USP Chapter 797>: De-mystifying Beyond
Transcription
USP Chapter 797>: De-mystifying Beyond
USP Chapter <797>: De-mystifying Beyond-Use Dating Eric S. Kastango, MBA, RPh, FASHP Clinical IQ, LLC Florham Park, NJ ClinicalIQ content © 2009, ClinicalIQ, LLC Special Thanks David W. Newton, PhD, FAPhA for his tutelage and forbearance regarding the establishment of beyond-use dating and the fundamentals of chemical drug stability. y Since 2000, his leadership as the Chairman of the USP Sterile Compounding Committee has been instrumental in making patient care safer. y ClinicalIQ content © 2009, ClinicalIQ, LLC Disclaimer “Although I am a member of the USP Sterile Compounding Expert Committee, I am speaking today in my individual capacity and not as a member of the Committee or as a USP representative. The views and opinions presented are entirely my own. They do not necessarily reflect the views of USP, nor should they be construed as an official explanation or interpretation of <797>.” ClinicalIQ content © 2009, ClinicalIQ, LLC 3 Beyond-Use Dating (BUD) ClinicalIQ content © 2009, ClinicalIQ, LLC USP <797> Risk Level High Risk Use non-sterile components (ex: epidurals, alum) Medium Risk Uses multiple sterile components. (ex: batch compounding, TPNs) Low Risk Simple, or single, sterile component mixing (ex: one vial into one delivery container) No Risk (premixed or RTU single doses) ClinicalIQ content © 2009, ClinicalIQ, LLC Parameters for Establishing BUD y Recognizes the probability of contamination even under best conditions: ◦ Optimal employee performance x 0.1% (1 contaminated dose out of 1,000) ◦ Contamination rates published in the literature x 0.3% – 16% y y Patient Safety: Protect patients from dangerous or even fatal overgrowths of microorganisms that may have been accidentally introduced Storage time: needs to be greater than zero but less than positive infinity* ◦ (> 0 and < +∞) * Personal conversation with Dr. David W. Newton, September 30, 2009 ClinicalIQ content © 2009, ClinicalIQ, LLC BUD: Microbiological Limits y y y Must factor in chemical stability Extended storage of drugs not an initial consideration (greater than 2 weeks) Concern that microbial over-colonization of solutions would occur over time. ◦ pH of solution is a consideration x Neutral (pH 6-8) favorable for microbial colonization y Concern for proper storage conditions ◦ Floor inspections and temperature checks ClinicalIQ content © 2009, ClinicalIQ, LLC Ice-cold Milk http://www.sustainableisgood.com/blog/2008/07/sams-club-squar.html ClinicalIQ content © 2009, ClinicalIQ, LLC Enemies of the State: Time and Temperature Newton, DW. Three Drug Stability Lives. International Journal of Pharmaceutical Compounding 2000; 4:190-193 ClinicalIQ content © 2009, ClinicalIQ, LLC Enemies of the State: Time and Temperature Newton, DW. Three Drug Stability Lives. International Journal of Pharmaceutical Compounding. 2000; 4:190-193 ClinicalIQ content © 2009, ClinicalIQ, LLC Non-Visibility of Microbial Contamination Numbers of Bacteria per mL in 1L bottles Millipore Corp. Hospital Pharmacy Filtration Guide (Cat. No. MP801) Bedford, MA; 1980:3 ClinicalIQ content © 2009, ClinicalIQ, LLC Microbial Growth in PN solution The results of incubating four microorganisms: Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilis, and Candida albicans, (50 to 1000 cfu/mL) at undefined ambient room temperature (likely 20o-25oC or 68o-77oF) for 72 hours in 4.25% amino acids and 25% dextrose at pH 6.2 Organism Approximate Colony Forming Units per mL and % Changea 0 hour 3 hours 24 hours 48 hours 72 hours 1000, 0% 400, -60% 250, -40% 125, -50% 100, -20% Pseudomonas a 300, 0% 200, -33% 80, -60% 25, -70% 10, -60% Klebsiella p 150, 0% 30, -80% 15, -50% 10, -33% Staphylococcus a 150, 0% 1000, 0% 200, -80% 15, -93% 3, -80% 0, -100% Bacillus s 30, 0% 20, -33% 100, 400% 125, 25% 150, 20% Candida a Rowlands DA, Wilkinson WR, Yoshimura N. Storage stability of mixed hyperalimentation solutions. Am J Hosp Pharm. 1973; 30:436-438. aValues estimated from graphed lines in Figure 1. ClinicalIQ content © 2009, ClinicalIQ, LLC BUD: Microbiological Limits y USP risk levels focus on microbial risk to patient ◦ Principle source: breach of aseptic technique y Vary in duration by risk Level • Greater # of aseptic manipulations, the greater the risk of microbial contamination, shorter the BUD y Applied whenever an actual sterility test in accordance with USP Chapter <71> has not been performed ClinicalIQ content © 2009, ClinicalIQ, LLC BUD: Microbiological Limits y y Most shelf life labels or listed expiration dates are used as guidelines based on normal handling of products. Use prior to the BUD does not necessarily guarantee the safety of the drug. Thus, immediately after the date, a CSP is not always dangerous nor ineffectivea. a Report 1 of the Council on Scientific Affairs (A-01) Full text: Pharmaceutical Expiration Dates. American Medical Association, June 2001. AMA Policy H-115.983 ClinicalIQ content © 2009, ClinicalIQ, LLC Contamination Events Basic tenets of proper hand hygiene and aseptic technique typically ignored y Some of the “best” providers working in optimal environments have had incidences of CSP contamination y All dosage forms have been contaminated y ◦ SDVs, MDVs, SVPs, LVPs and syringes ClinicalIQ content © 2009, ClinicalIQ, LLC Pharmacy Urban Legend: Chemotherapy drugs have an antimicrobial effect • • • • • • • • • • • • • • • Cisplatin- Inhibits microbial growth (1) Cladribine- No antimicrobial effect (2) Cytarabine- No antimicrobial effect (3) Docetaxel- No antimicrobial effect (2) Doxorubicin HCl- No antimicrobial effect (4; 5) Etoposide phosphate- No antimicrobial effect (5; 6) Floxuridine- No antimicrobial effect (4) Fludarabine phosphate- No antimicrobial effect (2) Fluorouracil- Inhibits microbial growth (3; 7; 8) Gemcitabine HCl- No antimicrobial effect (2) Idarubicin HCl- No antimicrobial effect (2) Irinotecan HCl- No antimicrobial effect (6) Paclitaxel- No antimicrobial effect (2) Pentostatin- No antimicrobial effect (2) Topotecan HCl- Inhibits microbial growth (9) ClinicalIQ content © 2009, ClinicalIQ, LLC References 1. Holmes CJ, Kubey WY. Viability of microorganisms in fluorouracil and cisplatin small-volume injections. Am J Hosp Pharm 1988; 45:1089-91. 2. Kramer I. Viability of microorganisms in novel antineoplastic and antiviral drug solutions. J Oncol Pharm Pract 1998; 4:32-7. 3. Briceland LL, Fudin J. Evaluation of microbial growth in selected inoculated antineoplastic solutions. Hosp Pharm 1990; 25:338-40. 4. Gaj E, Sesin GP. Evaluation of growth of five microorganisms in doxorubicin and floxuridine media. Pharm Manufacturing 1984; 1:50, 52-3. 5. Yuan P, Grimes GJ, Shankman SE, et al. Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate in 0.9% sodium chloride injection. Am J Health-Syst Pharm 2001;58:594-8. (NOTE: USP Preservative Effectiveness test performed.) 6. Karstens A, Kramer I. Viability of micro-organisms in novel anticancer drug solutions. Eur J Hosp Pharm Sci 2007; 13:27-32. 7. Gaj E, Griffin RE, Evaluation of growth of six microorganisms in fluorouracil, bacteriostatic sodium chloride 0.9%, and sodium chloride 0.9% media. Hosp Pharm 1983; 18:348-49. 8. Holmes CJ, Kubey WY. Viability of microorganisms in fluorouracil and cisplatin small-volume injections. Am J Hosp Pharm 1988;45:1089-91. 9. Patel K, Craig SB, Mcbride MG, et al. Microbial inhibitory properties and stability of topotecan hydrochloride injection. Am J Health-Syst Pharm. 1998; 55:1584-7. ClinicalIQ content © 2009, ClinicalIQ, LLC Expiration Date: History y y y Under Section 501(a)(2)(B) of the federal Food, Drug and Cosmetic Act (FDCA), manufacturers of prescription drug products must establish controls for the manufacture, processing, packing, and holding of drug products to ensure their safety, identity, strength, quality, and purity. Requirements for these controls, also known as current good manufacturing practices (CGMPs), are established and monitored by the FDA. Expiration dates only apply when the drug product is stored in the manufacturer’s original, unopened container under defined conditions. ClinicalIQ content © 2009, ClinicalIQ, LLC Expiration Date: History y y As part of the CGMP regulations, the FDA requires that drug products bear an expiration date determined by appropriate stability testing (21 CFR 211.137 and 211.166). The FDA defines an expiration date as “the date placed on the container/labels of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications if stored under defined conditions, and after which it may not be used.” ClinicalIQ content © 2009, ClinicalIQ, LLC Expiration Dates y y y Applies to manufactured drug products Determined by multiple, scientifically valid, product/package-specific research studies Based on the Arrhenius Equation ( statistical analysis ) with ◦ Formula for rate of a chemical reaction x Oxidation, Hydrolysis and Reduction y y y Strict, specific, and proven to be valid Approved by the FDA USP 24/NF 19, <795>, and <797> requires that the label of an official drug product bear an expiration date. ClinicalIQ content © 2009, ClinicalIQ, LLC Svante August Arrhenius ClinicalIQ content © 2009, ClinicalIQ, LLC Beyond-Use Dating y y y y Once the manufacturer’s container is opened and the drug product is transferred to another container for dispensing or repackaging, the expiration date no longer applies. The USP has developed recommendations for pharmacists to place a “beyond-use” date on the label of the new container. The “beyond-use” date can be no longer than the manufacturer’s expiration date and often may be shorter, i.e., one year for repackaged unit-dose orals. Unlike expiration dates, there is little scientific basis for beyond-use dating. ClinicalIQ content © 2009, ClinicalIQ, LLC Beyond-Use Dating (BUD) y The American Pharmacists Association (APhA) encourages, and 17 states require, that pharmacists place a “beyond-use” date on the label of the prescription container that is dispensed to the patient. y Based on the BUD on the drug’s chemical stability in conjunction with microbiological limits for patient safety. ClinicalIQ content © 2009, ClinicalIQ, LLC Microbial Populations in the Digestive Tract of Normal Humans Stomach Jejunum Ileum Colon Viable bacteria per gram 0 - 103 0 - 104 105 - 108 1010 - 1012 pH 3.0 6.0-7.0 7.5 6.8-7.3 The gastrointestinal tract is sterile at birth, but colonization typically begins within a few hours of birth, starting in the small intestine and progressing caudally over a period of several days. In most circumstances, a "mature" microbial flora is established by 3 to 4 weeks of age. http://www.vivo.colostate.edu/hbooks/pathphys/digestion/basics/gi_bugs.html ClinicalIQ content © 2009, ClinicalIQ, LLC USP <797> Focus: People and Work Practices y We are all microbially-contaminated and error-prone y USP Chapter <797> notes that human transfer of microorganisms via direct contact is the principal cause of contaminated CSPs y Poor work practices contaminate more CSPs that any other cause y Britain’s NHS recognizes this with a new effort among staff to reduce hospital-acquired infections • No neckties, white coats, fake nails, or jewelry • Bare below the elbows ClinicalIQ content © 2009, ClinicalIQ, LLC Direct Contact Contamination ClinicalIQ content © 2009, ClinicalIQ, LLC Ideal Microbial Growth* y Depending on the particular organism, ideal microbial growth factors feature, but are not limited to, presence of particular carbohydrate and protein nutrients, optimum pH range (6-8 for bacteria and 5-6 for fungi), optimum temperature range, and an oxygen-rich or carbon dioxide-rich environment. y When introduced into a new and finite ideal environment, a population of bacteria and/or fungi exhibits four stages of growth, which are illustrated in Figure 1, and estimated in parts 1-4 below for a hypothetical 24-hour duration. * A review of Bacterial and Fungal Growth Rates: Implications for Immediate-Use Compounded Sterile Drugs for Virginia Board of Medicine. David W. Newton, October 12, 2009. ClinicalIQ content © 2009, ClinicalIQ, LLC Ideal Microbial Growth y Figure 1: Theoretical Rate Curve of Ideal Microbial Growth ClinicalIQ content © 2009, ClinicalIQ, LLC Ideal Microbial Growth y y Lag Phase ◦ Little to no increase in population. ◦ Lag phase is longer in less than ideal environments. Exponential or Logarithm Growth Phase ◦ The duration is micro-organism specific but range for 1-4 hours. ◦ Binary cell population doubling or generation times range from 20 minutes for Escherichia coli to more than 20 hours for Treponema pallidum (syphilis) or Mycobacterium tuberculosis. ClinicalIQ content © 2009, ClinicalIQ, LLC Ideal Microbial Growth y Figure 1: Theoretical Rate Curve of Ideal Microbial Growth ClinicalIQ content © 2009, ClinicalIQ, LLC Ideal Microbial Growth y Stationary Phase: All nutrients are exhausted in the finite environment. Duration 4-12 hours y Death Phase: Microorganisms die rapidly from lack of nutrients. Begins after 6-20 hours. Progression to cell death, also called Apoptosis www.realscience.us ClinicalIQ content © 2009, ClinicalIQ, LLC Microbial Population Table Approximate Cell Population Quantitya Doubling Time, d Growth Time, t At Time = 0b At Time = t 20 minutes 1 hour 50 400 20 minutes 4 hours 10 41,300 4 hours 1 hours 50 60 4 hours 10 hours 10 60 aThis quantity is typically described as the number of colony forming units, or cfu. quantities of microorganisms that may be introduced by inadvertent direct contact, e.g., human touch or secretions, into non-nutrient sterile solutions during clinical practice. bTheoretical The table above illustrates population increases for two population doubling or generation times according to the equation, Nt=Nox2t/d, where Nt = cell population quantity at time, t; No = cell population quantity at time of inoculation, t = time of cell population quantity measurement, and d = cell population doubling or generation time. ClinicalIQ content © 2009, ClinicalIQ, LLC Calculated Microbial Growth Time (Hours) Microbial Count (CFU per mL) 6 10 9 640 12 41,000 18 1.7 X 107 24 6.9 X 109 Cundell AM, USP Committee on Analytical Microbiology, Pharmacopeial Forum 2002; 28 (6) Stimuli to the Revision Process ClinicalIQ content © 2009, ClinicalIQ, LLC Environment vs. Personnel “ The most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded. ” Thomas M, Sanborn M, Couldry R. I.V. admixture contamination rates: Traditional practice site versus a class 1000 cleanroom. Am J Health-Syst Pharm 2005;62:2386-92. ClinicalIQ content © 2009, ClinicalIQ, LLC Compounding Personnel y y y y y 1954, Charles Schultz Copyright, United Feature Syndicate, Inc. ClinicalIQ content © 2009, ClinicalIQ, LLC A person in a cleanroom is considered a broad spectrum particle generator enclosed by inefficient mechanical filters which may also be sources of particles The human body harbors an average of 150-200 different classes of bacteria Hands have an average of 100,000 organisms / sq mm The body sheds 5 grams of skin fragments each day along with shedding 1 layer of skin every 5 days (size range 10 to 300 micron – 1000th of a mm) “Our greatest asset and also our biggest liability!” Sources of Microbial Contamination in Aseptic Processing* Ranks Source 1986 2001 Personnel 1 1 Human error 2 2 Aseptic assembly 4 3 Non-routine activity 3 4 Mechanical failure 5 5 Airborne contaminants 7 6 Improper sanitization 6 7 Surface contaminants 7 7 0.2 µm filter failure 8 8 HEPA failure 9 9 *AgallocoJ, Akers J, MadsenR. Aseptic Processing: A Review of Current Industry Practice. Pharmaceutical Technology. 2004; 28(10, Oct):128. ClinicalIQ content © 2009, ClinicalIQ, LLC Medium-Risk Level Media Fill y y y y y Evaluated 2 years of media fill tests of aseptic technique – over 600 tests Gowning and gloving not required 10-step complicated preparation A trainer provided guidance as to proper technique Contamination rate was found to be 5.2%!!! Trissel LA, Gentempo JA, Anderson RW, et al. Using a media fill simulation to evaluate the microbial contamination rate for USP medium risk level compounding. AJHP. 2005;62:285-288 ClinicalIQ content © 2009, ClinicalIQ, LLC Reducing the Contamination Rate by Changing Work Practices y Evaluated 2 more years of media fill tests of aseptic technique using the same 10-step preparation y Year 1: ◦ Gowns and non-sterile gloves required ◦ Reduced to about 1% contamination y Year 2: ◦ Sterile gloves with repeated 70% IPA wiping of gloves ◦ Reduced to 0.3% contamination Trissel LA, Gentempo JA, Saenz LM, et al. Reducing the microbial contamination rate of pharmacy-compounded sterile preparations: Evaluation of two simple and inexpensive work practice changes. AJHP. 2007;64:837-41. ClinicalIQ content © 2009, ClinicalIQ, LLC Microbiological Beyond-Use Dating Risk Category Room Temp Refrigerator Freezer (≤-10 °C) Immediate Use 1 hour 1 hour N/A Low 48 hours 14 days 45 days Low w/ 12-hr BUD 12 hours or less 12 hours or less N/A Medium 30 hours 9 days 45 days High 24 hours 3 days 45 days ClinicalIQ content © 2009, ClinicalIQ, LLC Putting it All Together Beyond-Use Dating (point in time) Risk Level Chemical Stability Microbial Stability Aseptic technique ar b r g pe Pro g r in ee ls g in En ontro c ASSUMPTION! CSP is stored at its optimal temperature at all times THINK MILK! F and A C D Air ClinicalIQ content © 2009, ClinicalIQ, LLC irst‐ Making BUD work y Reduce waste and rework in the sterile compounding area ◦ Consider lean principles-PDSA Analyze current medication distribution system and location of medication storage areas y Increase # of batches-JIT y 64% reduction in rework and waste y Davis, J. Use of Lean Production to Reduce Waste When Compounding Sterile Pharmaceutical Products. Hospital Pharmacy. 2009;44:974-977 ClinicalIQ content © 2009, ClinicalIQ, LLC Summary y Meticulous aseptic technique is required. y Proper garb and engineering controls are necessary. y Time and temperature must be controlled throughout the entire life cycle of a CSP. y USP <797> BUDs can be exceeded if sterility testing according to USP <71> is performed. ClinicalIQ content © 2009, ClinicalIQ, LLC Thank you! Keep it cold. ClinicalIQ content © 2009, ClinicalIQ, LLC