PSCIG 1542 Sterile Products Lecture 6 PDF

PSCIG 1542: Pharmaceutics II - Sterile Products Reference Materials and USP Chapter Pharmaceutical Compounding – Sterile Preparations Objectives 1. Understand and explain the guidelines in USP related to sterile product preparation; a. Be able to assign an appropriate Category to a co...

PSCIG 1542: Pharmaceutics II - Sterile Products Reference Materials and USP Chapter Pharmaceutical Compounding – Sterile Preparations Objectives 1. Understand and explain the guidelines in USP related to sterile product preparation; a. Be able to assign an appropriate Category to a compounded sterile product; 2. Understand how to use King’s Guide to Parenteral Admixtures and the Handbook on Injectable Drugs; 3. Understand additional criteria for hazardous product and radiopharmaceutical compounding (USP and ) 4. Be able to assign an appropriate beyond use date (BUD) to a compounded sterile product using all available resources. References and Resources 1. United States Pharmacopeia (43) – National Formulary (38). United States Pharmacopeial Convention: Rockville, MD, 2020. Available online through http://library.midwestern.edu/mwuhome. Click on the link through the library to register for a username and password to access the USP-NF. Pertinent chapters: USP , USP , USP. 2. McEvoy, GK. Handbook on Injectable Drugs, 20th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2018. Searchable database version available through MWU Libraries under Micromedex > I.V. Compatibility: http://library.midwestern.edu/pharmacy. 3. King Guide to Parenteral Admixtures. Napa, CA: King Guide Publications, Inc.; 2012. Searchable database version available through MWU Libraries under Lexicomp > I.V. Compatibility: http://library.midwestern.edu/pharmacy. 99 PSCIG 1542: Pharmaceutics II - Sterile Products History of USP Revision implemented Nov. 1, 2023 100 PSCIG 1542: Pharmaceutics II - Sterile Products Objectives and Responsibilities Responsibilities of Compounding Personnel Accurately identify, measure, dilute, and mix CSPs Correctly purify, sterilize, package, seal, label, store, dispense, and distribute CSPs Ensure that CSPs maintain labeled strength within monograph limits for USP articles or ±10% if not specified Prepare and follow a written quality assurance protocol to determine accuracy and precision, identity, purity, and stability Responsibilities of the Pharmacist and Other Healthcare Providers Train, educate, and observe the performance of personnel and document activities such as hand cleansing, selection of appropriate garb, aseptic technique, measuring and weighing, and proper use of engineering controls Validate the identity, purity, and quality of all ingredients Properly store all items under appropriate restricted access where necessary Ensure all non-sterile aqueous products are sterilized within (6) hours Validate that sterilization methods work while maintaining the strength and stability of the CSP and packaging Ensure all measuring, mixing, sterilizing, and purifying equipment is clean and accurate/effective 101 PSCIG 1542: Pharmaceutics II - Sterile Products Evaluate potential harm and effect on bioavailability of admixtures Ensure packaging is appropriate Ensure the compounding environment maintains sterility and purity Ensure labels are appropriately prepared Ensure beyond use dating is assigned appropriately Ensure all compounding protocols conform to the correct sequence and quality for the CSP Ensure that any deficiencies in compounding, labeling, packaging, and quality testing/inspection can be rapidly identified and corrected Ensure compounding manipulations and procedures are separated from post compounding quality inspection and review (when possible) USP , CATEGORY, & B.U.D. ASSIGNMENT Assignment of Risk of Contamination 1. Evaluate the probability of contamination (microbial, chemical, physical) Note: USP beyond use dates are based solely on the risk of microbial contamination. One must use appropriate drug information resources (see below) to determine if a more conservative beyond use date should be assigned based on physical or chemical stability. Increases in the USP BUD cannot be made without proof of a passing sterility and endotoxin test or proof of stability. 2. Evaluate sources of contamination a. How many sources are there? b. What are the sources (personnel, non-sterile components, etc.)? c. What is the compounding protocol (complicated manipulations, lengthy procedure, cleanroom vs. SGA)? Drug Information Resources Beyond use dating of compounded drug products is typically assigned based on the stability of the product (e.g. chemical and/or physical stability). Recall, for non-sterile drug products the following general USP guidelines (Chapter ; updated implemented Nov. 1, 2023) are typically followed: Dosage Form BUD* Aqueous Dosage Forms (aw  0.6): emulsions, gels, creams, sprays, solutions, suspensions Non-preserved 14 days, refrigerated Preserved 35 days, controlled room temperature or refrigerated Non-Aqueous Dosage Forms (aw < 0.6): capsules, tablets, granules, powders, nonaqueous topicals, suppositories, troches or lozenges, nonaqueous liquids (non-oral) Oral liquids (nonaqueous) 90 days, controlled room temperature or refrigerated Non-aqueous dosage forms 180 days, controlled room temperature or refrigerated 102 PSCIG 1542: Pharmaceutics II - Sterile Products However, beyond use dating can be extended if there is supporting physical and chemical stability data. This is not the case with compounded sterile products (CSPs). For CSPs USP dictates the maximum beyond use dating (in the absence of microbial and endotoxin testing) based upon potential microbial stability. Additional references are used to assess physical or chemical stability to determine if beyond use dating should be decreased for a particular drug product. Best professional judgement should be used when choosing a BUD. Considerations for Assigning a BUD Presence of water (hydrolysis) Container / packaging Compatibility with diluents (dilution) Duration of therapy Compatibility with additives Assumptions / extrapolation of data Storage conditions (temperature, light) Level of control (e.g. institutional versus home health care) The most common issue is hydrolysis (aqueous preparations), which also exhibit increased degradation in the presence of heat. Always refer to manufacturer's recommendations, appropriate, references, and/or direct stability testing data when determining an appropriate BUD. For proprietary bag and vial systems, the manufacturer's recommended BUD may be used. Storage areas should be monitored (daily and/or via continuous recording). USP Temperature Ranges Controlled Room Temperature 20 - 25 oC Controlled Cold Temperature 2 - 8 oC Freezing Temperature –25 - –10 oC The most common resources used for assessing beyond use dating for CSPs are: 103 PSCIG 1542: Pharmaceutics II - Sterile Products 1. ASHP Injectable Drug Information – A Comprehensive Guide to Compatibility and Stability. Bethesda, MD: American Society of Health-System Pharmacists, ASHP; 2023. McEvoy, GK. Handbook on Injectable Drugs, 20th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2018. Searchable database version available through MWU Libraries under Micromedex or Facts & Comparisons > Trissel’s I.V. Compatibility: http://library.midwestern.edu/pharmacy. Reference guide containing parenteral stability and compatibility monographs arranged alphabetically according to generic name. Includes bibliography of primary references for stability data. Designates if a combination product (admixture) is compatible (C ) or incompatible (I) and supplies comments/remarks regarding the conditions for the designation. 104 PSCIG 1542: Pharmaceutics II - Sterile Products 105 PSCIG 1542: Pharmaceutics II - Sterile Products 106 PSCIG 1542: Pharmaceutics II - Sterile Products 2. King Guide to Parenteral Admixtures.[online database] Napa, CA: King Guide Publications, Inc.; 2023. Searchable database version available through MWU Libraries: http://library.midwestern.edu/pharmacy; https://kingguide.com/kgpa2/x1.asp Reference guide containing parenteral stability and compatibility monographs arranged alphabetically according to generic name. Includes bibliography of primary references for stability data. Updated quarterly. Designates if items are compatible (C), incompatible (X), or if conflicting information is available (). 107 PSCIG 1542: Pharmaceutics II - Sterile Products 3. Package inserts. 108 PSCIG 1542: Pharmaceutics II - Sterile Products 4. Other Resources: Primary Literature, Databases, Reference Materials and Textbooks (i) Sheskey, PJ, Cook WG and Cable, CG, eds. Handbook of Pharmaceutical Excipients. London: Pharmaceutical Press, 2017. Searchable database version available through MWU Libraries under Medicines Complete: http://library.midwestern.edu/pharmacy. (ii) Brayfield, A (ed). Martindale – The Complete Drug Reference. London: Pharmaceutical Press. Searchable database version available through MWU Libraries under Medicine Complete: http://library.midwestern.edu/pharmacy. (iii) The Merck Index. Whitehouse Station, NJ: Merck & Co, Inc. Available online through MWU at https://www/rsc/org/merck-index. Alphabetical list of chemical monographs. (iv) Remington: The Science and Practice of Pharmacy, 23rd ed. Philadelphia, PA: University of the Sciences in Philadelphia. Searchable reference available through MWU Libraries under Medicines Complete: http://library.midwestern.edu/pharmacy. Comprehensive information on pharmacy practice, including pharmaceutical compounding, manufacturing, and analysis information. (v) United States Pharmacopeia – National Formulary (USP-NF). Rockville, MD: USP. Available online through MWU Libraries: http://library.midwestern.edu/pharmacy. The National Formulary lists pharmaceutical excipients and methods of validation of strength and purity. However, the text may not list the common uses for each excipient. (vi) Allen, L , Popovich, N and Ansel, HC (eds). Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia, PA: Lippincott Williams & Wilkins. Searchable reference available through MWU Libraries under LWW Health Library: http://library.midwestern.edu/pharmacy. 109 PSCIG 1542: Pharmaceutics II - Sterile Products Category Selection Note that mixing, reconstituting or other such acts performed according to the manufacturer’s package insert directions are not considered compounding as long as (1) the product is prepared as a single dose for a single patient and (2) the approved labeling includes the diluent, resultant strength, container closer system,, and storage time. “Immediate Use” Products A special case is made for "immediate use products" to be compounded in poorer than ISO Class 5 air and used within 4 hours if the following criteria are met: Aseptic processes are followed and written procedures are in place to minimize potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, and mix-ups with other conventionally manufactured products; The preparation is performed in accordance with evidence-based information for physical and chemical compatibility of the drugs; The preparation involves not more than 3 different sterile products; 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; Administration begins within (4) hours of the start of preparation, otherwise the product must be discarded; Must bear a label with the exact beyond use time (4 hours) if not immediately and completely administered by the person preparing the CSP. Also note that preparation of a proprietary bag and vial system for immediate use according to the manufacturer instructions is not considered compounding and is not subject to USP Category requirements. However, preparation of such a system for future use must follow BUD guidelines for Category 1 or 2 as stated above. 110  Starting Compounding Sterility Room Refrigerated Frozen Components Method Testing Temperature and/or Performed and (2oC to 8oC) (-25oC to -10oC) Equipment Passed? (20oC to 25oC) Segregated Compounding Area (SGA) YES 12 hr or less 24 hr or less An unclassified Aseptically space with a processed defined perimeter STERILE NO containing a PEC Compounding Environment CATEGORY 1 YES 30 days 45 days 60 days Aseptically processed NO 4 days 10 days 45 days Cleanroom Suite STERILE A classified area YES 45 days 60 days 90 days containing an ante Terminally area (ISO Class 8 or sterilized better) and a buffer NO 14 days 28 days 45 days area (ISO Class 7 or better) containing a PEC (ISO Class 5) YES 30 days 45 days 60 days Aseptically CATEGORY 2 processed NO 1 days 4 days 45 days NONSTERILE YES 45 days 60 days 90 days Terminally sterilized NO 14 days 28 days 45 days Terminal sterilization = autoclave, dry heat, or irradiation Aseptic processing = use of aseptic technique with all sterile starting ingredients and/or filtration of final product using aseptic methods Category 3 A third category has been added to the proposed guidelines in response to comments that allows for extended BUD with increased training and cleaning requirements as well as additional sterility, endotoxin, and other testing as dictated by Category 3 requirements for: Compounding Controlled Room Refrigerated Frozen Method Temperature Aseptically 60 days 90 days 120 days processed CSPs Terminally 90 days 120 days 180 days sterilized CSPs Source Ingredients What is a Compounded Sterile Product (CSP)? Sterile biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals (see ) Sterile aqueous bronchial and nasal inhalation Baths and soaks for live organs and tissues Injections (all dosage forms) Irrigations for wounds and body cavities Ophthalmic drops and ointment Tissue implants Any manufactured sterile product prepared either strictly according to product package insert instructions or differently than such labeling states Single and Multiple Dose Containers (manufactured products) Once opened/punctured, manufactured products will have the following beyond use times: BEYOND USE TIME* Single Dose Container Multi-Dose Container Opened or needle punctured vial or bag in discard