

Remove all other disposable garb when exiting the ISO class room and discard in appropriate hazardous waste bag.




Aseptic Techniques: Hazardous Drug Compounding Added precautions are required when handling and compounding with hazardous drugs.

Washing, Garbing and Gloving for Hazardous Drug Compounding

Aprons: Acid aprons worn over a coveralls will provide better protection than the coveralls alone, and can be removed much more quickly. They are recommended when using large volumes of chemicals or whenever highly corrosive or toxic materials are being used. Be especially careful to wear proper protection when heating and mixing chemicals. Remove aprons carefully to prevent any chemicals on them from contaminating other areas. Coveralls: Disposable coveralls made from polyethylene-coated polypropylene or other laminate materials are recommended as they offer better protection than standard coveralls. Absorbent materials permit penetration by hazardous drugs and can potentially hold these agents against the skin increasing exposure.

1. Dispose of coveralls after each use 2. Wear coveralls during compounding whenever there is a possibility of splash or spill 3. Do not wear exposed coveralls outside the compounding area to avoid the spread of chemical agents outside

designated compounding areas.

4. If there is no permeation information for the coveralls in use, change them every 2 to 3 hours and immediately after a splash or spill. Gloves: Gloves may be made of a number of different materials with varying resistances. Sometimes double gloving (a second pair of gloves worn over the initial gloves) will suffice for adequate extra protection. When working with mixtures, choose gloves that are suitable for all of the chemicals in the mixture. If one component in the mixture can penetrate the gloves, it may carry the other components with it, exposing you to all the chemical hazards in the mixture. Also, be sure to remove your gloves when leaving the clean room to prevent harmful chemicals from being transported to other areas. Eyewear: Safety glasses should be worn in the clean room at all times. These will provide protection against flying objects and some chemical splashes. When working with chemicals, especially when heating or mixing chemicals, goggles that seal around the face will provide better protection and prevent injury. Face shields should be worn whenever working with corrosive chemicals. High-risk operations: High-risk operations require attention to minimizing the risk of contamination on lab coats, bunny suits, and other garbs to be worn in ISO class environments. Preferably, a fresh clean garb should be put on before each entry into the ISO 7 class environment to avoid liberating contaminants from a previously worn garb. Alternatively, worn garbs may be removed with the intention of re-garbing for re-entry into the ISO 7 class environment and stored during the interim under proper control and protection in the ISO 8 class environment. Garbs worn or taken outside the confines of the ISO 8 class environment area cannot be worn in the ISO 7 class environment.



Appropriate body positioning is important both for the comfort of

the personnel, as well as for minimizing contamination. Equipment features which

encourage good body position include an adjustable chair which

can accommodate workers of various heights, a foot rest to ease pressure on the lower extremities,

and a lumbar cushion to support the lower back. It is important that

personnel be comfortable, maintaining good spinal posture,

minimizing restless body movements which enhance

particulate movement and increase the risk of contamination.

Working in the Clean Room Body Positioning and Posture

The Six Inch Rule In an undisturbed laminar airflow workstation with vertical flowing air (LAFW – V), air moves from the top down. Air will either flow into, out of or travel in parallel to the artificial wall of air at the front opening of the workstation depending on the air pressure differential between the air inside the LAFW and the ISO class room in which the LAFW is operating. In order to not offset this balance in airflow dynamics, all critical operations should be performed at least six inches into the LAFW. The Four Inch Rule In an undisturbed laminar airflow workstation with vertical flowing air (LAFW – V), air moves from the top down. As the air moves to the work surface and toward the front or rear vents, there is potential for pick-up of surface contamination. Therefore, critical operations should not be carried out directly over any vent and manipulations must be performed above the level of the work surface; preferably four inches above the work surface.



General Rules Regarding Aseptic Manipulations Rules

1. Disposable devices are normally steri-wrapped by soft plastic and / or paper packaging, or by a hard plastic shell. When

opening steri-wraps or plastic shells, orient the open end toward the flow of HEPA filtered air (back wall of horizontal hood, top ceiling of vertical hood, or upward in an open architecture environment).

2. To discard the steri-wrapping or plastic coverings from disposable devices, place packaging materials outside the critical zone of the direct compounding area. Do not allow a hood to become littered with packaging materials. It is unacceptable to place packaging material on the floor by pushing it outside a primary engineering control or off any other work surface. It is unacceptable to place packing materials in a waste disposal unit located outside of a primary engineering control during a procedure. In the case of a compounding aseptic isolator there is a waste disposal unit inside the direct compounding area. Maintain your hands inside the primary engineering control during the making up of a preparation.

3. Critical site exposure to HEPA filtered air is crucial to maintaining sterility. Critical sites of disposable devices are often capped; luer or slip. When removing these caps ensure the critical site is pointed in the direction of HEPA filter air. Never allow contact between hands, fingers or work surface and the hub of a needle, the body of a syringe plunger, or the tip of a syringe barrel.

4. Manipulating electromechanical, reusable or disposable equipment or devices is a learned skill that requires

considerable practice. When performing these manipulations never come between the flow of HEPA filtered air and the critical sites of any technology or chemical container.

5. Whenever you bring electromechanical, reusable or disposable equipment or devices into the direct compounding area, be certain to disinfect all surfaces with sterile Isopropyl alcohol 70%. Remember that when moving from one class environment to another of a cleaner class, a wipe down is required. Leave remaining particulates and microbes behind, no matter how little there might be. Leave nothing to chance.



Use/Application: Used to open sterile wrap package to minimize the risk of touch contamination. Manipulation: Remove steri-wrap from device, continually pointing the end of the packaging being opened toward flow of HEPA filtered air; back of horizontal airflow hood, top of vertical airflow hood, or upward in open architecture environment. Avoid touch contamination as a result of critical site contact with hands, fingers or surface of hood or table. Hold device by grasping its sides while still in contact with steri-wrap. Never touch a needle hub or body of a syringe plunger. Peel apart sides of packaging just enough to expose connection. For hard plastic packaging, twist off end of covering. Always orient point of unwrapping or uncovering toward source of unobstructed HEPA filtered air.

Aseptic Manipulation - Opening Sterile Packaging

Tips:

If a device is packaged with an unprotected tip, remove the steri-wrap just prior to use. Items with contaminated critical sites must be discarded immediately. They cannot be used.

If a device is packaged with a protected critical site or tip protector, the steri-wrap may be removed at the edge of the hood and the device placed on the work surface. Critical sites or tip protectors are removed just prior to use, while maintaining the critical site in direct contact with HEPA filtered air.

In the case of plastic packaging, remove the outer covering of the shell by turning the cap of the container counter clockwise. There should be some resistance to this action; this indicates the intact integrity of the packaging. If there is no resistance to the removal of the cap, discard the entire package.



Use/Application: Used to ensure sterility and prepare a vial or bottle for needle insertion. Manipulation: Prepare vial by first removing outer protective cap by lifting it and then pulling it away from container. Disinfect exterior of rubber stopper by wiping it several times with different surfaces of a fresh alcohol swab, always wiping in same direction. Keep the critical site (rubber stopper), exposed to sterile and HEPA filtered air (Critical First Air). Allow alcohol to dry on rubber stopper before inserting a needle or spike.

Aseptic Manipulation - Opening and and Swabbing a Vial or Bottle

Tips:

When using alcohol swabs multiple times within a procedure, be sure to manipulate the swab so that a fresh surface is being used each time. As a general rule, an alcohol swab should not be used more than five times before it is discarded. If, however, in your professional judgment, there is any question relative to the integrity or effectiveness of an alcohol swab, it should be discarded immediately.



Use/Application: Used to decontaminate entry ports prior to needle or spike puncture. Manipulation: Using the non-dominant hand secure the port so that it remains exposed to critical first air. With dominant hand, wipe entry port of vial, bottle or bag several times in the same direction.

Aseptic Manipulation - Swabbing Rubber Stoppers and Entry Ports



Aseptic Manipulation - Needle-to-Syringe Connection (Luer) sdfsd Tip:

Be very careful not to allow your hands or fingers to block the critical first air coming through the HEPA filter and passing over the critical site where the needle hub is being attached to the syringe tip.

When attaching the needle to the syringe, be sure to keep your fingers away from the point of attachment.

Keep the needle guard in place until the needle is to be used.

Before doing this step, carefully choose the size and length needle necessary for the procedure.

Assemble the needle-to-syringe assembly before opening vials or ampules of drugs in order to shorten the exposure time of the drug.

Use/Application: Used mostly with large syringes and / or transferring larger volumes. Luer lock connections are more sturdy than luer slip connections. Manipulation: In one hand, hold needle while still partially in its’ protective wrapping with needle hub exposed to critical first air. Attach needle hub to the tip of luer syringe held in other hand. Twist syringe barrel clockwise approximately one-quarter turn until needle is tightly attached. Remove needle packaging and place outside of critical zone. The syringe with needle attached may be placed on the work surface, so long as the needle guard remains in place.



Aseptic Manipulation - Needle-to-Syringe Connection (Slip) Tips:

Be very careful not to allow your hands or fingers to block the critical first air from the HEPA filter that passes over the critical site where the needle hub is being attached to the syringe tip.

Keep the needle guard in place until the needle is to be used.

Before doing this step, carefully choose the size and length needle necessary for the upcoming procedure.

Use/Application: Used for transferring from a syringe; a luer slip connection is less sturdy, but desirable when speed is necessary. Manipulation: Hold needle in one hand, most of the needle should still in its’ protective wrapping. The needle hub should be exposed to critical first air. Attach needle hub to tip of luer syringe held in the other hand. Push needle onto tapered tip of syringe with a firm forward motion until the needle is tightly attached. A slight twisting motion along with the forward force is helpful in securing needle to slip-tip syringe. Remove needle packaging and place outside of critical zone. The syringe with needle attached may be placed on work surface as long as needle guard remains in place covering needle.



Use/Application: Used to open sterile wrap package to minimize the risk of touch contamination Manipulation: Technique A (Top): Grasp guard between thumb and index finger of non-dominant hand. Pull guard firmly away in a straight line from needle-to-syringe connection. Technique B (Bottom): Referred to as Needle Sparing Technique-if needle is to be reused. Retain needle sterility by placing it between 4

th and 5

th fingers for remainder of procedure until it can be replaced over needle. Alternately, needle guard may

be placed on an alcohol swab. If needle is not to be reused, then guard may be placed directly on work surface.

Aseptic Manipulation - Removing or Recapping a Needle Guard

Tips:

In order to maintain sterility of the needle guard, always place the guard with the open end facing the flow of critical first air.

Do not remove the needle guard until the needle is to be used.

Be very careful not to puncture yourself or the needle guard in the process of recapping. Do not rush in this process. Guide the needle slowly down the center of the guard to avoid puncturing the plastic.

Should you touch the shaft or the hub of the needle, it must be discarded.



Use/Application: Used when multiple withdrawals from a vial are anticipated. Manipulation: Open the syringe packaging first. Hold dispensing pin in one hand, still partially in its protective wrapping. The luer port should be exposed to HEPA filtered air. Attach luer port to luer tip syringe held in other hand. Twist syringe barrel approximately one-quarter turn clockwise until vented dispensing pin is tightly attached. Remove vented dispensing pin packaging and place outside of critical zone. The syringe-to-vented dispensing pin connection may be placed on the work surface, so long as the needle guard remains in place.

Aseptic Manipulation - Syringe-to-Vented Dispensing Pin Connection (Luer)

Tips:

If the syringe is packaged with a protected critical site (tip), the steri-wrap may be removed at the edge of the hood and the syringe placed onto the work surface of the hood lying on the barrel while the vented dispensing pin is unwrapped and the luer port exposed for attachment.

If the syringe is packaged with an unprotected tip, remove the steri-wrap just prior to use with critical site in critical first air while the vented dispensing pin is unwrapped and the luer port exposed for attachment.



Use/Application: Used prior to discarding a needle Manipulation: Recap needle. For luer tipped syringes, turn the needle approximately ¼ turn counter-clockwise and pull to loosen and detach needle. In the case of a luer slip tip syringe, just pull the syringe and needle apart.

Aseptic Manipulation - Needle-from-Syringe Removal



FLAT END (LIP)

Use/Application: Used in order to avoid contamination of syringe and contents. Manipulation: When removing plunger of syringe, body of plunger must not come in contact with fingers. In order to avoid contamination of contents of barrel, only touch flat portion at very end of plunger.

Aseptic Manipulation - Syringe-from-Plunger Removal Tips:

The two hand manner of moving the plunger in a syringe is the more common method. This process involves grasping the outside of the syringe barrel between the thumb and four fingers of one hand, and using the other hand to take hold of the flat lip at the end of the plunger and exert pressure to move the plunger as directed.

The one hand method of moving the plunger involves grasping the outside of the barrel with the four fingers of one hand, and securing the barrel against the palm of the hand. Use the thumb against the flat end of the plunger to move the plunger as desired. This leaves the other hand free to do other functions required in the procedure.



Use/Application: Used to minimize volume occupied by air bubbles in a syringe, maximizing accuracy of measurement. Manipulation: Hold syringe perpendicular to work surface with the needle pointing upward. Cause vibration on outside of the syringe barrel by:

Flicking barrel with finger

Tapping syringe barrel with inside of finger(s)

Tapping with knuckle(s) Once air bubbles have been removed from syringe be sure to recheck final measurement of fluid in syringe.

Aseptic Manipulation - Air Bubble Removal from Syringe

Tip:

If you are unable to tap free the air bubbles adhering to the inside surface of the syringe barrel, draw the plunger back slightly to bring excess sterile air into the syringe. Hold the syringe in a horizontal position and rotate it using the large bubble to collect the smaller ones. Once the air is in the large bubble, return the syringe to the vertical position and eject the air from the syringe, using the tapping techniques to float any remaining bubbles to the top.



Aseptic Manipulations & Techniques - Syringe Volume Reading and Adjustment Tips:

If there is too little fluid in the syringe to meet the line of measurement, re-enter the container and draw more fluid into the syringe; repeat the process to arrive at the correct measurement.

If too much fluid is present in the syringe, expel the excess; depending on quantity, expel onto a sterile absorbent material such as a sterile gauze pad or into a small depyrogenated beaker located in DCA.

NEVER SQUIRT FLUID TOWARD THE HEPA FILTER OF THE HOOD.

Use/Application: Used to perform accurate volume readings on a syringe. Manipulation: Before bringing a syringe to final volume, be sure that all air bubbles have been expelled. The line of measurement is the final edge of plunger piston indicated in red in the diagram above. Align final edge of plunger piston with line on the measurement scale of syringe barrel representing desired amount of fluid.



Aseptic Manipulation - Luer-to-Luer Adaptor Connection Tips:

Be sure to avoid contaminating one luer port by touch, while performing a connection to the other luer port. Touch luer ports only on the flat platform area between the two ports of the adaptor.

Make sure that the critical sites of connection are in full flow of critical first air.

Use/Application: Used to connect two luer tip devices Manipulation: Hold luer-to-luer adaptor with thumb and index finger over platforms. Hold another luer device in the other hand. Attach exposed luer lock to luer port with approximately ¼ turn counter-clockwise.



Aseptic Manipulation - Syringe-to-Syringe Via Adaptor Mixing

Use/Application: Used to connect a luer tip syringe to another luer tip syringe when there are fluids in two different luer tipped syringes that need to be mixed. Manipulation: Select syringe sizes which will accommodate the final volume when contents of both syringes are mixed into one single syringe. Connect one luer tipped syringe to each side of adaptor being careful to maintain sterile airflow across the critical sites of connection. Once syringes are connected to each side of adaptor, contents of two syringes may be mixed by pushing on barrel of each syringe in an alternating manner, mixing contents first into one syringe, and then the other.



Aseptic Manipulation - Syringe-to-Cap Connection (Luer & Slip)

Use/Application: Used to seal a luer tip dispensing syringe once filled Manipulation: With critical sites exposed to critical first air, connect luer syringe cap to syringe with a ¼ turn clockwise rotation of cap while maintaining pressure against syringe luer tip. In case of a slip cap, connect slip syringe cap to syringe with a twisting motion of cap and pressure against syringe slip tip.



Use/Application: Often used to draw from ampules, small vials or beakers Manipulation: Use the thumb of dominant hand to manage withdrawal process as you first place filter needle or filter straw under surface of fluid inside opened end of ampule, vial or beaker. In non-dominant hand, grasp opened amp between thumb and index finger, being sure to keep critical site in flow of critical first air. Place barrel of syringe in palm of dominant hand, with fingers of that hand providing a steadying grasp of syringe barrel. In case of ampule, opened ampule and syringe are held approximately at 45 degrees to each other, the thumb of dominant hand is worked at plunger tip to withdraw fluid.

Aseptic Manipulation - Syringe Plunger Draw (Single Handed) Tips:

Be careful to avoid injury from the broken glass edge at the open end of the ampule.

Be sure that the needle and the opened end of the ampule are positioned in the direct flow of unopposed sterile air from the HEPA filter (critical first air).

The thumb of the dominant hand touches only the tip of the plunger in the withdrawal process.

Once the required amount of fluid is withdrawn from the ampule, the amp may be placed on the work surface. Both hands are now free to manage the syringe, replace the filter needle or filter straw with a regular needle, and bring the measurement in the syringe to final volume.



Use/Application: Used to draw fluid from hanging bags or vials; typically large volumes Manipulation: Swab injection port of hanging bag, large vial or other large volume container. Using appropriate size sterile luer syringe for volume of fluid to be withdrawn, puncture injection port with needle bevel up. If fluid is being withdrawing from a vial, then it must be inverted. The needle tip must be maintained below level of fluid in vial while withdrawal takes place. Use non-dominant hand to grasp barrel of syringe, and use dominant hand to pull syringe plunger back, withdrawing fluid from larger sterile container.

Aseptic Manipulation - Syringe Plunger Draw (Two Handed) Tips:

Be sure that the critical site, the needle and the injection port of the larger sterile container, are positioned in the direct flow of unopposed sterile air from the HEPA filter.

The thumb of the dominant hand must touch only the tip of the plunger in the withdrawal process.



Aseptic Manipulation - Swabbing Ampule Neck

Use/Application: Used to decontaminate an ampule prior to its opening. Manipulation: Before opening ampule, thoroughly clean neck using an alcohol swab. Allow alcohol to dry before opening ampule.



Use/Application: Used to move fluid that may be trapped in stem to body of ampule Manipulation: All fluid content must be contained in body of ampule prior to opening. If there is fluid in stem of ampule, grasp ampule securely by base or body. Using index finger of opposite hand, tap alongside of ampule stem. If fluid does not move to body readily, gently use a flick of finger to cause more vibration of ampule.

Aseptic Manipulation - Ampule Fluid Shift from Stem Tips:

If fluid is persistent in clinging inside the stem, rotate the ampule horizontally, then return to vertical position and repeat the above techniques. Sometimes, additional fluid flowing into the stem increases the weight of the fluid and the stem clears more readily.



Aseptic Manipulation - Ampule Opening Tips:

NEVER BREAK AN AMPULE IN THE DIRECTION OF THE HEPA FILTER or any other sterile items which may be in the hood. The critical site is the breakage point which must be covered by an unopposed flow of sterile air. In practice, aiming the snapping motion toward the side of the hood satisfies this requirement and also protects the HEPA filter from flying shards of glass as well as droplets of the ampule contents.

Make sure your grip is secure so as to assure a good break. Also be careful to protect your fingers to avoid being cut by the glass.

Once the ampule has been opened, it should be positioned in the flow of unopposed sterile air. The contents of the ampule should be used as soon as possible.

GAUZE SEPARATED FOR EASE OF VIEWING

Use/Application: Used to open an ampule with a dot or line indicator; break along indicator dot or line Manipulation: Opening of a glass ampule requires safety measures to minimize risk of injury to personnel from broken glass. Some product ampules bear an indicator dot or stripe marking a specific line along which the ampule is designed to be broken. If the ampule does not bear such an indicator, it may be advisable to use a small file to score a line over which break should occur. Use sterile 4” x 4” gauze squares to pad surface between glass ampule and hands. Grasp stem of ampule wrapped in gauze in dominant hand and body of ampule also wrapped in gauze in opposite hand. Orient grasp so that thumbnails are aligned opposite each other where the break will occur, and hold ampule perpendicular to work surface. Break neck away from body of am pule by applying force through thumbnails in a quick snapping motion away from body. If glass does not break easily, slightly readjust grasp and point of force, and then repeat snapping motion.



Aseptic Manipulation - Filter Needle

FILTER LOCATED HERE

Use/Application: Since there is risk of glass shards inadvertently entering opened ampule, it is necessary to filter contents of an opened glass ampule before using the fluid. This can be accomplished efficiently by using either a filter needle or a filter straw.



Aseptic Manipulation - Opening Filter Steri-wrap

Use/Application: Used to open sterile packaging to minimize risk of touch contamination of critical sites. Manipulation: Since a filter is a flow through device it will have an inflow connector on one side, and an outflow connector on other side. Filters are available with a luer port on each side or a luer port on one side and a slip port on the other. When opening steri-wrap of a filter, open packaging just enough to expose one connection port. Continue to hold filter partially in its steri-wrapping. Connect exposed luer port of filter to desired sterile device.



Aseptic Manipulation - Handling a Disc Filter (Luer)

Use/Application: Used to avoid touch contamination of critical sites when handling a disc filter and to filter out particulate from fluid. Manipulation: With filter partially open in one hand, attach other end of filter to sterile luer connection with approximately ¼ turn counter-clockwise.



Use/Application: Used to avoid touch contamination of critical sites when handling a disc filter and to filter out particulate from fluid. Manipulation: With filter partially open in one hand, attach other end of filter to sterile luer connection of syringe with a slight twisting motion at same time as forward force.

Aseptic Manipulation - Handling a Disc Filter (Slip)



Use/Application: Used to avoid touch contamination of critical sites when handling a cartridge filter. Manipulation: Attach cartridge port to another sterile connection such as a syringe, dispensing syringe or tubing. Remove protective cap from opposite end of filter. Use this end port of cartridge filter to attach another sterile connection such as tubing or a needle. Once all connections are made, it is necessary to prime the entire connection with fluid to void air from the connected devices.

Aseptic Manipulation - Handling Cartridge Filter



Use/Application: Used to filter large volumes of fluids with the assistance of an automated compounding device (ACD) or peristaltic pump. Manipulation: Handling this filter is similar to that of a smaller disc or cartridge filter. Following selection of appropriately sized tubing, attach tubing to one port of barrel filter while the filter itself remains in its sterile steri-wrap. Tubing is then attached to the opposite side of filter barrel. Once all connections are made, it is necessary to prime the entire connection with fluid to void connected devices of air. It is then necessary to calibrate the peristaltic pump.

Aseptic Manipulation - Large Volume Filter Barrels



Use/Application: Used to insert the needle through rubber stopper of vial. Manipulation: Keeping needle in an upright position, draw a quantity of air equal to amount of fluid to be withdrawn from vial into the barrel of the syringe. This sterile air needs be pushed into the vial in order to avoid development of negative pressure inside vial when fluid is drawn into syringe. While using a pencil grasp-type grip on barrel of syringe, hold syringe-to-needle assembly at a 45º angle with needle bevel upward. Touch tip of needle to the bull’s eye of disinfected rubber stopper on vial. Begin to apply downward pressure pushing point of needle through rubber stopper, simultaneously and quickly rotating syringe-to-needle assembly to a position perpendicular to top of vial, completing penetration. The intent is to have the very small and sharp point of the needle penetrate the rubber making only a tiny opening and to change the angle of entry quickly so that the heel of bevel penetrates through the same opening made by the needle point. This technique attempts to limit any fragments of rubber (cores) from being cut from rubber vial stopper and deposited either in barrel of syringe or in vial.

Aseptic Manipulation - Needle Insertion into Vial Tips:

In the penetration process, do not apply too much pressure as you change the angle of entry. It is possible to bend the needle if this is done.

At all times, be sure there is unopposed sterile air from the HEPA filter flowing across the needle to vial interface; this is considered a critical site.

If cores or fragments of rubber are seen either in the vial or in the syringe containing fluid to be used in a preparation, either filter or discard the fluid.



NEGATIVE PRESSURE PULLS FLUID INTO BOTTLE

Use/Application: Used to inject into an evacuated glass bottle; requires puncturing of stopper with tip of needle always entering at same point. Evacuated bottles have a vacuum and will draw fluid from syringe immediately.

Aseptic Manipulation - Injection into Evacuated Glass Bottle



EASY IN

VENTED FOR EASY OUT

SYRINGE-TO-NEEDLE ASSEMBLY WITHOUT BARREL;

ALTERNATIVE METHOD

TO VENT

Use/Application: Used to insert vented spike into rubber stopper of a bottle; prevents vacuum formation and flow stoppage. Due to rigid nature of glass bottles, there is a requirement for venting a bottle in order for fluid to flow from it; air replaces fluid exiting in bottle. If bottle is not vented, a vacuum develops and flow from bottle ceases. Rubber stoppers in glass bottles can vary somewhat in design, allowing a variety of options for attaching administration sets and injection of medications into a bottle with a needle-to-syringe assembly. A common closure is the type with a single bull’s eye port in its center. This single hole may be used as an injection port or an administration port; however, a vented administration set must be used with this bottle. Manipulation: Uncap vented sterile spike of administration set, and insert it into hole of rubber stopper with a twisting motion. Since this is a vented set, once the bottle is inverted and the sterile point of spike is in fluid, flow will begin from bottle.

Aseptic Manipulation - Venting a Bottle



ADMINISTRATION PORT

INJECTION PORT ADMINISTRATION

PORT

BELLY PORT

Use/Application: Used to insert spike into administration port of bag. The polyvinyl chloride (PVC) bag does not require venting because flexibility of bag allows it to collapse as fluid is removed. The end of bag has two separate ports; one is an injection port, and the other is an administration port. The administration port is covered with a plastic cover which is removed in unopposed sterile air just prior to insertion of sterile spike of administration set. Manipulation: Uncap sterile spike of administration set, and insert it into administration port of bag with a twisting motion. Since this system requires no venting, once bag is inverted and sterile point of spike is in fluid, flow will begin from bottle. Use roller clamp of set to control or stop fluid flow.

Aseptic Manipulation - Bag-to-Tubing Connection (Vented) Tips:

In the uncapping of the sterile spike, be sure to maintain the critical site in unopposed sterile air until the connection through the administration port of the bag is complete.



Aseptic Manipulation - Drawing from Beaker

Tips:

Keep the top / opening of the beaker directly in the path of sterile and HEPA filtered air.

Ensure use of sterilized and depyrogenated beaker.

Use/Application: Used during high risk compounding after a solution has formed from non-sterile powder or addition of liquid component that may or may not be sterile. Fluid must be moved from beaker so that subsequent filtration may be performed for particulate removal and sterilization. Wet heat sterilization is indicated. Manipulation: Set up the syringe-to-needle assembly. Hold beaker with non-dominant hand and tilt beaker slightly so that fluid flows toward one side of beaker. Hold needle-to-syringe assembly in dominant hand and place needle into fluid below surface. Use thumb of dominant hand to move plunger back as fluid is withdrawn. As withdrawal proceeds, the needle should be moved downward so that it ultimately can reach the bottom corner of beaker. The needle can touch inside of beaker when removing the last few drops of solution, since beaker is sterile and depyrogenated.



Use/Application: Used to draw liquid from a source container. On this transfer set, spike connects to source container: IV Bag, Bottle or Vial. This spike connection is vented to allow fluid to flow.

Use/Application: Used to control liquid transfer through use of a stop clamp. A stop clamp allows tubing to be open or closed for liquid transfer, however is not able to regulate rate of liquid transfer.

Aseptic Manipulation - Transfer Set Vented Spike Connection

Aseptic Manipulation - Transfer Set Stop Clamp



Aseptic Manipulation - Venting a Vial with Vented Spike

Aseptic Manipulation - Venting a Vial with a Syringe-to-Needle Assembly [Plunger Removed]

Use/Application: Used to allow air to escape when fluid is ejected into a vial, preventing positive pressure formation and the need to use an air exchange technique.

Use/Application: Used when other venting options are not available; a needle is attached to a small syringe with plunger removed, then punctured through rubber stopper of a vial. A second syringe-to-needle assembly is used to draw fluid from vial while air enters vial through the first syringe-to-needle assembly.



Aseptic Manipulation - Liquid Withdrawal from Vial with Syringe-to-Needle Connection

Use/Application: Used to draw liquid from a vial; a standard technique for liquid removal. Manipulation: Once needle is inserted into vial, invert vial to syringe-to-needle assembly such that syringe is under vial. Hold vial with non-dominant hand and syringe with dominant hand. Operate plunger tip with dominant thumb. If it is necessary to steady syringe with non-dominant hand, be very careful not to let fingers drop so that the path between sterile air and critical site is not obstructed; point of insertion and withdrawal. Slowly inject sterile air from syringe into vial. Avoid placing air directly into fluid so as to avoid foaming or bubbling. Since volume of air injected into vial equally displaces volume of fluid to be withdrawn, a release of syringe plunger with needle under level of fluid should readily draw into syringe approximate desired fluid volume. If necessary, slowly back needle out of rubber stopper such that the bevel of needle remains below level of fluid; otherwise, air will be drawn into syringe.



Use/Application: Used to allow for repeating process of exchanging small amounts of air in a syringe with small amounts of fluid in a vial, ultimately filling syringe with fluid from vial; this technique is known as “Milking”. When a vial has limited air space above level of liquid to be withdrawn, and it is impossible to eject total volume of sterile air from syringe into vial at one time, a technique is used which slowly ejects sterile air into vial, while slowly withdrawing fluid into syringe. Manipulation: Prep rubber stopper of vial and assemble syringe-to-needle connection. Insert needle into vial. Invert vial to syringe-to-needle assembly. Push a small amount of sterile air from syringe into vial. When you feel significant back pressure, change direction of syringe plunger, and withdraw a small amount of fluid from vial into syringe. Resume ejecting another small amount of sterile air from syringe into vial, followed by withdrawal of a small amount of fluid from vial. Depending on the total volume of fluid desired to be withdrawn, you may need to repeat this procedure several times until all of the sterile air from syringe is in vial and syringe contains total volume of fluid desired.

Aseptic Manipulation - Air Exchange in Withdrawing ("Milking")



Aseptic Manipulation - Drawing from Spiked Bottle

Use/Application: Used to repeatedly draw from a bottle without increasing risk of coring rubber stopper with repeated needle insertions. A vented dispensing pin must be used to withdraw from a bottle so that flow of air into bottle replaces fluid flowing out. Manipulation: Insert spike into center of bottle rubber stopper, and then connect a luer syringe to opposite end of spike. The tip of spike must remain under level of fluid in bottle in order for flow to occur. Invert bottle-to-dispensing pin-to-syringe assembly. Withdraw desired volume into syringe. For bottles larger than 100 mL a ‘meal bale’ or handle would be attached to its bottom. It is useful when hanging inverted bottle-to-dispensing pin-to-syringe assembly on a bar at top rear of a hood while withdrawal is in process. Since system is vented, it is not necessary to first eject sterile air into bottle. Detach syringe from dispensing pin and protect sterility of syringe tip until connected to another device. Subsequent luer syringes may be attached to luer port of dispensing pin and a measured amount of fluid withdrawn. As each syringe is detached, be sure to protect sterility of syringe tip.



Aseptic Manipulation - Drawing from Spiked IV Bags

Use/Application: Used to repeatedly draw from an IV bag without increasing the risk of coring diaphragm and causing leakage with repeated needle insertions. A vented dispensing pin is not necessary since the collapsing bag replaces space created by withdrawn fluid. Manipulation: Remove sterile cap from administration port of IV bag. Hold dispensing pin by its steri-wrap covering. Assure a clear path of sterile air over critical site. Apply a downward pressure with a twisting motion, and then insert spike into administration port of IV bag. Remove steri-wrap from luer port of dispensing pin and proceed to connect luer syringe. The tip of spike must remain under level of fluid in bag in order for flow to occur. Invert bag-to-dispensing pin-to-syringe assembly and withdraw desired volume of fluid into syringe. It is often useful to hang this assembly inverted from bar in top rear of hood when proceeding with withdrawal. Since system does not require venting due to collapsing bag, it is not necessary to first eject sterile air into bag. Detach syringe from dispensing pin and protect sterility of syringe tip until connected to another device. Subsequent luer syringes may be attached to luer port of dispensing pin and a measured amount of fluid withdrawn. As each syringe is detached, be sure to protect sterility of syringe tip.



Use/Application: Used to eject liquid into a plastic IV bag; requires puncturing both membranes of injection port of IV bag with a needle.

Aseptic Manipulation - Injection into a Plastic IV Bag Tips:

Be certain that the needle has penetrated the outer and inner portion of the membrane.



Aseptic Manipulation - Syringe Ejection through Needle into IV Bag Port Tips:

During the needle insertion process, grasp the syringe firmly by the barrel; avoid placing the thumb on the plunger tip so the fluid is not injected prematurely before the needle passes through both diaphragms.

The needle for use at the injection port of the bag should be 18 G or larger in order to avoid excessively large puncture holes, and 3/8” or longer in order to penetrate the inner diaphragm of the injection port.

Some pharmacies have policies relative to the use of the injection port of the bag. Such policies may limit the number of punctures of the port to five (using 20 G to 25 G needles) and only one puncture using an 18 G needle.

Use/Application: Used to eject solution through a needle into an IV bag port; the needle punctures both membranes of IV bag port. Manipulation: Closely examine IV bag for cracks or any signs of particulate matter or cloudiness. Lay bag on work surface. Using different surfaces of an alcohol swab disinfect its injection port. Wipe it several times in same direction. Hold injection port fully extended between thumb and index finger of non-dominant hand; extending port minimizes possibility of puncturing side wall of port or bag. As needle in inserted into port, be sure to extend needle through center of bull’s eye so that it punctures both outer and inner diaphragm of injection port. With dominant hand, slowly depress syringe plunger and eject syringe contents into bag. Shake or rotate bag a few times to mix contents, and examine bag for particulate matter or rubber cores.



Aseptic Manipulation - Syringe Ejection through Needle into Vented Bottle

Use/Application: Used to eject liquid through a needle into a vented bottle. Manipulation: With dominant hand, slowly depress syringe plunger and eject syringe content into bottle. If a vented needle is not available, this system can be vented with a regular needle as indicated in image. Connect a regular needle to a 1-ml syringe. Insert syringe without barrel-to-needle assembly through rubber stopper of bottle. The point of needle insertion should be alongside insertion of needle carrying fluid into bottle. The empty syringe barrel provides a channel for an equal volume of air to pass out as filtered fluid is ejected into vial. Finally, slowly push plunger of syringe so solution passes into bottle.



Use/Application: Used to maintain sterility; after tip of eye dropper is forced free from dropper bottle, it is stored in cap and placed in hood or on work surface exposed to HEPA filtered and sterile air until it is time to reconnect to dropper bottle.

Use/Application: Used to transfer liquid to an eye dropper bottle; remove tip from eye dropper bottle, and then eject liquid into bottle through its opening.

Aseptic Manipulation - Eye Dropper Bottle Tip Sparing Technique

Aseptic Manipulation - Injection into Eye Dropper Bottle



Aseptic Manipulation - Positive and Negative Pressure Plunger Effect Tips:

Negative pressure is desirable when working with hazardous substances; ex: Chemotherapy.

NEEDLE BEVEL IS MAINTAINED IN AIR

SPACE

NEEDLE BEVEL HAS CROSSED

FLUID INTO AIR SPACE

Use/Application: Used when drawing fluid from a vial. Positive Pressure: Air is ejected into vial first creating positive pressure. Once plunger is released positive pressure pushes back on plunger and fluid from vial will fill syringe. Negative Pressure: If a sufficient volume of air is not pre-ejected into vial, then a negative pressure or vacuum is created.



Aseptic Manipulation - Transferring from Bottle-to-Vial with Mechanical Transfer Device

CALIBRATE

PRIME

FILL



Aseptic Manipulation – Membrane Filtration Method of Sterility Testing

STEP 1 STEP 2 STEP 3

STEP 4: INCUBATE

Use/Application: Used for sterility testing compounded sterile preparations. Manipulation: In Step 1 you are attaching the container to a sample of a preparation. In Step 2 you are transferring a sample of a preparation through a container housing a filter on its distal side into a second sterile syringe. In Step 3 you are replacing the syringe from the original sample with a syringe containing a growth media. You are then transferring the media into the container and capping the distal end of the container with a luer cap. In Step 4 you are incubating the Media Syringe-to-Container Assembly for 14 days.



Aseptic Manipulation – Closed System Transfer Devices for Hazardous Compounding

Protector

Injector

Infusion Adapter

Syringe-to-Injector

Injector-to-Protector Syringe-to-Injector-to-

Protector-to-vial

Infusion Injector

spiked to Bag


Infusion Adaptor

(Syringe full)


Infusion Adaptor

(Syringe Empty)



References

1. Ansel, HC. Pharmaceutical Calculations. 13th Ed. Wolters Kluwer Health. Lippincott Williams & Wilkins; 2010. 2. Biological Indicators for Sterilization. In: United States Pharmacopeia (USP 1035). Rockville, MD: The United States

Pharmacopeia Convention. 2013. 3. Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH List of

Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2014. DHHS (NIOSH) Publication Number 2014-138. http://www.cdc.gov/niosh/docs/2014-138/. Published September 2014.

4. CETA. CETA Applications Guide for the use of Compounding Aseptic Isolators in Compounding Sterile Preparations in Healthcare facilities. Controlled Environment Testing Association. 2008.

5. CETA. CETA Certification Guide for Sterile Compounding Facilities. Controlled Environment Testing Association. 2008. 6. Dry Heat Sterilization. In: United States Pharmacopeia (USP 1229.8). Rockville, MD: The United States Pharmacopeia

Convention. 2013. 7. Hazardous Drugs—Handling in Healthcare Settings in the Pharmacopeial Forum 40(3) [May–Jun. 2014]. Available at:

http://www.usp.org/usp-nf/notices/general-chapter-hazardous-drugs-handling-healthcare-settings. 8. International Conference on Harmonisation Tripartite Guideline: Validation of Analytical Procedures: Text and

Methodology Q2 (R1). 1994. http://www.ich.org/products/guidelines/quality/quality-single/article/validation-of-analytical-procedures-text-and-methodology.html. Accessed March 17, 2014.

9. Pharmaceutical Calculations in Pharmacy Practice. In: United States Pharmacopeia (USP 1163). Rockville, MD: The United States Pharmacopeia Convention. 2014.

10. Pharmaceutical Compounding – Sterile Preparations. In: United States Pharmacopeia (USP 797). Rockville, MD: The United States Pharmacopeia Convention. 2014.

11. Powers L. Closed System Transfer Devices for Safe Handling of Hazardous Drugs. Pharmacy Practice News, June 2013. 12. Quality Assurance in Pharmaceutical Compounding. In: United States Pharmacopeia (USP 1163). Rockville, MD: The

United States Pharmacopeia Convention. 2013 13. Sterility Tests. In: United States Pharmacopeia (USP 71). Rockville, MD: The United States Pharmacopeia Convention.

2014. 14. United States Pharmacopeia and National Formulary (USP 37-NF 32). Rockville, MD: United States Pharmacopeia

Convention; 2014. 15. US Department of Labor. OSHA Brief. Hazard Communication Standard: Labels and Pictograms.

http://www.osha.gov/dsg/hazcom/index.html. DSG BR-3636 2/2013 16. World Health Organization. Annex 6. WHO good manufacturing practices for sterile pharmaceutical products. WHO

Technical Report Series; 2011: 961.

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