Chapter 41 - Pharmaceutically Compounded Sterile Products

3-41.1 INTRODUCTION

1. PURPOSE. This chapter establishes the minimum requirements for all staff that are responsible for compounding sterile products in facilities operated by the Indian Health Service (IHS). The requirements set forth in this chapter are intended to minimize harm and prevent the contamination of compounded sterile preparations (CSPs).
2. BACKGROUND.  Quality sterile compounding of medicine is foundational to patient safety and reduces the incidence of adverse health care-associated conditions such as infections and medication errors.  The United States Pharmacopeia (USP) Chapter 797 sets forth standards for preparing sterile preparations that are free from contaminants and are consistent in intended identity, strength and potency.  It describes a number of requirements, including responsibilities of compounding personnel, training, environmental monitoring, and storage and testing of finished preparations.  Accrediting organizations rely on USP 797 to provide the standard for accreditation of facilities that prepare CSPs.  Implementation of this policy will occur at the local level and include both Area Offices and Service Units.  Supplemental policies and procedures for sterile compounding will be tailored to meet specific needs at the local level but must have core elements in place, as described in this policy.  Components of this policy were developed using evidence-based practice standards and guidelines from USP 797, the American Society of Health-System Pharmacists (ASHP) Guidelines on Compounding Sterile Preparations, and the Institute for Safe Medication Practices (ISMP) Guidelines for Safe Preparation of Compounded Sterile Preparations as well as applicable statutory and regulatory provisions.
3. POLICY.  The IHS will ensure that all CSPs used in patient care meet standards for sterile compounding.
   1. Service Units and Facilities must comply with the most current USP 797 and, when applicable, USP 800 and the Indian Health Manual (IHM) Part 3 – Chapter 27: “Handling Hazardous Drugs in the Health Care Setting.”
   2. Service Units and Facilities will purchase conventionally manufactured sterile products whenever possible and utilize standardized concentrations.
   3. Infection control breaches related to CSPs will be reported, investigated, and resolved in accordance with facility-specific policy.
4. SCOPE.  This chapter applies to all IHS staff who prepare CSPs and all places where CSPs are prepared.  It also applies to preparing immediate-use, Category 1, and Category 2 CSPs.
5. RESOURCES AND GUIDELINES.  In addition to applicable legal authority, IHS policy incorporates best practices and guidelines from the following organizations and guidance:
   1. USP Convention General Chapter 797 Pharmaceutical Compounding – Sterile Preparations (USP 797);
   2. USP Convention General Chapter 800 Hazardous Drugs – Handling in Health Care Settings (USP 800);
   3. IHM Part 3 - Chapter 27: Handling Hazardous Drugs in the Health Care Setting;
   4. IHM Part 3 - Chapter 33: Infection Control and Prevention;
   5. ASHP, Guidelines on Compounding Sterile Preparations, Am. J. Health-Systems Pharm., 71:145–66 (Jan. 15, 2014);
   6. ASHP, Standardize 4 Safety Initiative, https://www.ashp.org/Pharmacy-Practice/Standardize-4-Safety-Initiative;
   7. Controlled Environment Testing Association (CETA), Certification Guide for Sterile Compounding Facilities for USP Compliance, CETA-CAG-003-2022 (Oct. 2022); and
   8. The Institute for Safe Medication Practices (ISMP), Guidelines for Sterile Compounding and the Safe Use of Sterile Compounding Technology (May 4, 2022).

3-41.2 RESPONSIBILITIES.

1. Chief Medical Officer. The IHS Chief Medical Officer (CMO) is administratively responsible for the issuance of this policy.
2. Principal Pharmacy Consultant.  The IHS Principal Pharmacy Consultant will have primary responsibility for the IHS Sterile Compounding Program, including the periodic review and revision of this chapter.
3. Area Directors.  The IHS Area Directors will ensure that administrative support and necessary resources are made available to implement this policy at pharmacies in their respective Areas.
4. Area Pharmacy Consultants.  The IHS Area Pharmacy Consultants will serve as technical advisors to Pharmacy Directors.  They will ensure the guidelines for sterile compounding are implemented in all IHS Federal facilities, in their respective Areas, that are compounding products that fall under these guidelines.
5. Chief Executive Officers.  A facility’s Chief Executive Officer is responsible for approving and ensuring the facility’s policy is fully reviewed and implemented.
6. Pharmacy Directors and Designee(s).  The Pharmacy Director or Designee(s) at each facility is (are) responsible for developing, implementing, and overseeing the healthcare facility’s sterile compounding program, including training for pharmacy and associated staff, quality assurance, program evaluation, and reporting issues to the Infection Control Program.
7. Facility Managers.  The Facility Manager at each facility is responsible for coordinating with the Pharmacy Director, to perform inspections, maintenance, and or modifications to the compounding area in accordance with IHS requirements and notifying the Pharmacy Director of any changes to the physical environment that may affect the operation of the compounding area.

3-41.3 DEFINITIONS (Exhibit 3.41 A)

3-41.4 CATEGORY 1 AND 2 CSPs - BEYOND USE DATES AND CLASSIFIED SPACE REQUIREMENTS (Exhibit 3-41 B)

3-41.5 REQUIRED TRAINING/COMPETENCY FOR FACILITIES THAT PERFORM CATEGORY 1 AND CATEGORY 2 COMPOUNDING (Exhibit 3-41 C)

1. A written training program must be in place that describes, at a minimum:
   1. Required training and frequency
   2. Process for evaluating the performance of personnel who:
      1. Compound;
      2. Have direct oversight of compounding personnel;
      3. Perform in-process checks;
      4. Perform final verification; and
      5. Dispense.
2. Didactic and multimedia training, required prior to any compounding and annually after that.  A written competency evaluating staff compounding knowledge is required annually.
   1. Minimum requirements as applicable to job function:
      1. Hand hygiene and garbing;
      2. Cleaning and disinfecting;
      3. Calculations, measuring, and mixing;
      4. Aseptic technique;
      5. Maintaining sterility;
      6. Use of equipment;
      7. Documentation;
      8. Principles of airflow in an International Standardization for Organization (ISO) Class 5 environment;
      9. Proper use of the primary engineering control (PEC); and
      10. Movement of materials and personnel in the compounding area.
3. Hands-On Training.  Witnessed assessment of the following procedures is required initially prior to compounding and at intervals as noted:
   1. Proper hand hygiene and garbing competency
      1. Competency includes visual observation of hand hygiene and garbing as well as a gloved fingertip and thumb test (GFT) of both hands.
      2. Visual hand hygiene and garbing evaluation example (see Exhibit 3-41 D).
      3. GFT example (see Exhibit 3-41 E).
      4. Initial assessment must be completed three separate times and personnel must successfully complete the three attempts in succession.
      5. Subsequent assessments must be completed every 6 months.
   2. Proper aseptic manipulation
      1. Competency includes visual observation, media-fill testing, GFT, and surface sampling of the direct compounding area.
      2. Visual aseptic technique evaluation (see Exhibit 3-41 F).
      3. Media fill testing example (see Exhibit 3-41 G).
      4. GFT example (see Exhibit 3-41 E).
      5. Surface sampling procedures should follow Section 3-41.9.F of USP 797.
      6. Completed initially, then subsequent assessments must be completed every 6 months.
   3. Proper cleaning and disinfection procedures
      1. Training may take place in ante-area and buffer rooms to facilitate learning.
      2. Local policy and procedure determine training requirements.
      3. Cleaning and disinfecting procedures performed by other support personnel will be thoroughly trained and evaluated annually, or per facility SOP, in proper hand hygiene, garbing, cleaning, and disinfection procedures by the designated person or assigned trainer.
   4. Immediate use training and related aseptic technique training. (see Section 3-41.11 and Exhibits 3-41 H and I)
4. Personnel are educated on the proper use of compounding equipment
   1. Required equipment calibration;
   2. Annual maintenance;
   3. Proper function/malfunction; and
   4. All records maintained on file at a minimum for the life of the equipment.
      Documentation is required of all training and competency assessments. If personnel fail to pass the above competencies, there must be documentation to show remediation and subsequent test(s) and successful results to ensure compliance. The designated person is responsible for ensuring documentation, action plan, and follow-up. Documentation will be readily retrievable within the pharmacy and maintained to provide a permanent record and long-term assessment of personnel competency.

3-41.6 COMPOUNDING ROOM STRUCTURE FOR ANTE-AREA, BUFFER ROOM, AND SEGREGATED COMPOUNDING AREA

Service Units and Facilities will construct and maintain sterile compounding areas in accordance with USP 797 Section 4. Requirements for a segregated compounding area (SCA) are detailed in Exhibit 3-41 J.

3-41.7 SUPPLY REQUIREMENTS FOR ANTE-AREA, BUFFER ROOM, AND SCA (see Exhibit 3-41 K)

3-41.8 REQUIRED CLEANING/DISINFECTION PROCEDURES, INTERVALS, AND DOCUMENTATION FOR ANTE-AREA, BUFFER ROOM AND SCA

1. Procedures
   1. Must be performed by trained and appropriately garbed personnel.
   2. Procedures, frequency, methods, locations, and agents must be described in written SOPs.
   3. Minimum contact time as described by the manufacturer for cleaning, disinfecting, and sporicidal agents must be followed.
   4. Agents used in the PEC must be sterile.
   5. Cleaning must be performed in the direction of clean to dirty.  Special consideration should be given to a facility that also compounds hazardous drugs (see IHM 3.27 and USP 800).
2. Minimum cleaning and disinfecting intervals are described in Exhibit 3-41 L
3. Documentation
   1. Daily cleaning and disinfection (Exhibit 3-41 M).
   2. Monthly cleaning and disinfection and application of sporicidal (Exhibit 3-41 M).
   3. Daily temperature, humidity, and pressure differentials in each classified area (Exhibit 3-41 N and Exhibit 3-41 O).
      1. Out-of-range readings must be addressed by local facility management. All issues and resolutions must be documented.

3-41.9 CERTIFICATION AND ENVIRONMENTAL SAMPLING REQUIREMENTS FOR ANTE-AREA, BUFFER ROOM, PRIMARY ENGINEERING CONTROL AND SCA

1. Before a compounding area is used to prepare CSPs, it must be independently certified using the requirements in USP 797 and, when applicable, manufacturer specifications.
2. Certification of the classified areas, including the PEC, must be performed initially with recertification every 6 months and must include: airflow testing, HEPA filter integrity testing, total particle count testing, and dynamic airflow smoke pattern test.
   1. Classified areas must also be recertified for any of the following changes: redesign, construction, replacement, or relocation of any PEC, or for any alteration in room configuration that could affect airflow or air quality.
3. Total airborne particle count testing must be completed in classified areas during dynamic operating conditions at least every 6 months, and all sampling sites and procedures must be described in the facility SOPs.
4. Microbiological air and surface testing must be clearly described in the facility SOPs including a diagram of the sampling locations, procedures for collecting samples, frequency of sampling, size of samples, time of day of sampling in relation to activities in the compounding area, and action levels that will trigger corrective action.
   1. Must be performed initially to establish a baseline level of environmental quality and then monitored:
      1. In conjunction with certification of new facilities or equipment, after any servicing of facilities or equipment, in response to identified problems or trends, and in response to changes that could impact the sterile cleaning environment (i.e., change of agents).
5. Viable Air Sampling must be completed at least every 6 months.
   1. Facilities that perform their own viable air sampling should refer to USP 797 for procedural guidance.
   2. Facilities should refer to USP 797 Table 7 to determine action levels for viable airborne particle air sampling.
   3. Colony-forming units (CFUs) above action levels require investigation and development of a documented corrective action plan.
   4. For CFUs above action levels, an attempt must be made to identify the organism to the genus level with the assistance of a microbiologist.
      1. Note:  Identification should be contracted with a laboratory that can identify environmental organisms in addition to pathological organisms.
6. Surface sampling must be completed at least monthly as well as part of the media-fill testing competency.
   1. Surface sampling procedures should follow manufacturer recommendations as well as the requirements listed in USP 797 Section 6.3.2 and Box 6: Surface Sampling Procedures.
      1. An incubator must be used during all phases of incubation, including during the 20? - 25? phase.
   2. Facilities should refer to USP 797 Table 8 to determine action levels for surface sampling.
   3. CFUs above action levels require investigation and development of a documented corrective action plan.
   4. For CFUs above action levels, an attempt must be made to identify the organism to the genus level with the assistance of a microbiologist.
      1. Note: Identification should be contracted with a laboratory that can identify environmental organisms in addition to pathological organisms.
7. All certification and recertification records must be reviewed by the designated person and must be maintained in accordance with the requirements in IHM 3-41.19

3-41.10 ACTIVITIES CONDUCTED IN THE ANTE-AREA, BUFFER ROOM, PRIMARY ENGINEERING CONTROL AND SCA

1. All personnel entering compounding areas for Category 1 and 2 CSPs must take appropriate steps to minimize contamination of the environment and CSPs:
   1. Hand hygiene and garbing.
      1. Order of hand hygiene and garbing is determined by placement of sink.
      2. All personnel must wash hands and forearms up to the elbows with soap and water before initiation of compounding services.
      3. Garbing procedures are determined according to facility best practices and SOPs.
         1. When using a restricted-access barrier system (RABS) disposable gloves must be worn inside of the gloves attached to the RABS; sterile gloves must be worn over the gloves attached to the RABS sleeve (triple gloving).
         2. Hands must be sanitized with alcohol-based hand rub before donning sterile gloves.
         3. Sterile gloves must be donned in a classified area or SCA.
         4. If eyeglasses are worn, they must be wiped prior to garbing.
   2. The compounding personnel will not enter into the ante-area, buffer room, or SCA to prepare CSP if they have the following:
      1. Food and/or beverage (including gum, mints, etc.);
      2. Rash, recent tattoos, weeping sores, conjunctivitis, or active respiratory infections.
      3. Cosmetics, nail products (including artificial nails or extenders and nail polish); nails must be neatly trimmed;
      4. Earbuds or headphones;
      5. Outerwear and personal garments such as scarves, coats, or jewelry, etc.;
      6. Electronic devices not necessary for compounding or other required tasks into the compounding area; and
      7. The designated person may permit accommodations to the above as long as quality of the CSP is not compromised; however, this must be documented.
2. Movement of materials in classified areas or the SCA.
   1. Only furniture, equipment, and other materials necessary to compounding activities are permitted in a classified area or SCA.
   2. Carts used to transport components or equipment into classified areas or the SCA must be constructed with nonporous materials with cleanable casters and cannot be moved from the dirty side to the clean side of the anteroom unless the entire cart, including casters, is cleaned and disinfected.
   3. Only equipment necessary for performing compounding duties is permitted in the primary engineering control (PEC).  When equipment is initially placed or relocated, a dynamic airflow smoke pattern test must be completed.
   4. Equipment and other items used in a classified area or SCA should not be removed except for calibration, servicing, cleaning, or other maintenance.  Items must be disinfected with sterile isopropyl alcohol (sIPA) or other suitable disinfectant before they are returned to the classified area or SCA.
   5. If a pass-through chamber is utilized, both doors may never be opened simultaneously.
3. Introduction of items into the SEC and PEC.
   1. All items introduced into the SEC must be wiped with a sporicidal disinfectant, EPA-registered disinfectant, or sIPA using low-lint wipes by gloved personnel. The wiping procedure should not compromise package integrity and the product label is to remain readable.
   2. All items to be introduced into the PEC must be wiped with sIPA using low-lint wipes and allowed to dry.  When sterile items are received in sealed containers designed to ensure sterility until opening, the covering from sterile items may be removed as the supplies are being introduced in the ISO Class 5 PEC without the need to wipe the individual sterile supply items with sIPA.
   3. Critical sites (vial stoppers, ampule necks, and IV bag septum) must be wiped with sIPA in the PEC to provide both chemical and mechanical actions to remove contaminants and must be allowed to dry before puncturing.

3-41.11 IMMEDIATE-USE CRITERIA

1. Immediate-use CSPs are prepared outside of an ISO Class 5 environment.
2. Immediate-use CSPs are exempt from requirements listed for Category 1 and Category 2 CSPs only when the following criteria are met:
   1. Personnel are trained and demonstrate competency in aseptic processes as they relate to assigned tasks;
   2. The preparation is performed in accordance with evidence-based information for physical and chemical compatibility of the drugs (e.g., approved labeling, stability and compatibility studies);
   3. The preparation involves not more than three different sterile products;
   4. Any unused starting components from a single-dose container must be discarded after preparation is complete.  Single-dose containers must not be used on more than one patient;
   5. Compounding occurs in a designated medication area that is clean and free from clutter to minimize the risk for contamination;
   6. Components will be visually examined for dating and integrity prior to compounding;
   7. Aseptic techniques will be followed;
   8. A final visual verification will be completed to ensure the integrity of the sterile preparation prior to administration;
   9. Product administration will be initiated within 4 hours from the time the compounding process begins; and
   10. Unless directly administered by the person who prepared it or administration is witnessed by the preparer, the immediate-use CSP must be labeled with the names and amount of all active ingredients, the name or initials of the person who prepared the preparation, and the expiration date and time within which administration must begin.
3. Required training and competencies for immediate use:  (see exhibit 3-41 H and 3-41 I)

3-41.12 CERTIFICATION FAILURE

1. Upon receiving notice of certification failure, the facility must document corrective action and schedule follow-up recertification. The follow-up results will be documented and retained for records.

3-41.13 SINGLE-DOSE VS MULTIPLE-DOSE CONTAINERS

1. Single-Dose Vials
   1. Opened or needle-punctured single-dose containers used outside of an ISO Class 5 must be discarded immediately.
   2. If single-dose vials are needle-punctured inside an ISO Class 5 environment, they may be used for up to 12 hours, as permitted by manufacturer recommendations.
2. Multi-Dose Vials
   1. May have a 28-day beyond-use date (BUD) after needle puncture of the diaphragm. The BUD may be less than 28 days if recommended by the manufacturer
   2. Once a multiple-dose vial is punctured, compounding personnel must date the expiration date on the vial.

3-41.14 COMPOUNDING ACCURACY CHECKS

1. Each facility must have written procedures for double-checking/verifying CSPs during preparation and immediately prior to dispensing the CSPs. At a minimum, those procedures will include:
   1. A person other than the compounder should visually check that all ingredients and quantities are accurate and consistent with the CSPs labels.
   2. The pharmacist will discuss with the compounder the appropriate volume to dilute and/or to withdraw prior to compounding.
   3. The syringes used to measure the additives should be quarantined with the final products until verified with other personnel.
   4. Facilities should consider (when practical) purchasing IV workflow programs to measure the accuracy of the additives when compounding.

3-41.15 MASTER FORMULATION AND COMPOUNDING RECORDS

1. Master formulation records (MFR).
   1. A MFR must be created for all CSPs prepared for more than one patient (batching) and must be approved and documented according to facility SOPs.
   2. At a minimum, a MFR must meet all requirements listed in USP 797 Box 9-Master Formulation Records.
2. Compounding Records (CR).
   1. A CR documents the compounding of each CSP.
   2. A CR must be created for all Category 1 and 2 CSPs that are made for more than one patient.
   3. The CR may be a prescription, order, or label but must meet, at a minimum, all requirements in USP 797 Section 11.2 and Box 10-Compounding Records.

3-41.16 PROPER STORAGE TEMPERATURES

1. Compounding personnel will monitor drug storage areas and document the following listed areas at least once daily:
   1. Controlled room temperature: 20 to 25°C;
   2. Refrigerated temperature:  2 to 8°C;
   3. Freezing:  -25 to -10°C; and
   4. Documentation is not required if stored in a continuous temperature recording device (must be readily retrievable).
2. The temperature device may include either:
   1. Calibrated continuous recording device; or
   2. National Institute of Standards and Technology calibrated thermometer.
3. Accuracy of the device must be tested at least every 12 months or as directed by the manufacturer.

3-41.17 LABELING

1. CSPs must be labeled appropriately and legibly and must include the following criteria at a minimum to prevent errors during storage, dispensing, and use. (See 3-41.11.B.(10) for immediate-use labeling requirements)
   1. Assigned internal identification number (e.g., barcode, lot, prescription, order).
   2. Active ingredients and amounts, activities, or concentrations.
   3. Storage conditions if other than controlled room temperature.
   4. Beyond-use dates and times (if less than 24 hours).
   5. Dosage form;
   6. Total amount or volume if not obvious from the container.
   7. A statement clarifying whether a container is single-dose or multi-dose.
   8. Route of administration;
   9. Special handling instructions and warning statements.
   10. Should indicate that the preparation is compounded.

3-41.18 PATIENT MONITORING AND ADVERSE EVENTS REPORTING

1. IHS facilities that dispense CSPs shall clinically monitor patients according to accepted standards of practice and regulations. Facilities shall provide patients with an avenue to address questions and concerns.
2. Reports of adverse events with CSPs shall be reviewed promptly with reporting according to facility procedures.
3. Written SOPs or facility policies must be in place for handling complaints and reporting adverse events.

3-41.19 RECORDS MAINTENANCE

1. All records pertaining to the equipment certification, personnel training, competencies, and CSPs will be maintained on file or stored electronically according to IHS records management policy.

3-41.20 QUALITY ASSURANCE (QA) PROGRAM

1. A quality assurance program aims to ensure that adequate controls exist and are employed to maintain the highest quality of CSPs and to comply with USP 797 standards. QA will encompass all aspects of the sterile compounding program and include documentation for all processes as applicable.
2. Facilities must have established QA and quality control (QC) programs that are documented in facility SOPs and ensure adherence to USP 797 and regulations.
3. A designated person(s) must ensure the program has written policies for adherence to procedures, quality and error detection and prevention, complaint and adverse event evaluation, and investigations and corrective actions.  The designated person must be adequately trained for their role and the roles and duties must be described in SOPs.
4. Sterile compounding program activities and documentation (e.g., inspection or analytical laboratory reports, competency forms and checklists, electronic and written records, and supporting documentation) are reviewed and audited by the designated person at least annually to ensure:
   1. All required regulatory and statutory sterile compounding requirements are successfully completed within the appropriate timeframe, and retained via the appropriate documentation for required duration per records management policy.
   2. Out-of-specification findings, occurrences, and events are investigated and remediated.
   3. Corrective actions to events are fully documented, and data collected in response to a corrective action is reviewed to confirm that the action taken was effective.
   4. Opportunities for continual process improvement are identified and initiated.