PhD in BioMedical Engineering (Ohio St.), Masters in Electrical Engineering (Ohio St.), J.D. (Concord Law School) Senior management positions with Pfizer, Baxter, American Hospital Supply; CEO of numerous start-ups Regulatory consultant Author of more than 100 peer-reviewed papers, holds more than 50 patents, received more than 50 FDA clearances and approvals, plus international approvals Former reviewer for National Institute of Health DR. COLETTE COZEAN
HAND HYGIENE: INTERNATIONAL TESTING AND REGULATORY Colette Cozean, PhD
As of December 2013, new rules were proposed to regulated antimicrobial soaps. These new rules state that products must be shown to be both effective and safe. Efficacy “We are proposing that data from clinical outcome studies (demonstrating a reduction in infections) are necessary to support….consumer antiseptic wash active ingredients.” Safety “(1) Safety data studies described in current FDA Guidance (e.g. preclinical and human pharmacokinetic studies, developmental and reproductive toxicology studies, and carcinogenicity studies )” “(2) data to characterize potential hormonal effects” “And, (3) data to evaluate the development of resistance . DECEMBER 2013 CHANGES TO SOAP MONOGRAPH
Prove Efficacy Prove no increase in resistance Prove no changes in hormones Timeframe: 18 months FDA PROPOSED MONOGRAPH REVISIONS FOR SOAPS
As of April 30, 2015, issued a proposed rule requesting additional scientific data to support the safety and effectiveness of ALL active ingredients used in health care antiseptics marketed under the OTC drug monograph. “The FDA recommends that health care personnel continue to use these products consistent with infection control guidelines while additional data are gathered.” This review was triggered by FDA concerns regarding the increased frequency of use of health care antiseptics up to 100 times per day and a limited number of adverse events with some of the most common sanitizers. No changes until 2018. APRIL 2015 CHANGES TO HEALTH CARE ANTISEPTIC MONOGRAPH
The FDA is requiring all active ingredients to undergo pharmacokinetic testing with 100 uses/day to determine the amount of active ingredient in the blood stream. Active ingredient Human PK (MUsT) Animal PK(ADME) Oral carcino-genicity Dermal carcino- Reproductive genicity toxicity (DART) ○ • • • • Alcohol ○ Benzalkonium chloride ○ • ○ Benzethonium chloride ○ ○ ○ Chloroxylenol ○ • Hexylresorcinol ○ • • • Iodine tincture USP Iodine topical solution ○ • • • USP NEW TESTING REQUIRED FOR HEALTH CARE ANTISEPTICS
Regulated by Monographs USA – 1994 Canada – 2009 Europe – 2004, 2012 Combination of In-vivo and In-vitro testing required INTERNATIONAL COMPARISON SIMILARITIES
Importance of Virus Testing and Claims USA – No virus testing required or claims allowed. Internationally, viral testing required and “ virucidal ” claims allowed. Type of Claims Allowed USA – very limited claims, Broad-Spectrum, Fast-Acting, Persistent International – much broader claims, virucidal, efficacy against specific pathogens, etc. Testing of Final Formulations vs. Active Ingredients All testing in Europe and Canada must be performed with final formulations, influence of formulation on efficacy Need for Approval under Monograph USA does not require a submission or approval, Canada and Europe both require data to be submitted and approved INTERNATIONAL COMPARISON MAJOR DIFFERENCES
Europe (2004) Canada U.S. (1994) U.S. (1994) (2009) Category I Category III Alcohol Ethanol Ethanol Isopropyl Alcohol BZK BZK BZK BZT BZT BZT CHG CHG PCMX PCMX Povidone-Iodine Iodine Povidone-Iodine Iodine Complex Hydrogen Peroxide MBC Organic Acids Peracetic Acid Triclosan Triclosan Triclosan/Triclocarbon APPROVED ACTIVE INGREDIENTS
Regulated under Tentative Final Monograph (1994) Only addresses products on the market before 1978. No submittal or specific approval needed, but testing must be on file according to the TFM Focus more on active ingredients than final formulations Limited Claims Only claims that can be made are “broad spectrum”, “fast - acting”, and “persistent” No claims against viruses, specific organisms, reduction of illness, etc . UNITED STATES
In-vitro Testing Time-Kill Testing against 25 different organisms (gram positive and gram negative bacteria, chosen to represent most prevalent causes) Resistance testing/literature review Minimum Inhibitory Concentrations (MICs) against bacteria list In-vivo Testing Healthcare Personnel Handwash Test, product applied 10 times against S. marscecans , requires 2 log reduction after initial application and 3 log after 10 th application Surgical Scrub Testing (Optional) for persistence, product applied and resident bacteria levels observed at six hours, resident bacteria only UNITED STATES - TESTING
Approved under Biocidal Directive (2012) or Medicinal Products Directive (2004), depending on claims Broad array of claims, including “kill viruses and harmful bacteria”, “active for up to __ hours”, “kid safe”, “__ hours protection”, etc. Claims against specific bacteria/viruses EUROPE
In-vitro testing EN12054 test – Tested against S. aureus, P. aeruginosa, E. coli, E. hirae, and MRSA at 30 seconds or 1 minute. Similar to FDA-required Time-Kill testing, though with fewer organisms required EN14476 test – Virucidal testing. Tests against Poliovirus and Adenovirus as reference viruses for “ virucidal ” claims, 4 log reduction necessary for virucidal claim In-vivo testing EN1500 test – Test on human skin that compares the alcohol reference product (2-propanol) against the antiseptic. Product passes test if it exceeds the reference product. Can be difficult to pass – some foaming alcohol sanitizers do not pass the test. EUROPE – TESTING REQUIREMENTS
Division between Professional Healthcare Use and Personal Domestic Use, as well as Commercial Use and Food Preparation Use Further divided into types of products in the Professional Healthcare Use CANADA
Professional hygienic handrub: product used for post-contamination treatment of lightly-soiled hands that involves rubbing hands without addition of water, and which is designed for frequent use. Professional hygienic handwash: product used for post-contamination treatment that involves washing hands, and which is designed for frequent use. Surgical handrub: product used for preoperative treatment, which involves rubbing hands without addition of water. Surgical handwash: product used for preoperative treatment that involves washing hands, either with or without the use of a scrub brush. Patient preoperative skin preparations: product used to prepare patient skin prior to surgical procedures. CANADA – TYPES OF PRODUCTS
General Healthcare Personnel Use Testing against bacteria, mycobacteria, fungi, and viruses Surgical Scrubs Testing against bacteria, fungi Patient Preoperative Skin Prep Testing against bacteria, fungi Efficacy against specific pathogens Can be claimed for any pathogen tested against (including viruses), must exceed minimum requirements for General Healthcare Personnel Use Persistence Persistence can be claimed against bacteria and fungi, if testing is completed and exceeds minimum requirements CANADA - CLAIMS
Bacteria - EN13727 Time-Kill Testing, requires 5 log reduction, against Acinetobacter, B. fragilis, E. faecium, E. hirae, E. coli, H. influenzae, K. pneumonia, M. luteus, P. mirabilis, P. aeruginosa, S. marcescens, S. aureus, S. epidermis, S. haemolyticus, S. hominis, S. saprophyticus, S. pneumoniae, S. pyogenes Mycobacterium – EN14348, requires 5 log reduction, M. terrae, M. avium Fungi – EN13624, 4 log reduction, C. albicans, A. niger Viruses – EN14476, 4 log reduction, Adenovirus, Hep. A, Hep B., Hep. C, Herpes Simplex (1 & 2), Influenza (A & B), Norovirus (MNV), Papovavirus, Poliovirus, Respiratory Synctitial Virus, Rhinovirus, Rotavirus CANADA – IN VITRO TESTING
EN1500 Test (same as Europe) – product compared against reference alcohol product at 1 minute (vs E. coli ) In-vivo tests against fungi and mycobacteria Viral Testing - ASTM E2011 test using whole hand, against Rotavirus, Rhinovirus, Hep. A, Norovirus surrogate (MNV), and Adenovirus, 2 log reduction needed Persistence – Glove Juice test (Same as US), testing against reference bacteria CANADA – IN VIVO TESTING
Europe ISO9001 Canada cGMP Submit 3 batch validation United States cGMP All require stability and validation testing MANUFACTURING REQUIREMENTS
Importance of Final Formulations in International Testing Importance of Virucidal Testing internationally Differences in approval processes under various Monographs Products approved internationally, and whether they fall under Category I or Category III in FDA TFM Claims allowed internationally that are not allowed in the United States TAKEAWAYS FROM INTERNATIONAL COMPARISONS
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