PSCIG 1542 Sterile Products Lecture 7 Aseptic Processing PDF

PSCIG 1542: Pharmaceutics II - Sterile Products Aseptic Processing Objectives 1. Define aseptic processing 2. Define/describe control measures used in aseptic processing 3. List the steps/methods necessary for effective aseptic processing 4. Describe the use of basic compoundi...

PSCIG 1542: Pharmaceutics II - Sterile Products Aseptic Processing Objectives 1. Define aseptic processing 2. Define/describe control measures used in aseptic processing 3. List the steps/methods necessary for effective aseptic processing 4. Describe the use of basic compounding equipment using proper aseptic processing controls References and Resources 1. Elder, D. (2018) Chapter 32: General Principles of Sterile Dosage Form Preparation. In A Practical Guide to Contemporary Pharmacy Practice, 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins. Available online at http://pharmacy.lwwhealthlibrary.com/books.aspx 2. McKeon, MR and Peters, GF. (2001) Valiteq™ Aseptic Technique Validation System: Compounding Manual, 2nd ed. Des Plaines, IL: Lab Safety Corporation, pp 10 - 70. 3. Ochoa, PS and Vega, JA. (2015) Concepts in Sterile Preparations and Aseptic Technique, 1st ed. Burlington, MA: Jones & Bartlett Learning, pp 17 - 64; 141 - 173; 175 - 223; 347 - 370. Available on reserve in the library. 117 PSCIG 1542: Pharmaceutics II - Sterile Products Aseptic Processing Quality Assurance: Environmental and Engineering Considerations Any site preparing CSPs must have a formal, written QA program in place through which all activities can be: Monitored Evaluated Corrected Improved in a timely manner. "Protection of critical sites by precluding physical contact and airborne contamination shall be given the highest priority in sterile compounding practice." Methods of Controlling Contamination In order to prevent contamination of compounded sterile products (CSPs) multiple systems are put in place: 1. Engineering Controls include facilities design (flooring, ceiling tiles, shelving, HVAC system, sink placement, etc.) 2. Barrier Controls include items which block contaminant transfer between CSPs and the compounded (personal hygiene (hand scrubbing), gloves, booties, mask, gown, gloves, etc.) 3. Personnel Controls include systems of CSP manipulation within the compounding environment in order to minimize introduction of contaminants during the compounding 118 PSCIG 1542: Pharmaceutics II - Sterile Products process (prepping the environment, placement of supplies, hand placement and product manipulation, etc.) Engineering Controls Engineering controls refer to any mechanical devices used in the compounding environment which assist in the attainment and maintenance of air purity. Such devices include the laminar flow hood(s), heating and cooling systems and air flow systems in addition to the architecture of the clean room itself. The environment should meet the following specifications: Ensure a comfortable working environment Surfaces should be smooth, impervious, free from cracks and crevices, non-shedding, cleanable, and resistant to disinfectants. The environment should be arranged that all nonessential equipment is located outside of the buffer zone or segregated compounding area. 119 PSCIG 1542: Pharmaceutics II - Sterile Products Conceptual Cleanroom Diagrams Segregated Compounding Area (SGA) Cleanroom CATEGORY 1 CATEGORY 2 ISO Air Purity Standards USP Terminology Ante Area At least ISO Class 8 Hand cleansing and garbing; under "dynamic" conditions Staging of components, order entry, labeling, and other high particulate generating activities; Transition area that provide assurance that pressure relationships are maintained for air flow purposes. 120 PSCIG 1542: Pharmaceutics II - Sterile Products Minimizes the needs for ventilation system to respond to large air disturbances; Separated into “dirty” and “clean”(closest to Buffer Area) areas by a line of demarcation or physical separation; ³30 ACPH (or 15 if HEPA filter contributes 15), adjusted based on number of compounding personnel. Buffer Area At least ISO Class 7 Contains the PEC; Segregated from surrounding areas; Limited to preparation and staging of components for use in compounding; Demarcation shall be continuously monitored OR physical separation shall provide at least 0.02 - 0.05 inch water positive pressure differential (see Environmental Sampling). PEC (Primary At least ISO Class 5; Laminar Flow Clean Bench (LFCB): horizontal, vertical, Engineering biological safety cabinet, compounding aseptic Control) Unidirectional, high (containment) isolator; velocity air that sweeps particles from Placed within buffer area such as to avoid conditions that the DCA would adversely affect operations; Shall perform in situ air pattern analysis via smoke studies Only authorized personnel and materials permitted; Per-sterilization procedures (e.g. high risk products) must be completed in at least ISO 8 air; Special conditions for CAI/CACI placement. DCA (Direct (see PEC) Critical area within the PEC where critical sites are Compounding exposed to HEPA filtered air. Area) Segregated -- Designated space restricted to preparing Category 1 Compounding CSPs; Area Contains the PEC; Restricts item and activities unnecessary to sterile compounding. 121 PSCIG 1542: Pharmaceutics II - Sterile Products Environmental Sampling The compounding environment must be periodically sampled for potential contamination issues using qualified personnel as follows: Certification of new equipment or facilities Every (6) months thereafter Following service or repair of equipment of facilities In response to issues with CSPs, personnel work practices, or patient-related infections potentially due to CSPs. Non-Viable Particle Testing http://www.youtube.com/watch?v=FSJ9aCkuSEc Used to test that particle counts, per ISO Standards, are within limits. Equipment generally used for this purpose include electronic particle counters or air membrane filtration devices. Pressure Differential Monitoring Prior to beginning any compounding activity (beginning of day and/or beginning of each shift) the pressure differentials between compounding zones must be checked and recorded to ensure that positive pressure exists from the buffer zone to the ante area. (Note that in the case of hazardous substances compounding a negative pressure relationship should be maintained). The pressure differential should be 0.02 inch water (5 Pa; 0.2 m/s ;40 ft/min). Viable and Airborne Particle Testing https://www.youtube.com/watch?v=2PNwBFs7n1Y The risk of product contamination by viable particles is related to proper hygiene, garbing practices, aseptic technique, and surface contamination. Products utilizing nonsterile components or equipment pose the greatest danger since compounding personnel are responsible for proper terminal sterilization of the product. A sampling and observational auditing program must be put into place in order to assess contamination: At locations within each ISO Class room (i.e. buffer zone, ante area; within the PEC) At locations prone to contamination During compounding, staging, hygiene and garbing procedures and other activities (e.g. "dynamic" conditions) Sampling methods include (*recommended): Impaction (e.g. settling plates)* Electronic air sampling devices (e.g. slit-to-agar plates)* Rodac plates 122 PSCIG 1542: Pharmaceutics II - Sterile Products General growth media such as soybean-casein digest media should be used. Fungi should be assayed for in facilities compounding high risk products using a media that supports fungal growth. Any media used for surface sampling should contain additives that neutralize disinfecting agents (e.g. TSA + lecithin + polysorbate 80). Recommended ACTION LEVELS for Microbial Contamination ISO Class Air Sample (cfu/m3 at 1000 L air)* 5 >1 7 > 10 8 or worse >100 *Identify Genus for further corrective action Cleaning and Disinfection USP outlines procedures for proper cleaning and disinfection of engineering controls, compounding supplies, and personnel. The Ante Area - hand cleansing and garbing occurs in this location along with all uncartoning of shipments. All packaging should be wiped down with 70% sterile isopropyl alcohol (IPA) prior to transfer into the buffer zone. The Buffer Zone - no outer packaging should enter this location nor should it be used for storage or any activities that would be considered high particulate generating Cleaning and Disinfection Guidelines Standard Operating Procedures (SOPs) for all cleaning and disinfection practices should be developed and specific policies should be generated. Compounding personnel are responsible for ensuring that all SOPs are followed! See USP for recommended cleaning/disinfecting agents (e.g. 70% sterile isopropyl alcohol, 0.5% accelerated H2O2, 0.4-1.6% quaternary ammonium , 100-5000 ppm chlorine, 30-50 ppm iodophors). Minimum Frequency of Cleaning and Disinfection Site Minimum Frequency PEC At the beginning of each shift Before each batch Not longer than 30 minutes after the previous disinfection (during continuous compounding) After spills Following known or suspected surface contamination Counters and work surfaces Daily Floors Daily Walls Monthly 123 PSCIG 1542: Pharmaceutics II - Sterile Products Ceilings Monthly Storage/Shelving Monthly The Laminar Flow Cleanbench (LFCB) The LFCB provides an environment with unidirectional HEPA filtered air of ISO Class 5 or better air quality. It is essential to use proper aseptic manipulation technique so that disruption of airflow is minimized and that airflow emanating from the HEPA filter ("first air") is never blocked from contacting critical sites of compounding supplies. HEPA filter - High Efficiency Particulate Air filter that removes > 99.97% of particulates > 0.3 m First Air - the air emanating directly from the HEPA filter, which is the cleanest air Critical Site - a crucial region on compounding supplies which should be kept at the highest level of cleanliness; proper aseptic manipulations should be ensured such that these sites are not physically touched nor blocked from direct contact with first air The Horizontal Flow Cleanbench (HFCB) Airflow emanates from the back of the hood where the HEPA filter is located. Air from the HFCB flows directly out of the front of the hood. Slow, methodical hand movements are required to prevent airflow disruption Repeated removal and insertion of the hands into the hood is discouraged Avoid placing hands behind critical sites as this blocks first air The HFCB (video on Canvas) Types of Contamination During Compounding (video on Canvas) 124 PSCIG 1542: Pharmaceutics II - Sterile Products The Vertical Flow Cleanbench (VFCB) Airflow emanates from the top of the hood where the HEPA filter is located. In a standard VFCB the air flows directly out of the front of the hood. The VFCB The Biological Safety Cabinet (BSC) is a specialized VFCB used when working with hazardous substances (e.g. chemotherapeutic agents). Most commonly a Class II VFCB is used for this purpose. The airflow is designed to not only protect the product from introduced contamination, but also to protect the compounder and exterior environment from being contaminated by hazardous drugs. Avoid placing hands above critical sites The BSC (video on Canvas) 125 PSCIG 1542: Pharmaceutics II - Sterile Products Smoke Split – in a BSC, the airflow splits and diverts air to downdraft vents at the front and back of the hood. At the smoke split there is a “Zone of Confusion” where the airflow is turbulent. Working directly within the smoke split may result in cross contamination of products placed too close together. Restricted Access Barrier System (RABS): Compounding Aseptic Isolator (CAI) / Compounding Aseptic Containment Isolator (CACI) (also Pharmaceutical Isolator) Otherwise known as a “Glove box”, this type of hood provides an environment that is isolated from room air. Placement of these types of hoods may be in a “segregated compounding area”. RABS units (providing HEPA filtered air) must be placed in a Class 7 area for compounding Category 2 or 3 products while a Pharamceutical Isolator (complete internal separatation from the surrounding envirnment) may be placed in a Class 8 area. Preparing to Work in the Laminar Flow Hood (see Laboratory #1) Verify Operational Conditions (see video on Canvas) Ensure that the engineering controls in the cleanroom, including the LFCB, have bee properly maintained. Verification that a working environment is in place PRIOR to the start of compounding (e.g. through log checks or visual observation) is necessary. Items include: checking pressure differentials between the hood and buffer room or buffer room and ante area; checking the maintenance of the LFCB: a. Pre-filters should be changed MONTHLY b. The HEPA filter should be changed every 6 MONTHS or whenever the hood has been moved, had scheduled maintenance, or suspected damage has occurred (e.g. impact against the filter, accidental exposure to liquids). Establish the Aseptic Field Prior to working in the hood, the air quality must be brought to ISO Level 5: 126 PSCIG 1542: Pharmaceutics II - Sterile Products a. Allow the LFCB to run for 15-30 minutes prior to use b. Clear all unnecessary items from the hood (NO paper, pens, books, etc.) Clean the LFCB Clean the LFCB before each shift, in between products, and every 30 minutes (e.g. during long/complex processes). 1. Begin with a low residue, water based cleaner and disinfectant to remove any residual dirt or drug residue (see Laboratory #1 for proper cleaning methods). 2. Follow with sterile 70% isopropyl alcohol (IPA) and allow to dry 3. Always wipe from *CLEAN-TO-DIRTY using non-overlapping strokes (*clean = closest to HEPA filter) 4. DO NOT spray cleaner directly into the HEPA filter (saturate wipes first) There are slight variances in the order of cleaning for a HFCB (start at top and do not clean the back) and VFCB (start at the back and do not clean the top) (see laboratory #1 for more information). Additional protocols are used when cleaning the BSC to prevent cross contamination with hazardous substances (see video on Canvas). Working Inside the LFCB Process Planning Plan the process BEFORE you start to ensure you do not have to leave the hood once compounding is begun. CHECK STAGE Check calculations SUPPLIES Wipe down with SUPPLIES Think through the Identity sterile 70% IPA Place supplies process! Concentration logically Expiry Critical sites in first Integrity air OBTAIN CLEAN SUPPLIES SUPPLIES 127 PSCIG 1542: Pharmaceutics II - Sterile Products Staging Supplies (placement) (see video on Canvas) 1. Choose proper equipment (see Basic Compounding Equipment) 2. Keep critical sites in first air at all time a. Do not place supplies directly in front of each other to prevent downstream contamination b. Syringe should be places with the needle/hub pointing toward the back of the hood c. IV bags should be placed with the injection site pointing toward the back of the hood (or hung from the IV pole [in a HFCB only]). Bags may temporarily be moved to inject additives in order to increase accuracy and safety. 3. Prevent cross-contamination a. Do not place supplies within 6” of the front of the hood or 3” from the sides/back of the hood to prevent airflow disruption and cross-contamination b. Do not place supplies too close to one another (i.e. within 3”) to allow for ease of accessibility during compounding and to prevent cross-contamination from disrupted airflow. ‘ Barrier Controls Barrier controls consist of any type of process that minimizes risk of cross contamination between the compounder and the compounded sterile products (CSP). 1. Personal Hygiene 2. Remove all jewelry (rings, watch, bracelets, necklaces, earrings, etc.) 3. No makeup, nail polish, synthetic (“fake”) nails 4. No eating, drinking, chewing gum, applying makeup 5. Pull long hair back to completely contain it within the bonnet/cap; males must be free of facial hair or must cover moustache/beard with a covering 6. No unnecessary talking while working in the cleanroom 128 PSCIG 1542: Pharmaceutics II - Sterile Products Hand Scrubbing and Garbing (see Laboratory #1) Scrubbing and Gloving Procedures Garbing Procedures (see video on Canvas) (see video on Canvas) 1. Don mask, bonnet/cap, and shoe covers 2. Scrub hands according to institutional protocol (e.g. thorough hand washing with antimicrobial soap) 3. Don gown or chemo-resistant gown 4. Re-sanitize hands with gel based sanitizer, allow to dry, and don snug-fitting sterile gloves over the gown cuffs (double glove with resistant gloves when working with hazardous substances) 5. Other personnel protective equipment (PPE) as recommended: goggle, face mask, respirator Personnel Controls A series of systems put into place that ensure the sterility of CSPs is maintained. These systems include behaviors and skills of compounding personnel in use prior to, during and after compounding of sterile products. 129 PSCIG 1542: Pharmaceutics II - Sterile Products Personnel Training Topics that must be covered include the principles and practices of: o Hygiene o Garbing o Aseptic manipulation o Achieving and maintaining ISO Class 5 environments o Cleaning and disinfection procedures Must complete didactic training, pass a written competency assessment, and undergo skills assessment (observation and media fill test) prior to aseptic compounding If an assessment is failed, retraining must occur and reassessment must be passed prior to beginning/continuing work Housekeeping and other personnel also need to be trained in hygiene, garbing, cleaning and disinfection protocols with routine evaluation Competency evaluation must be documented and a record maintained Evaluation must be repeated every 12 months 130 PSCIG 1542: Pharmaceutics II - Sterile Products Competency Evaluations and Action Levels Prior to compounding sterile products, all compounding personnel must pass competency assessment. Assessments should be done in order to capture normal working conditions such as length or process, complexity of CSPs normally encountered, and working conditions (e.g. number of personnel in room). Garbing Competency Before sterile compounding, compounding personnel must pass at least 3 separate garbing evaluations in succession which includes: Visual observation of hand hygiene and garbing procedures, followed by Gloved fingertip and thumb sampling (GFT) Aseptic Manipulation Competency Following a passing garbing evaluation, compounding personnel must pass evaluation in aseptic manipulation including: Visual observation Media-fill testing GFT testing following completion of compounding Surface sampling of the direct compounding area Passing GFT Test Gloved Fingertip and Thumb Sampling Action Levels (cfu, total from both hands) After garbing >0 After media-fill testing (see below) >3 Competency assessments (both garbing and aseptic manipulation) shall be completed every 6 months (Category 1 and 2) or 3 months (Category 3) thereafter. Quality Assurance: Compounded Sterile Products Compounding Policies and Procedures Policies and procedures must be put into place in order to assess compounding quality assurance (QA). Such policies should include the following: When an item cannot be validated, verified, or identified it MUST be discarded Validate moisture content upon storage Quantitative stability-indicating assays should be performed (recommended) Validate Sterilization Methods using biological indicators NO food, drinks, material exposed in patient areas are allowed into the compounding area If blood or other biologic fluids are needed in compounding, they must be clearly separated from routine use areas. 131 PSCIG 1542: Pharmaceutics II - Sterile Products Final Product Quality Assurance Before release of a product it should be checked for quality according to quality assurance protocols in place at the institution. Such policies should include the following: Visual observation for particulates, discoloration, leakage, etc. Inspection of the order, procedures, and compounding records. Check materials for: o accuracy o identity o quantity o aseptic processing o packaging o labeling o appearance Use a "double-check" system Don't throw anything away until all inspection and checking is complete Someone other than the compounder should check ingredients and volumes (if possible) Quality Control Tests for Product Release Sterility Test Direct inoculation Membrane filtration Pyrogen Test Rabbit test (not used much anymore; industrial) Endotoxin Test Limulus Amoebocyte Lysate Assay (LAL) Particulate Matter Test Light obscuration Microscopy Preservative Efficacy Test Container-Closure Integrity If products are dispensed before results of sterility testing are received, a protocol must be in place for recall and/or patient and physician notification To identify correct identity and quality of CSPs, facilities "shall": o Be labeled appropriately (see General Laboratory Guidelines for specifics) o Compare the original order to the compounding records o Verify the correct fill volumes and quantities either by direct observation or assay. 132 PSCIG 1542: Pharmaceutics II - Sterile Products Perform appropriate post-compounding clean-up: o Place waste into appropriate containers (e.g. sharps in red-box sharps containers ONLY, etc.) o DO NOT RECAP NEEDLES BY HAND – use the “scoop method” or directly dispose of into a red sharps container CSP Packaging, Handling and Transport () Pharmacy is responsible for quality and control of CSP until administration o Develop SOPs and training mechanisms for in-pharmacy and non-compounding personnel Evaluate the effect of the transport mechanism and conditions of the product (e.g. shaking in a pneumatic tube system) o Choose packaging that maintains stability, purity, and physical integrity of the CSP o Avoid leaking, contamination, degradation, etc. o Include handling, opening, and storage instructions for the receiver Use tamper evident seals Chemo/ radiopharmaceuticals/ other hazardous substances should be transported with great care to prevent spilling. Have spill protocols in place. Label will prominently display storage conditions and BUD Monitor storage conditions in the pharmacy (daily) and other locations (monthly) for storage conditions, proper separation of drugs, reuse of single versus multiple-dose vials, security of medication in patient care areas o For home health, ensure that proper labeling instructions are provided and that the site can store the products properly Stability and sterility assurances of CSPs outside the pharmacy (e.g. hygiene, proper techniques, effects of temperature) Professional judgment in re-dispensing unused/unopened CSPs (sterility, stability, purity); reassign BUD of if there is supporting evidence Develop and administer training and education for home health care patient/caregiver and continually monitor STUDY GUIDE 1. Describe the three main methods of controlling contamination 2. Describe engineering controls (hood, room design, ISO criteria) and their proper use in contamination control. a. Describe the characteristics of the ante room, buffer area, and PEC 133 PSCIG 1542: Pharmaceutics II - Sterile Products b. Define first air, critical site, and HEPA c. Explain the proper methods for preparing the compounding environment (filter changes, how long the hood should be left on, cleaning and disinfection procedures) – refer also to Laboratory #1 information 3. Explain the different types of environmental sampling that are required a. Understand what an “action level” is for microbial contamination. b. Understand the requirements for cleaning and disinfection (KNOW the frequency for cleaning the PEC). 4. Understand what personnel training entails and how it is assessed. a. Describe the proper use of barrier controls. b. Explain the proper procedures for scrubbing and garbing c. Explain the proper use of basic compounding equipment within the sterile environment (e.g. staging, hand placement, etc.; the practical application of these concepts will also be tested on the laboratory practical exam). 134