797 PHARMACEUTICAL COMPOUNDING_STERILE PREPARATIONS.pdf

<797> Pharmaceutical Compounding—Sterile Preparations

Type of Posting Revision Bulletin Posting Date 22–Nov–2019 Official Date 01–Dec–2019 Expert Committee Compounding Reason for Revision Compliance—Postponement

In accordance with the Rules and Procedures of the 2015–2020 Council of Experts, USP is postponing the official date of Pharmaceutical Compounding—Sterile Preparations <797>.

After publication of the revised <797> on June 1, 2019, USP received appeals on certain provisions of the chapter. In accordance with USP’s Bylaws, the responsible Expert Committees worked with a sense of urgency to consider the information raised in the appeals and issued decisions on the appeals. As part of the formal USP appeals process, stakeholders who submitted appeals to the compounding chapters had the opportunity to request further review by an appointed Panel, and USP has received three (3) such requests on <797>.

In light of these appeals, and in accordance with our Bylaws, USP is postponing the official date of <797> until further notice. In the interim, the currently official version of <797> (last revised in 2008) including the section Radiopharmaceuticals as CSPs will remain official. The decisions on the appeals to <797> do not foreclose the possibility of future revisions to this chapter.

Should you have any questions, please contact Jeanne Sun, Senior Manager, Healthcare Quality and Safety (CompoundingSL@usp.org).

C242016-M99925-CMP2015, rev. 00 20191122

Change to read:

▲á797ñ PHARMACEUTICAL COMPOUNDING—STERILE PREPARATIONS

The official date for this chapter is postponed until further notice. When the official date is reestablished, the period allowed for implementation will not be less than six months.

TABLE OF CONTENTS

1. INTRODUCTION AND SCOPE

1.1 Scope

1.2 Administration

1.3 Immediate Use CSPs

1.4 Preparation Per Approved Labeling

1.5 CSP Categories

2. PERSONNEL TRAINING AND EVALUATION

2.1 Demonstrating Proficiency in Core Competencies

2.2 Demonstrating Competency in Garbing and Hand Hygiene

2.3 Competency Testing in Aseptic Manipulation

3. PERSONAL HYGIENE AND GARBING

3.1 Personnel Preparation

3.2 Hand Hygiene

3.3 Garbing Requirements

4. FACILITIES AND ENGINEERING CONTROLS

4.1 Protection from Airborne Contaminants

4.2 Facility Design and Environmental Controls

4.3 Creating Areas to Achieve Easily Cleanable Conditions

4.4 Water Sources

4.5 Placement and Movement of Materials

5. CERTIFICATION AND RECERTIFICATION

5.1 Total Airborne Particle Sampling

6. MICROBIOLOGICAL AIR AND SURFACE MONITORING

6.1 General Monitoring Requirements

6.2 Monitoring Air Quality for Viable Airborne Particles

6.3 Monitoring Surfaces for Viable Particles

7. CLEANING, DISINFECTING, AND APPLYING SPORICIDAL AGENTS IN COMPOUNDING AREAS

7.1 Cleaning, Disinfecting, and Sporicidal Agents

7.2 Cleaning Supplies

7.3 Cleaning, Disinfecting, and Applying Sporicidal Agents in the PEC

8. INTRODUCING ITEMS INTO THE SEC AND PEC

8.1 Introducing Items into the Cleanroom Suite and SCAs

8.2 Introducing Items into the PEC

8.3 Use of Sterile 70% IPA on Critical Sites within the PEC

9. EQUIPMENT, SUPPLIES, AND COMPONENTS

9.1 Equipment

9.2 Supplies

9.3 Components

10. STERILIZATION AND DEPYROGENATION

10.1 Depyrogenation

10.2 Sterilization by Filtration

10.3 Sterilization by Steam Heat

10.4 Sterilization by Dry Heat

11. MASTER FORMULATION AND COMPOUNDING RECORDS

11.1 Creating Master Formulation Records

11.2 Creating Compounding Records

12. RELEASE INSPECTIONS AND TESTING

12.1 Visual Inspection

12.2 Sterility Testing

12.3 Bacterial Endotoxins Testing

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© 2019 The United States Pharmacopeial Convention All Rights Reserved.

13. LABELING

14. ESTABLISHING BEYOND-USE DATES

14.1 Terminology

14.2 Parameters to Consider in Establishing a BUD

14.3 Establishing a BUD for a CSP

14.4 Multiple-Dose CSPs

15. USE OF CONVENTIONALLY MANUFACTURED PRODUCTS AS COMPONENTS

15.1 Use of Conventionally Manufactured Single-Dose Containers

15.2 Use of Conventionally Manufactured Multiple-Dose Containers

15.3 Use of Conventionally Manufactured Pharmacy Bulk Packages

16. USE OF CSPs AS COMPONENTS

16.1 Use of Compounded Multiple-Dose CSPs

16.2 Use of Compounded Single-Dose CSPs and CSP Stock Solutions

17. SOPs

18. QUALITY ASSURANCE AND QUALITY CONTROL

18.1 Notification About and Recall of Out-of-Specification Dispensed CSPs

18.2 Complaint Handling

18.3 Adverse Event Reporting

19. CSP HANDLING, STORAGE, PACKAGING, SHIPPING, AND TRANSPORT

19.1 Handling and Storing CSPs

19.2 Packaging of CSPs

19.3 Shipping and Transporting CSPs

20. DOCUMENTATION

21. COMPOUNDING ALLERGENIC EXTRACTS

GLOSSARY

APPENDIX

1. INTRODUCTION AND SCOPE

This chapter describes the minimum standards to be followed when preparing compounded sterile human and animal drugs [compounded sterile preparations (CSPs)]. Sterile compounding is defined as combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug or bulk drug substance to create a sterile medication.

The requirements in this chapter must be followed to minimize harm, including death, to human and animal patients that could result from 1) microbial contamination (nonsterility), 2) excessive bacterial endotoxins, 3) variability from the intended strength of correct ingredients, 4) physical and chemical incompatibilities, 5) chemical and physical contaminants, and/or 6) use of ingredients of inappropriate quality.

Aseptic technique must be followed for preparing any sterile medication. Procedures must be in place to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, and mix-ups with other products or CSPs.

Pursuant to General Notices, 2.30 Legal Recognition, assuring compliance with USP standards is the responsibility of regulatory bodies. Accreditation or credentialing organizations may adopt and enforce USP standards. USP has no role in enforcement.

1.1 Scope

CSPS AFFECTED

The requirements in this chapter must be met to ensure the sterility of any CSP. Although the list below is not exhaustive, the following must be sterile:

• Injections, including infusions

• Irrigations for internal body cavities (i.e., any space that does not normally communicate with the environment outside of the body such as the bladder cavity or peritoneal cavity). [NOTE—Irrigations for the mouth, rectal cavity, and sinus cavity are not required to be sterile.]

• Ophthalmic dosage forms

• Preparations for pulmonary inhalation. [NOTE—Nasal dosage forms intended for local application are not required to be sterile.]

• Baths and soaks for live organs and tissues

• Implants

SPECIFIC PRACTICES

Repackaging: Repackaging of a sterile product or preparation from its original container into another container must be performed in accordance with the requirements in this chapter.

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Allergenic extracts: Licensed allergenic extracts are mixed and diluted to prepare prescription sets for administration to patients. A prescription set is a vial or set of vials of premixed licensed allergenic extracts for subcutaneous immunotherapy diluted with an appropriate diluent for an individual patient. Because of certain characteristics of allergenic extracts and allergy practice, preparation of allergenic extract prescription sets is not subject to the requirements in this chapter that are applicable to other sterile CSPs. The standards for compounding allergenic extracts are in 21. Compounding Allergenic Extracts and are applicable only when:

1. The compounding process involves transfer via sterile needles and syringes of conventionally manufactured sterile allergen products and appropriate conventionally manufactured sterile added substances, and

2. Manipulations are limited to penetrating stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile vials

Otherwise, compounding of allergenic extracts prescription sets must meet the requirements for Category 1 or Category 2 CSPs, which are described in this chapter.

Hazardous drugs: Compounding of sterile hazardous drugs (HDs) must additionally comply with Hazardous Drugs—Handling in Healthcare Settings á800ñ.

Blood-derived and other biological materials: When compounding activities require the manipulation of a patient’s blood-derived or other biological material (e.g., autologous serum), the manipulations must be clearly separated from other compounding activities and equipment used in CSP preparation activities, and they must be controlled by specific standard operating procedures (SOPs) in order to avoid any cross-contamination. Handling of blood components must additionally comply with jurisdictional standards and guidelines.

Sterile radiopharmaceuticals: Compounding of radiopharmaceuticals is not required to meet the standards of this chapter for Category 1 and Category 2 CSPs and is subject to the requirements in Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging á825ñ.

PERSONNEL AND SETTINGS AFFECTED

This chapter describes the minimum requirements that apply to all persons who prepare CSPs and all places where CSPs are prepared. This includes, but is not limited to, pharmacists, technicians, nurses, physicians, veterinarians, dentists, naturopaths, and chiropractors in all places including, but not limited to, hospitals and other healthcare institutions, medical and surgical patient treatment sites, infusion facilities, pharmacies, and physicians’ or veterinarians’ practice sites. Any person, whether preparing a CSP or not, entering a sterile compounding area must meet the requirements in 3. Personal Hygiene and Garbing.

The compounding facility must designate one or more individuals [i.e., the designated person(s)] to be responsible and accountable for the performance and operation of the facility and personnel in the preparation of CSPs and for performing other functions as described in this chapter.

1.2 Administration

For the purposes of this chapter, administration means the direct application of a sterile medication to a single patient by injecting, infusing, or otherwise providing a sterile medication in its final form. Administration of medication is out of the scope of this chapter. Standard precautions such as the Centers for Disease Control and Prevention’s (CDC’s) safe injection practices apply to administration.

1.3 Immediate Use CSPs

Compounding of CSPs for direct and immediate administration to a patient is not subject to the requirements for Category 1 or Category 2 CSPs when all of the following are met:

1. Aseptic processes are followed and written procedures are in place to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, and mix-ups with other conventionally manufactured products or CSPs.

2. The preparation is performed in accordance with evidence-based information for physical and chemical compatibility of the drugs (e.g., FDA-approved labeling, stability studies).

3. The preparation involves not more than 3 different sterile products.

4. Any unused starting component from a single-dose container must be discarded after preparation for the individual patient is complete. Single-dose containers must not be used for more than 1 patient.

5. Administration begins within 4 hours following the start of preparation. If administration has not begun within 4 hours following the start of preparation, it must be promptly, appropriately, and safely discarded.

6. Unless administered by the person who prepared it or administration is witnessed by the preparer, the CSP must be labeled with the names and amounts of all active ingredients, the name or initials of the person who prepared the preparation, and the exact 4-hour time period within which administration must begin.

1.4 Preparation Per Approved Labeling

Compounding does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product’s manufacturer and other manufacturer directions consistent with that labeling [21 USC 353a (e)].

Preparing a conventionally manufactured sterile product in accordance with the directions in the manufacturer’s approved labeling is out of scope of this chapter only if:

1. The product is prepared as a single dose for an individual patient, and

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2. The approved labeling includes information for the diluent, the resultant strength, the container closure system, and storage time.

PROPRIETARY BAG AND VIAL SYSTEMS

Docking and activation of proprietary bag and vial systems (e.g., addEASE, ADD-Vantage, Mini Bag Plus) in accordance with the manufacturer’s labeling for immediate administration to an individual patient is not considered compounding and may be performed outside of an International Organization for Standardization (ISO) 5 environment.

Docking of the proprietary bag and vial systems for future activation and administration is considered compounding and must be performed in accordance with this chapter, with the exception of 14. Establishing Beyond-Use Dates. Beyond-use dates (BUDs) for proprietary bag and vial systems must not be longer than those specified in the manufacturer’s labeling.

1.5 CSP Categories

This chapter distinguishes two categories of CSPs, Category 1 and Category 2, primarily based on the conditions under which they are made, the probability for microbial growth, and the time period within which they must be used. Category 1 CSPs are those assigned a BUD of 12 hours or less at controlled room temperature or 24 hours or less when refrigerated if made in accordance with all of the applicable requirements for Category 1 CSPs in this chapter. Category 2 CSPs are those that may be assigned a BUD of greater than 12 hours at controlled room temperature or greater than 24 hours if refrigerated (see 14.

Establishing Beyond-Use Dates) if made in accordance with all of the applicable requirements for Category 2 CSPs in this chapter.

The requirements that are not specifically described as applicable to Category 1 or Category 2, such as training, competency testing, and personal hygiene for personnel, are applicable to the compounding of all CSPs.

CSPs can be compounded either by using only sterile starting ingredients or by using some or all nonsterile starting ingredients. If all of the components used to compound a drug are sterile to begin with, the sterility of the components must be maintained during compounding to produce a CSP. If one or more of the starting components being used to compound is not sterile, the sterility of the compounded preparation must be achieved through a sterilization process (e.g., terminal sterilization in the final sealed container) or sterilizing filtration, and then maintained if the CSP is subsequently manipulated.

When compounding with nonsterile starting components, supplies, or equipment, the quality of the components and the effectiveness of the sterilization step are critical to achieving a sterile preparation.

2. PERSONNEL TRAINING AND EVALUATION

All personnel involved in the compounding of CSPs must be initially trained and qualified by demonstrating proficiency in compounding CSPs. A designated person must oversee the training of personnel. Training and observation may be performed by the designated person(s) or an assigned trainer. Personnel must complete training every 12 months in appropriate sterile compounding principles and practices.

Each compounding facility must develop a written training program that describes the required training, the frequency of training, and the process for evaluating the performance of individuals involved in preparing CSPs. This program should equip personnel with the appropriate knowledge and train them in the required skills necessary to perform their assigned tasks.

Training and evaluation of personnel must be documented.

2.1 Demonstrating Proficiency in Core Competencies

Before beginning to prepare CSPs independently, all compounding personnel must complete training and be able to demonstrate knowledge of principles and proficiency of skills for performing sterile manipulations and achieving and maintaining appropriate environmental conditions. Competency must be demonstrated every 12 months in at least the following:

• Hand hygiene

• Garbing

• Cleaning and disinfection

• Calculations, measuring, and mixing

• Aseptic technique

• Achieving and/or maintaining sterility and apyrogenicity

• Use of equipment

• Documentation of the compounding process (e.g., master formulation and compounding records)

• Principles of high-efficiency particulate air (HEPA)-filtered unidirectional airflow within the ISO Class 5 area

• Proper use of primary engineering controls (PECs)

• Principles of movement of materials and personnel within the compounding area All compounding personnel must complete written or electronic testing every 12 months. Any other personnel handling

CSPs and/or accessing the compounding area must complete training and demonstrate competency in maintaining the quality of the environment in which they are performing their assigned task. The designated person(s) must ensure that any person who enters the sterile compounding area maintains the quality of the environment.

If the facility has only one person in the compounding operation, that person must document that they have obtained training and demonstrated competency, and they must comply with the other requirements of this chapter.

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2.2 Demonstrating Competency in Garbing and Hand Hygiene

All compounding personnel must be visually observed initially and every 6 months while performing hand hygiene and garbing procedures (see 3. Personal Hygiene and Garbing). The visual audit must be documented and the documentation maintained to provide a record of personnel competency.

Initial gloved fingertip and thumb sampling evaluates a compounder’s competency in correctly performing hand hygiene and garbing (see Box 2-1). Before being allowed to independently compound, all compounders must successfully complete an initial competency evaluation, including visual observation and gloved fingertip and thumb sampling on both hands, no fewer than 3 separate times. Each fingertip and thumb evaluation must occur after performing a separate and complete hand hygiene and full garbing procedure. After the initial competency evaluation, compounding personnel must successfully complete gloved fingertip and thumb sampling at least every 6 months after completing the media-fill test (see 2.3 Competency Testing in Aseptic Manipulation).

Initial gloved fingertip and thumb sampling must be performed on donned sterile gloves in a classified area or segregated compounding area (SCA). Subsequent gloved fingertip and thumb sampling must be performed on donned sterile gloves inside of an ISO Class 5 PEC. If conducting gloved fingertip and thumb sampling in a compounding aseptic isolator (CAI), compounding aseptic containment isolator (CACI), or a pharmaceutical isolator, samples must be taken from the sterile gloves placed over the gloves attached to the restricted-access barrier system (RABS) sleeves.

Successful completion of initial gloved fingertip and thumb sampling is defined as zero colony-forming units (cfu). Successful completion of subsequent gloved fingertip and thumb sampling after media-fill testing is defined as ≤3 cfu (total from both hands). Action levels for gloved fingertip and thumb sampling results are shown in Table 1.

Failure is indicated by visual observation of improper hand hygiene and garbing procedures and/or gloved fingertip and thumb sampling results that exceed the action levels in Table 1. Results of the evaluation and corrective actions, in the event of failure, must be documented and the documentation maintained to provide a record and long-term assessment of personnel competency. Documentation must at a minimum include the name of the person evaluated, evaluation date/time, media and components used including manufacturer, expiration date and lot number, starting temperature for each interval of incubation, dates of incubation, the results, and the identification of the observer and the person who reads and documents the results.

Box 2-1. Gloved Fingertip and Thumb Sampling Procedures

• Use one sampling device per hand (e.g., plates, paddles, or slides) containing general microbial growth agar [e.g., trypticase soy agar (TSA)] supplemented with neutralizing additives (e.g., lecithin and polysorbate 80) as this agar supports both bacterial and fungal growth.

• Label each sampling device with a personnel identifier, whether it was from the right or left hand, and the date and time of sampling.

• Do not apply sterile 70% isopropyl alcohol (IPA) to gloves immediately before touching the sampling device because this could cause a false-negative result.

• Using a separate sampling device for each hand, collect samples from all gloved fingers and thumbs from both hands by rolling finger pads and thumb pad over the agar surface.

• Incubate the sampling device at a temperature of 30°–35° for no less than 48 hours and then at 20°–25° for no less than 5 additional days. Store media devices during incubation to prevent condensate from dropping onto the agar and affecting the accuracy of the cfu reading (e.g., invert plates).

• Record the number of cfu per hand (left hand, right hand).

• Determine whether the cfu action level is exceeded by counting the total number of cfu from both hands.

Table 1. Action Levels for Gloved Fingertip and Thumb Samplinga

Gloved Fingertip and Thumb Sampling Action Levels

(total number of cfu from both hands)

Initial sampling after garbing >0

Subsequent sampling after media-fill testing (every 6 months) >3 a Action levels are based on the total cfu count from both hands.

2.3 Competency Testing in Aseptic Manipulation

All compounding personnel must perform media-fill testing to assess their sterile technique and related practices (see Box 2-2) initially and every 6 months thereafter. Gloved fingertip and thumb sampling must be performed inside of an ISO Class 5 PEC following media-fill tests to evaluate the ability of the compounder to demonstrate acceptable aseptic processing.

When performing a media-fill test, simulate the most difficult and challenging compounding procedures and processing conditions encountered by the person replacing all the components used in the CSPs with soybean–casein digest media.

If using commercial sterile microbial growth media, a certificate of analysis (COA) must be obtained from the supplier stating that the lot of the growth media will support the growth of microorganisms. Store microbial growth media in accordance with manufacturer instructions and initiate the media-fill test before the expiration date of the media. If preparing sterile microbial growth media in-house for sterile-to-sterile media-fill testing, the growth promotion capability of the media must be demonstrated for each batch and documented as described in Sterility Tests á71ñ, Culture Media and Incubation Temperatures, Growth Promotion Test of Aerobes, Anaerobes, and Fungi.

Failure is indicated by visible turbidity or other visual manifestations of growth in the media in one or more container–closure unit(s) on or before the end of the incubation period.

Results of the evaluation and corrective actions, in the event of failure, must be documented and the documentation maintained to provide a record and long-term assessment of personnel competency. Documentation must at a minimum include the name of the person evaluated, evaluation date/time, media and components used including manufacturer, expiration date and lot number, starting temperature for each interval of incubation, dates of incubation, the results, and the identification of the observer and the person who reads and documents the results.

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Box 2-2. Media-Fill Testing Procedures

• If all of the starting components are sterile to begin with, manipulate them in a manner that simulates sterile-to-sterile compounding activities, and transfer the sterile soybean–casein digest media into the same types of container–closure systems commonly used at the facility. Do not further dilute the media unless specified by the manufacturer.

• If some of the starting components are nonsterile to begin with, use a nonsterile soybean–casein digest powder to make a solution. Dissolve nonsterile commercially available soybean–casein digest medium in nonbacteriostatic water to make a 3% nonsterile solution. Manipulate it in a manner that simulates nonsterile-to-sterile compounding activities. Prepare at least 1 container as the positive control to demonstrate growth promotion, which is indicated by visible turbidity upon incubation.

• Once the compounding simulation is completed and the final containers are filled with the test media, incubate them in an incubator for 7 days at 20°–25° followed by 7 days at 30°–35° to detect a broad spectrum of microorganisms.

• Failure is indicated by visible turbidity or other visual manifestations of growth in the media in one or more container–closure unit(s) on or before 14 days.

3. PERSONAL HYGIENE AND GARBING

Personal hygiene and garbing are essential to maintain microbial control of the environment. Most microorganisms detected in cleanrooms are transferred from individuals. Squamous cells are normally shed from the human body at a rate of 106 or more per hour, and those skin particles are covered with microorganisms.1, 2 Individuals entering a compounding area must be properly garbed and must maintain proper personal hygiene to minimize the risk of contamination to the environment and/or CSPs.

Individuals that may have a higher risk of contaminating the CSP and the environment (e.g., personnel with rashes, recent tattoos, oozing sores, conjunctivitis, or active respiratory infection) must report these conditions to the designated person(s).

The designated person(s) is responsible for evaluating whether these individuals should be excluded from working in compounding areas before their conditions have resolved because of the risk of contaminating the CSP and the environment.

3.1 Personnel Preparation

Individuals entering a compounding area must take appropriate steps to minimize microbial contamination of the environment and the CSPs, including hand hygiene (3.2 Hand Hygiene), garbing (3.3 Garbing Requirements), and consideration of needed materials to be brought into the compounding area. Before entering a compounding area, individuals must remove any items that are not easily cleanable or that are not necessary for compounding. At a minimum, individuals must:

• Remove personal outer garments (e.g., bandanas, coats, hats, jackets, sweaters, vests).

• Remove all cosmetics because they shed flakes and particles.

• Remove all hand, wrist, and other exposed jewelry including piercings that could interfere with the effectiveness of garbing

(e.g., the fit of gloves, cuffs of sleeves, and eye protection) or otherwise increase the risk of contamination of the CSP.

Cover any jewelry that cannot be removed.

• Not wear earbuds or headphones.

• Not bring electronic devices that are not necessary for compounding or other required tasks into the compounding area.

• Keep nails clean and neatly trimmed to minimize particle shedding and avoid glove punctures. Nail products (e.g., polish, artificial nails, and extenders) must not be worn.

• Wipe eyeglasses, if worn.

The designated person(s) may permit accommodations as long as the quality of the CSP and environment will not be affected.

3.2 Hand Hygiene

Personnel must wash hands and forearms up to the elbows with soap and water before initiating compounding activities Box 3-1). Brushes must not be used for hand hygiene. Hand dryers must not be used. A closed system of soap (i.e., non-refillable container) to minimize the risk of extrinsic contamination must be readily available or in close proximity to the sink.

Box 3-1. Hand Washing Procedures

• Remove visible debris from underneath fingernails under warm running water using a disposable nail cleaner.

• Wash hands and forearms up to the elbows with soap and water for at least 30 seconds.

• Dry hands and forearms to the elbows completely with low-lint disposable towels or wipers.

The order of hand washing and garbing depends on the placement of the sink (see 4.4 Water Sources). The order of garbing must be determined by the facility and documented in the facility’s SOP. Hands must be sanitized with alcohol-based hand rub before donning sterile gloves (see Box 3-2). Sterile gloves must be donned in a classified room or SCA.

Box 3-2. Hand Sanitizing Procedures

• Apply an alcohol-based hand rub to dry skin following the manufacturer’s instructions for the volume of product to use.

• Apply product to one hand and rub hands together, covering all surfaces of hands and fingers, until hands are dry.

• Allow hands to dry thoroughly before donning sterile gloves.

1 Agalloco J, Akers JE. Aseptic processing: a vision of the future. Pharm Technol. 2005; Aseptic Processing supplement, s16.

2 Eaton T. Microbial risk assessment for aseptically prepared products. Am Pharm Rev. 2005;8(5):46–51.

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3.3 Garbing Requirements

Any person entering a compounding area must be properly garbed in accordance with the facility’s SOPs. Garb must be donned and doffed in an order that reduces the risk of contamination. The order of garbing must be determined by the facility and documented in the facility’s SOP. Sterile gloves must be donned in a classified room or SCA. Skin must not be exposed inside the ISO Class 5 PEC (e.g., gloves must not be donned or doffed inside the ISO Class 5 PEC exposing bare hands). Donning and doffing garb should not occur in the ante-room or the SCA at the same time. The minimum garbing requirements include:

• Low-lint garment with sleeves that fit snugly around the wrists and that is enclosed at the neck (e.g., gowns or coveralls)

• Low-lint, disposable covers for shoes

• Low-lint, disposable covers for head that cover the hair and ears, and if applicable, disposable cover for facial hair

• Face mask

• Sterile powder-free gloves

• If using a RABS, such as a CAI or CACI, disposable gloves (e.g., cotton, nonsterile, sterile) should be worn inside gloves attached to the RABS sleeves. Sterile gloves must be worn over gloves attached to the RABS sleeve Garb must be replaced immediately if it becomes visibly soiled or if its integrity is compromised. Gowns and other garb must be stored in a manner that minimizes contamination (e.g., away from sinks to avoid splashing). When personnel exit the compounding area, garb except for gowns cannot be reused and must be discarded. Gowns may be re-used within the same shift if the gown is maintained in a classified area or inside the perimeter of an SCA.

If compounding a HD, appropriate personal protective equipment (PPE) must be worn and disposed of in accordance with á800ñ.

GLOVES

Gloves must be sterile and powder free. Application of sterile 70% IPA to gloves must occur regularly throughout the compounding process and whenever nonsterile surfaces (e.g., vials, counter tops, chairs, or carts) are touched.

All gloves must be inspected for holes, punctures, or tears and must be replaced immediately if such defects are detected.

The RABS sleeves and gloves and the pharmaceutical isolator gauntlet sleeves and gloves should be changed per the manufacturer’s recommendations and as defined in the facility’s SOP.

4. FACILITIES AND ENGINEERING CONTROLS

Sterile compounding facilities must be designed, outfitted, and maintained properly to minimize the risk of contamination of CSPs. The required air quality must be achieved and maintained through PECs and secondary engineering controls (SECs).

The ante-room, buffer room, and SCA must be separated from areas not directly related to compounding. The ante-room and buffer room must be appropriately controlled to achieve and maintain the required air quality classifications. The design of the facility should take into account the number of personnel and their movements, and the equipment, supplies, and components to maintain and facilitate the maintenance of air quality. The number of operations being performed, the equipment (e.g., PECs, carts, computers), the personnel in the compounding area (and in adjacent areas), and the complexity of the compounding procedures are critical considerations for maintaining control of environmental conditions in the facility.

4.1 Protection from Airborne Contaminants

Sterile compounding facilities must be designed to minimize the risk of airborne contamination of the area in which sterile compounding occurs. Proper design and controls are required to minimize the risk of exposure of CSPs to airborne contaminants.

AIR QUALITY STANDARDS

The ISO standards for air quality in controlled environments are provided in Table 2 and referenced throughout this chapter.

Table 2. ISO Classification of Particulate Matter in Room Aira

ISO Class Particle Countb /m3

3 35.2

4 352

5 3520

6 35,200

7 352,000

8 3,520,000 a Adapted from ISO 14644-1, Cleanrooms and associated controlled environments—Part 1: Classification of air cleanliness by particle concentration.

b Limits for number of particles ≥0.5 µm measured under dynamic operating conditions.

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DESIGN REQUIREMENTS TO MAINTAIN AIR QUALITY

Facilities used for compounding CSPs must be designed so that air quality improves with movement through separate operational areas to the PEC. Classified areas in which the air quality is controlled (see Table 2) include ante-rooms, buffer rooms, and PECs.

• Ante-rooms providing access to positive pressure buffer rooms must meet at least ISO Class 8 classification. Ante-rooms providing access to negative pressure buffer rooms must meet at least ISO Class 7 classification (see á800ñ). Typically, personnel hand hygiene and garbing procedures, staging of components, and other activities that potentially generate higher levels of particulates are performed in the ante-room. Ante-rooms are also transition areas to ensure that proper air classification and pressure relationships are maintained between classified and unclassified areas.

• A buffer room must meet at least ISO Class 7 air quality. Activities in the buffer room must be controlled to minimize any effects on air quality in the area where CSPs are prepared.

• Category 1 and Category 2 CSPs must be prepared in an ISO Class 5 or better PEC.

If compounding only Category 1 CSPs, the PEC may be placed in an unclassified SCA.

4.2 Facility Design and Environmental Controls

In addition to minimizing airborne contamination, sterile compounding facilities must be designed and controlled to provide a well-lighted and comfortable working environment (see Physical Environments That Promote Safe Medication Use á1066ñ). The cleanroom suite should be maintained at a temperature of 20° or cooler and a relative humidity below 60% to minimize the risk for microbial proliferation and provide comfortable conditions for compounding personnel attired in the required garb.

The temperature and humidity must be monitored in each room of the cleanroom suite each day that compounding is performed, either manually or by a continuous recording device. The results of the temperature and humidity readings must be documented at least once daily or stored in the continuous recording device, and must be retrievable. The temperature and humidity readings must be reviewed as described in the facility’s SOPs. Temperature and humidity in the cleanroom suite must be controlled through a heating, ventilation, and air conditioning (HVAC) system. Free-standing humidifiers/dehumidifiers and air conditioners must not be used within the classified area or within the perimeter of the SCA. Temperature and humidity monitoring devices must be verified for accuracy at least every 12 months or as required by the manufacturer.

The designated person(s) is responsible for ensuring that each area related to CSP preparation meets the classified air quality standard appropriate for the activities to be conducted in that area. The designated person(s) must also ensure that the ISO Class 5 areas are located, operated, maintained, monitored, and certified to have appropriate air quality.

TYPES OF SECS AND DESIGN

The PEC must be located in the buffer room of the cleanroom suite or the SCA in a manner that minimizes conditions that could increase the risk of microbial contamination. For example, strong air currents from opened doors, personnel traffic, or air streams from the HVAC system(s) can disrupt the unidirectional airflow of an open-faced PEC such as a laminar airflow workbench (LAFW). Access to the SEC must be restricted to authorized personnel and required materials.

Cleanroom suite: The ISO-classified ante-room and buffer room must be separated from the surrounding unclassified areas of the facility by fixed walls and doors, and controls must be in place to minimize the flow of lower-quality air into the more controlled areas. Air supplied to the cleanroom suite must be introduced through HEPA filters that are located in the ceiling of the buffer and ante-rooms.

Air returns in the cleanroom suite must be low on the wall unless a visual smoke study demonstrates an absence of stagnant airflow where particulate will accumulate. This smoke study along with environmental monitoring must be repeated whenever a change to the placement of equipment within the room is made or any other alteration is performed within the cleanroom suite that affects the quality of the air (e.g., HVAC alterations, change of HEPA filter units).

The classified rooms must be equipped with a pressure-differential monitoring system. The ante-room must have a line of demarcation to separate the clean side from the dirty side. Alternatively, facilities may be designed with two separate ante-rooms, a clean ante-room and a dirty ante-room. The ante-room is entered through the dirty side/room, and the clean side/ room is the area closest to the buffer room. Required garb must be donned prior to entering the clean side/room of the ante-room (see 3. Personal Hygiene and Garbing).

It is also critical to control materials (e.g., supplies and equipment) as they move from classified areas of lower quality to those of higher quality (e.g., ISO Class 8 ante-room to ISO Class 7 buffer room to ISO Class 5 PEC) to minimize the influx of contaminants. Airlocks and interlocking doors may be used to facilitate better control of air balance between areas of differing ISO classification (e.g., between the buffer room and ante-room), or between a classified area and an unclassified area (e.g., between the ante-room and an unclassified area such as a hallway). If a pass-through is used, both doors must never be opened at the same time, and doors should be interlocking.

Due to the interdependence of the various rooms or areas that make up a sterile compounding facility, it is essential to carefully define and control the dynamic interactions permitted between areas and rooms. Consider the placement of door closures, door surfaces, and the movement of the doors, all of which can affect airflow. Seals and sweeps should not be installed at doors between buffer and ante-rooms. Access doors should be hands-free. Tacky mats must not be placed within ISO-classified areas.

Segregated compounding area (SCA): A PEC may be located within an unclassified area, without an ante-room or buffer room. This type of design is called an SCA. Only Category 1 CSPs can be compounded in an SCA. The SCA must be located away from unsealed windows, doors that connect to the outdoors, and traffic flow, all of which may adversely affect the air quality in the PEC. An SCA must not be located where environmental control challenges (e.g., restrooms, warehouses, or food preparation areas) could negatively affect the air quality of the PEC within the SCA. The impact of activities (e.g., patient care

8 á797ñ Revision Bulletin Official December 1, 2019 activities) that will be conducted around or adjacent to the SCA must be considered carefully when designing such an area. A visible perimeter must establish the boundaries of the SCA.

THE CSP COMPOUNDING ENVIRONMENT

The PEC must be certified to meet ISO Class 5 or better conditions (see Table 2) during dynamic operating conditions and must be designed to prevent contamination during compounding of CSPs.

Unidirectional airflow must be maintained in the PEC. HEPA-filtered air must be supplied by the PEC at a velocity sufficient to sweep particles away from critical sites and maintain unidirectional airflow during operations. Proper design, control, and use minimizes turbulence and creation of eddies or stagnant air in the PEC.

TYPES OF PECS AND PLACEMENT

Proper placement of the PEC is critical to ensuring an ISO Class 5 environment for preparing CSPs. Placement of the PEC must allow for cleaning around the PEC. See Table 3 for a summary of minimum requirements for the placement of PECs for preparing non-HD CSPs.

Types of PECs and their placement include the following.

Laminar airflow system (LAFS): An LAFS provides an ISO Class 5 or better environment for sterile compounding. The LAFS provides unidirectional HEPA-filtered airflow that is designed to prevent contamination of a sterile compounding environment.

The unidirectional airflow within the LAFS helps protect the direct compounding area (DCA) from process-generated contamination (e.g., opening wrappings of sterile containers, compounder movement) as well as from outside sources.

Types of LAFS: Examples of LAFS include LAFWs, integrated vertical laminar flow zones (IVLFZs), and biological safety cabinets (BSCs).

LAMINAR AIRFLOW WORKBENCH (LAFW): An LAFW is a device that provides an ISO Class 5 or better environment for sterile compounding. The LAFW provides either horizontal or vertical unidirectional HEPA-filtered airflow. [NOTE—An LAFW must not be used for preparation of antineoplastic and/or active pharmaceutical ingredient (API) HDs (see á800ñ).]

INTEGRATED VERTICAL LAMINAR FLOW ZONE (IVLFZ): An IVLFZ is a designated ISO Class 5 area serving as the PEC within an ISO Class 7 or cleaner buffer room. In the IVLFZ, unidirectional airflow is created by placing HEPA filters over the entire surface of the work tables and effective placement of air returns. The unidirectional HEPA-filtered zone must be separated from the ISO Class 7 area with a physical barrier to direct the airflow downward over the work area to separate the DCA from potential sources of contamination. Strategic location of air returns in addition to full coverage of HEPA filters above the work surface is required.

Both static and dynamic smoke studies verifying a continuous flow of HEPA-filtered air void of turbulence, dead air zones, and refluxing from the HEPA filters to and across the entire work area and to the air returns must be documented (e.g., with video).

[NOTE—Dynamic airflow smoke pattern tests have shown that it is difficult to achieve this type of design and also achieve and maintain unidirectional airflow under dynamic operating conditions.] [NOTE—A IVLFZ must not be used for preparation of antineoplastic and/or API HDs (see á800ñ).]

CLASS II BIOLOGICAL SAFETY CABINET (BSC): A Class II BSC is a ventilated cabinet with an open front and inward and downward unidirectional HEPA-filtered airflow and HEPA-filtered exhaust. The BSC is designed to provide worker protection from exposure to airborne drugs and to provide an ISO Class 5 or better environment for preparing CSPs. [NOTE—The exhaust air from the BSC must be externally vented for preparation of antineoplastic and/or API HDs (see á800ñ).]

Placement of LAFS: The LAFS must be located out of traffic patterns and away from room air currents that could disrupt the intended airflow patterns inside the PEC. If used to prepare only Category 1 CSPs, the ISO Class 5 PEC may be located in an unclassified SCA. If used to prepare Category 2 CSPs, the LAFS must be located within a cleanroom suite with an ISO Class 7 or better buffer room with an ISO Class 8 or better ante-room. A dynamic airflow smoke pattern test must be performed in the PEC initially and at least every 6 months to ensure that 1) the LAFS is properly placed into the facility and 2) compounders understand how to utilize the unidirectional airflow to maintain first air in the DCA.

Restricted-access barrier system (RABS): A RABS is an enclosure that provides HEPA-filtered ISO Class 5 unidirectional air. It allows for the ingress and/or egress of materials through defined openings that have been designed and validated to preclude the transfer of environmental air contamination, and that generally are not to be opened during compounding operations.

Types of RABS: Examples of RABS include CAIs and CACIs. In a CAI or CACI, glove ports are used to provide physical separation between the surrounding area and the aseptic manipulations.

COMPOUNDING ASEPTIC ISOLATOR (CAI): A CAI is designed for compounding non-HD CSPs. It is designed to maintain an ISO Class 5 environment throughout the compounding and material transfer processes. Air exchange into the CAI from the surrounding environment must not occur unless the air has first passed through a HEPA filter. [NOTE—A CAI must not be used for preparation of antineoplastic and/or API HDs (see á800ñ).]

COMPOUNDING ASEPTIC CONTAINMENT ISOLATOR (CACI): A CACI is designed to provide worker protection from exposure to undesirable levels of airborne drug throughout the compounding and material transfer processes, and to maintain an ISO Class 5 environment for compounding sterile HD preparations (see á800ñ).

Placement of RABS: If used to prepare only Category 1 CSPs, the ISO Class 5 environment may be achieved by placing the RABS in an unclassified SCA. If used to prepare Category 2 CSPs, the RABS must be located within a cleanroom suite with an ISO Class 7 or better buffer room with an ISO Class 8 or better ante-room. For placement of a CACI used for the preparation of antineoplastic and/or API HDs, see á800ñ.

When a RABS is used, the recovery time after opening the transfer chamber to achieve ISO Class 5 air quality must be documented (e.g., by the manufacturer), and internal procedures must be developed to ensure that adequate recovery time is allowed after opening and closing the RABS, both before and during compounding operations. A dynamic airflow smoke pattern test must be performed in the PEC under dynamic operating conditions initially and at least every 6 months to ensure that 1) the RABS is properly integrated into the facility and 2) compounders understand how to utilize the unidirectional airflow to maintain first air in the DCA.

Revision Bulletin Official December 1, 2019 á797ñ 9

Pharmaceutical isolator: A pharmaceutical isolator provides isolation from the surrounding area and maintains ISO Class 5 air quality during dynamic operating conditions. [NOTE—A CAI or CACI is not a pharmaceutical isolator.] A pharmaceutical isolator comprises four elements:

1. Controlled workspace

2. Transfer device(s)

3. Access device(s)

4. Integral decontamination system Placement of pharmaceutical isolators: A pharmaceutical isolator used to prepare only Category 1 CSPs can be placed in an unclassified SCA. If the pharmaceutical isolator is used to prepare Category 2 CSPs, the pharmaceutical isolator must be placed in an ISO Class 8 or better room. [NOTE—An ante-room is not required when using a pharmaceutical isolator.] A dynamic airflow smoke pattern test must be performed in the PEC initially and at least every 6 months to ensure that 1) the pharmaceutical isolator is properly placed into the facility and 2) compounders understand how to utilize the unidirectional airflow to maintain first air in the work zone. For placement of a pharmaceutical isolator used for the preparation of HDs, see á800ñ.

Table 3. Summary of Minimum Requirements for Placement of PEC for Compounding Non-HD CSPsa

PEC

Type

Device Type

Placement for Compounding Category 1 CSPs

Placement for Compounding Category 2 CSPs

LAFS

LAFW Unclassified SCA

ISO Class 7 positive pressure buffer room with an ISO Class 8 positive pressure ante-room

IVLFZ N/Ab

ISO Class 7 positive pressure buffer room with an ISO Class 8 positive pressure ante-room

BSC Unclassified SCA

ISO Class 7 positive pressure buffer room with an ISO Class 8 positive pressure ante-room

RABS CAI or CACI Unclassified SCA

ISO Class 7 positive pressure buffer room with an ISO Class 8 positive pressure ante-room

Pharmaceutical isolator Pharmaceutical isolator Unclassified SCA ISO Class 8 positive pressure room a For compounding HDs, refer to á800ñ.

b An IVLFZ must not be used in an unclassified area.

If a robotic enclosure is used as the PEC, a dynamic airflow smoke pattern test must be performed initially and every 6 months thereafter to ensure 1) that it is properly integrated into the facility, 2) that there is no turbulence or refluxing at any critical site, 3) that room air does not enter the PEC where sterile products and/or preparations may be exposed, and 4) that all processes can be performed without introducing contamination to the DCA(s).

AIR EXCHANGE REQUIREMENTS

For cleanroom suites, adequate HEPA-filtered airflow to the buffer room(s) and ante-room(s) is required to maintain the appropriate ISO classification during compounding activities. Airflow is measured in terms of the number of air changes per hour (ACPH). The ACPH may need to be higher to maintain the required ISO classification and microbial state of control depending on the following factors:

• number of personnel permitted to work in the area

• number of particulates that may be generated from activities and processes in the area

• the equipment located in the room

• the room pressure

• the effects of…