DR. COLETTE COZEAN HAND HYGIENE: INTERNATIONAL TESTING AND - - PowerPoint PPT Presentation

 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

DECEMBER 2013 CHANGES TO SOAP MONOGRAPH

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.

FDA PROPOSED MONOGRAPH REVISIONS FOR SOAPS

 Prove Efficacy  Prove no increase in resistance  Prove no changes in hormones  Timeframe: 18 months

APRIL 2015 CHANGES TO HEALTH CARE ANTISEPTIC MONOGRAPH

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.

NEW TESTING REQUIRED FOR HEALTH CARE ANTISEPTICS

• 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- genicity Reproductive toxicity (DART) Alcohol ○

• Benzalkonium chloride

○ Benzethonium chloride ○

• ○

Chloroxylenol ○ ○ ○ Hexylresorcinol ○

• Iodine tincture USP

○

• Iodine topical solution

USP ○

INTERNATIONAL COMPARISON SIMILARITIES

 Regulated by Monographs  USA – 1994  Canada – 2009  Europe – 2004, 2012  Combination of In-vivo and In-vitro testing required

INTERNATIONAL COMPARISON MAJOR DIFFERENCES

 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

APPROVED ACTIVE INGREDIENTS

Europe (2004) Canada (2009) U.S. (1994) Category I U.S. (1994) 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

UNITED STATES

 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

• f illness, etc.

UNITED STATES - TESTING

 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 10th application

 Surgical Scrub Testing (Optional) for persistence, product applied

and resident bacteria levels observed at six hours, resident bacteria

• nly

EUROPE

 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 – TESTING REQUIREMENTS

 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

• rganisms 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.

CANADA

 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 – TYPES OF PRODUCTS

 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 - CLAIMS

 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 – IN VITRO TESTING

 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 VIVO 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

MANUFACTURING REQUIREMENTS

 Europe  ISO9001  Canada  cGMP  Submit 3 batch validation  United States  cGMP  All require stability and validation testing

TAKEAWAYS FROM INTERNATIONAL COMPARISONS

 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

MY “CRYSTAL BALL”

 Changes in US Monograph in Next 5 Years  Healthcare and First Aid Monographs will be revised to

include “true efficacy” testing as being required for soaps

 New monograph for Consumer Antiseptic Products will be

drafted

 First company will receive claims for “virucidal,” “specific

• rganisms” and will cause monograph revision

 Monographs will approve most of the products cleared

internationally and may approve “combo-products”

 Triclosan will be removed from the Monographs  Monographs will be finalized