Summary Basis of Decision for Swish Silver Supreme
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Swish Silver Supreme
Silver dihydrogen citrate 0.003% and citric acid 4.846%
Ready-to-Use Solution
Charlotte Products Ltd.
Submission control no: 121017
Date issued: 2010-12-13
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
4.846% Citric acid
Dosage form:
Route of administration:
Disinfectant (Hospital/Health Care facilities)
Disinfectant (Domestic)
Drug identification number(DIN):
- 02335212
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 13, 2009, Health Canada issued a Notice of Compliance to Charlotte Products Limited for the hard surface disinfectant Swish Silver Supreme.
Swish Silver Supreme contains the active ingredients silver dihydrogen citrate and citric acid, and is considered for use as a broad-spectrum antimicrobial disinfectant and deodorizer.
Swish Silver Supreme is indicated for use as a hard surface disinfectant for non-porous surfaces which may contain bacteria, fungi, and viruses.
The market authorization was based on quality, efficacy, and safety information submitted. The efficacy and safety of Swish Silver Supreme were established through twenty-nine assessment studies that included microbiology and toxicological studies, along with supporting reference articles. The microbiological efficacy studies conducted support the general bactericidal, virucidal, and fungicidal claims of Swish Silver Supreme.
Swish Silver Supreme (0.003% silver dihydrogen citrate and 4.846% citric acid) is presented as a colourless, odourless ready-to-use aqueous solution contained in a plastic bottle with a trigger spray nozzle. Prior to use of the product, surfaces to be treated must be pre-cleaned of soiled material. The product is then directly sprayed on the hard surface, thoroughly wetting the surface, for the specified amount of required contact time as indicated on the product label. The surface should then be wiped down with a clean towel. A rinse with potable water is required for surfaces in direct contact with food and with children at the mouthing stage of development.
Swish Silver Supreme may cause eye or skin irritations. As such, direct contact to eyes or skin should be avoided. Inhalation of the spray should also be avoided as it may cause respiratory irritation and discomfort which may result in coughing, sneezing and/or wheezing. Detailed conditions for the use of Swish Silver Supreme are described on the product label.
Based on the Health Canada review of data on quality, efficacy, and safety Health Canada considers that the benefit/risk profile of Swish Silver Supreme is favourable for its use as a hard surface disinfectant for non-porous surfaces which may contain bacteria, fungi, and viruses.
3 Scientific and Regulatory Basis for Decision
In proposing to introduce a silver dihydrogen citrate-based disinfectant for the first time on the Canadian market, this submission was processed and reviewed as a new drug under Division 8 of the Food and Drug Regulations.
3.1 Quality Basis for Decision
3.1.1 Active Substance
General Information
Silver dihydrogen citrate and citric acid are the active ingredients of Swish Silver Supreme, which is a broad spectrum antimicrobial disinfectant. Swish Silver Supreme is indicated for use on hard non-porous surfaces which may contain bacteria, fungi, and viruses. Environmental surfaces for disinfection, may include but are not limited to: homes, hospitals, nursing home, medical and dental clinics, laboratories, ambulance and patient transfer vehicles, funeral homes, hotels, restaurants, schools, day care facilities, offices, veterinary clinics, animal shelters, kennels, exercise facilities, beauty and barber shops, trucks, trailers, shipping containers, rail cars, subways, trains, airplanes, ships, buses and other public transportation vehicles, locker rooms, kitchens, and restrooms. For surfaces in direct contact with food and with children at the mouthing stage of development, a rinse with potable water is required upon cleaning with Swish Silver Supreme.
Manufacturing Process and Process Controls
Silver dihydrogen citrate is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be adequately controlled within acceptable limits. In-process controls performed during manufacture were reviewed and are considered acceptable.Control of Active Substance
The active substances used in Swish Silver Supreme is tested using Professed standards. The specifications and analytical methods used for quality control of Swish Silver Supreme are considered acceptable.
Stability
The proposed shelf-life and storage conditions for the active substance are supported and are considered to be satisfactory.
3.1.2 Disinfectant Product
Description and Composition
Swish Silver Supreme is presented as a clear, colourless, and odourless ready-to-use solution. The active ingredients are comprised of silver dihydrogen citrate and citric acid which acts as a stabiliser. The non-active ingredients consist of sodium lauryl sulfate (surfactant) and water (dilutant).
Swish Silver Supreme is packaged in six different sizes. The 946 mL, 1 L, and 3.78 L sizes are packaged in opaque high-density polyethylene containers. The 18.9 L, 20 L and 208 L sizes are packaged in green high-density polyethylene drums. The bottle sizes come along with a trigger sprayer.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development are considered acceptable.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: mixing and blending. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Product
Swish Silver Supreme is tested as per the Professed standard to verify that its clarity, colour, odour, presence of silver, citric acid concentration, pH, specific gravity, particulates, heavy metals, and fill volume, are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
Stability
The proposed one year shelf-life at room temperature (10 to 30°C) for Swish Silver Supreme is considered acceptable.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production of Swish Silver Supreme are considered suitable for the activities and products manufactured. The site is compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Swish Silver Supreme has demonstrated that the two active substances and the disinfectant product can be consistently manufactured to meet the approved specifications. Proper development and test studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Given the product is a hard surface disinfectant, pharmacodynamic studies do not apply.
3.2.2 Pharmacokinetics
Given the product is a hard surface disinfectant, non-clinical pharmacokinetic studies do not apply.
3.2.3 Microbiology
Microbiological efficacy studies were submitted in support of the bactericidal, virucidal and fungicidal claims. All non-clinical studies described below were performed under Good Laboratory Practices (GLP) and in accordance to standard operating procedures and standard protocols. Quality assurance was maintained through regular inspections of the ongoing studies to assure and maintain integrity of the study results. In addition, use of study controls [i.e. culture purity, organic soil sterility, carrier sterility, neutralizing subculture medium sterility, viability, neutralization confirmation, and carrier population] were also used throughout the tests conducted to ensure integrity of the study results obtained.
Bactericidal Studies
A general bactericidal claim was established based upon the following organisms: Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella choleraesuis.
Additional bacterial claims were made for Listeria monocytogenes, vancomycin resistant Enteroccus faecium, Campylobacter jejuni, Acinetobacter baumanii, Escherichia coli, community associated methicillin resistant Staphylococcus aureus (CA-MRSA, PVL positive), and community associated methicillin resistant Staphylococcus aureus (CA-MRSA/NRS 123)
Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella choleraesuis
Tests were also conducted on P. aeruginosa, S. aureus, and S. choleraesuis organisms to determine the efficacy of Swish Silver Supreme under 'worse case conditions'. This time Swish Silver Supreme was tested against 60 carriers for each P. aeruginosa, S. aureus, and S. choleraesuis organisms. The AOAC Use-Dilution Method test was used. Contact time of the organism to the disinfectant was 30 seconds. To "pass" the 60 carrier test, at least 59 of the 60 carriers tested had to show no detectable growth of the target organism in the test tubes containing neutralizing growth medium. Results from these tests showed that Swish Silver Supreme passed the 60 carrier test for all three organisms when tested at a 30-second exposure period. These results were also confirmed at the 10-minute exposure period.
Campylobacter jejuni, Acinetobacter baumanii, community associated methicillin resistant Staphylococcus aureus (CA-MRSA, PVL positive), and community associated methicillin resistant Staphylococcus aureus (CA-MRSA/NRS 123)
For each of the four bacteria - C. jejuni, A. baumanii, S. aureus (CA-MRSA, PVL positive), and S. aureus (CA-MRSA/NRS 123), testing was done in accordance with the Association of Official Analytical Chemists (AOAC) Use-Dilution Method. The primary objective was to determine the efficacy of Swish Silver Supreme to disinfect. The organisms used were prepared following conventional industry methods. For each target organism tested, two lots of Swish Silver Supreme were used.
For each target organism tested, the following methodology was used. Individual species of the bacteria were dried onto a test surface carrier. Once dried, ten contaminated carriers were then collected from the test surface and individually transferred to individual tubes containing 10.0 mL of Swish Silver Supreme (at the requested dilution) and exposed for periods of two and five minutes at room temperature (20 ± 1°C).
Following exposure, each carrier was then transferred to primary subculture tubes and subsequently into secondary subculture tubes to neutralize the action of the disinfectant. The neutralized subculture tubes were then incubated under microaerophilic conditions for a specified time period, depending on the organism being tested. Following incubation, the subcultures were then visually examined for the presence or absence of visible bacterial growth.
In order to demonstrate efficacy against C. jejuni, A. baumanii, S. aureus (CA-MRSA/PVL positive/NRS192) and S. aureus (CA-MRSA/NRS 123), respectively, each lot tested of Swish Silver Supreme had to demonstrate no growth for all 10 out of the 10 inculated carriers for each organism tested. Results of each organism lot tested confirmed no growth in any of the 10 subculture tubes following both the two and five minute exposure periods. Therefore, complete inactivation was shown for C. jejuni, A. baumanii, S. aureus (CA-MRSA, PVL positive) and S. aureus (CA-MRSA/NRS 123), thereby confirming efficacy of Swish Silver Supreme.
Staphylococcus aureus (MRSA), Enterococcus faecium(VRE), Listeria monocytogenes, and Escherichia coli
For each of the four bacteria, S. aureus (MRSA), E. faecium, L. monocytogenes, and E. coli testing was also done in accordance to the AOAC Use-Dilution Method. The primary objective of these tests was to determine the efficacy of Swish Silver Supreme to disinfect. The organisms were prepared following conventional industry methods. Two lots of Swish Silver Supreme were used in testing each organism. For each target organism, the following testing methodology was used. Ten contaminated dried carriers were placed into individual tubes. The tubes were then agitated vigorously enough to get bacteria into the solution and then incubated at 37 ± 2°C. Each lot of Swish Silver Supreme was tested in the following manner:- 30 ppm disinfectant solution against 10 dried carriers of S. aureus (MRSA), at 30 seconds, 1 and 2 minutes
- 30 ppm disinfectant solution against 10 dried carriers of E. faecium(VRE), at 30 seconds, 1 and 2 minutes
- 30 ppm disinfectant solution against 10 dried carriers of L. monocytogenes, at 30 seconds, 1 and 2 minutes
- 30 ppm disinfectant solution against 10 dried carriers of E. coli, at 30 seconds, 1 and 2 minutes
Using sterile pipettes, 10 mL aliquots of the disinfectant were placed into sterile test tubes and allowed to equilibrate in a 20 ± 0.5°C waterbath. Without touching the sides of the test tubes, dried carriers were then added to each tube of disinfectant and swirled three times prior to being placed back into the waterbath. Following the exposure periods, the carriers were removed from the disinfectant, shaken to remove residual disinfectant, and transferred to a tube and shaken thoroughly. The 10 carrier test (kill 10 out of the 10 inculated carriers) for each organism was performed. Results showed no growth of L. monocytogenes at the 30 second exposure period. For the remaining bacteria, S. aureus (MRSA), E. faecium, and E. coli respectively, no growth was shown at the two minute exposure period. Therefore, complete inactivation was demonstrated for S. aureus (MRSA), E. faecium, L. monocytogenes, and E. coli, thereby confirming efficacy of Swish Silver Supreme.
Evaluation of residual activity
This study details the evaluation for residual activity after an initial application of Swish Silver Supreme to a hard surface. Two lots of Swish Silver Supreme were tested at 30 ppm against the following three organisms: S. aureus, S. chloraesuis, and P. aeruginosa. For each of the three bacteria, similar test procedures were used as described below. In addition, the bacteria used within these tests were prepared following conventional industry methods.
One millilitre of Swish Silver Supreme was spread evenly over the entire surface of a sterilized test slide. At 0, 1, 6, and 24 hours, 0.01 mL of the test organism was transferred onto the sterile slide and immediately spread uniformly over an approximate 1x1 inch area. Eighteen slides per organism, per lot of Swish Silver Supreme, per time point were prepared, for a total of 216 slides. The test slides were then placed in a petri dish and covered. Three slides per organism, per lot of Swish Silver Supreme, were held for exposure periods of 30 seconds, 1 minute, and 2 minutes. After completion of the exposure period, the slides were individually transferred to a bottle of Letheen Broth. One slide per organism, per time point was extracted as a quantative control by shaking manually for 1 minute. A plate count was then performed in triplicate. Results demonstrated that Swish Silver Supreme does provide protection from S. aureus, S. chloraesuis, and P. aeruginosa for up to 24 hours after the initial application.
Virucidal Studies
The virucidal claim was established using efficacy studies based upon the following nine viruses: poliovirus type 2, rotavirus, human coronavirus, avian influenza H3N2 (Avian reassortment), feline calicivirus (surrogate virus for Norovirus), rhinovirus type 37, human immunodeficiency virus type 1, herpes simplex virus type 1, and influenza A virus (Hong Kong).
The primary objective of these studies was to determine the virucidal efficacy of Swish Silver Supreme. For each of the above noted viruses, similar test procedures were used. The viruses used within these tests were prepared following conventional industry methods. For each of the nine viruses assessed, two lots of Swish Silver Supreme were tested.
For each virus tested, the following methodology was used. Films containing the viruses were prepared by spreading the virus inoculum uniformly over the bottom of several separate sterile glass petri dishes. The virus films were then air-dried at room temperature until visibly dry. The virus films were then sprayed three times with Swish Silver Supreme at a distance of 6-8 inches ensuring that the treatment surface was throughly wet. The contact period of the organism to the disinfectant varied from 1, 3 and/or 10 minutes depending on the virus being tested. The virus films were then scraped and assayed for infectivity and/or cytoxicity. Results from the studies demonstrated a complete inactivation of all viruses tested following the recommended 10-minute exposure period at room temperature.
Fungicidal Studies
Fungicidal claim was established based upon the fungus Trichophyton mentagrophytes. The main objective of these tests was to determine the fungicidal efficacy of Swish Silver Supreme. Testing procedures used in these studies were in accordance to the AOAC - Fungicidal Test Method. The fungi used within these tests were prepared following conventional industry methods.
Results from the study demonstrated efficacy of Swish Silver Supreme against Trichophyton mentagrophytes after 10-minutes exposure period at 22°C. In addition, evaluation of growth in subcultures after 10-minutes exposure period also showed efficacy of Swish Silver Supreme against Trichophyton mentagrophytes.
3.2.4 Toxicology
Primary eye irritation
An acute eye irritation study was conducted in three rabbits by placing 0.1 mL undiluted Swish Silver Supreme into the conjuctival sac of the right eye. The left eye remained untreated and served as a control. Irritation was evaluated using a high-intensity white light at 1, 24, 48, and 72 hours. The fluorescein dye evaluation procedure was used at 24 hours to verify corneal damage. The classification of eye irritation scores ranged from 0.0 to 110 points. The maximum mean total score for Swish Silver Supreme was 10.7 out of a possible 110 irritation score. However, given that two of the rabbits showed a score of 2 instead of 0 at 48 hours, the level of irritation was therefore increased from minimally to mildly irritating.
Primary skin irritation
An acute skin irritation study was conducted in three rabbits by applying 0.5 mL undiluted Swish Silver Supreme on a gauze and keeping it in contact to the skin for 4 hours. Twenty-four hours after the patch was removed, well-defined erythema was observed at all three treated sites. Very slight oedema was also evident in two of the three rabbits. The overall incidence and severity of irritation decreased over time. All three rabbits were free from irritation by Day 10 (study termination). Overall, Swish Silver Supreme was rated as slightly irritating to skin based on a Draize primary dermal irritation index (PDII) of 1.7, for well-defined erthema with 100% frequency and very slight oedema in 2 out of 3 rabbits.
Acute dermal sensitization
An acute dermal sensitization test (Buehler Method) on shaved skin in guinea-pigs was also conducted to determine the highest non-irritating concentration (HNIC) of Swish Silver Supreme. The fur was removed by clipping the dorsal area and flanks of each pig. This area was then divided into four test sites (two sites on each side of the midline) on each animal. The test substance was subsequently applied undiluted (100%) and also diluted with distilled water to yield concentrations of 75%, 50%, and 25% weight-in-weight. Each concentration was applied to a test site using special chambers and then wrapped with non-allergenic adhesive tape. After 6 hours of exposure, the chambers were removed. Twenty-four hours after application, each site was evaluated for local reactions (erythema). The highest non-irritating concentration of Swish Silver Supreme was determined to be at 50% concentration.
Acute oral toxicity
An acute oral toxicity test was conducted in ten rats following the administration of one dose of 5,000 mg/kg of bodyweight (bw). The rats were then observed at least once daily for 14 days for any signs of gross toxicity, behavioral changes, or mortality. Results from the 14 days post-treatment period, showed that all animals survived and remained active and healthy, with the exception of one male rat that exhibited weight loss between days 7 through 14. All rats gained bodyweight over the 14 days post-treatment period. At Day 14, all rats were euthanized and gross necropsies were performed to investigate possible pathological findings. No gross abnormalities were found. Therefore, the single acute lethal dose (LD50; the concentration that produces mortality in 50% of those treated) is determined to be greater than 5,000 mg/kg of bodyweight in rats.
Acute dermal toxicity
An acute dermal toxicity study for Swish Silver Supreme was conducted using ten rats. A single dose of 5,000 mg/kg/bw of the test substance was applied evenly over the animal's clipped dorsal and trunk areas (approximately 10% of the body surface) and then covered with a 2x3 inch gauze pad. The gauze pad and entire trunk of each animal were then wrapped with tape to avoid dislocation of the pad and to minimize loss of the test substance. After 24 hours of exposure to the test substance, the pads were removed and test sites were assessed. Results of the study showed that all animals tested survived and gained bodyweight over the 14 days post-treatment period and remained active and healthy throughout the 14 days post-treatment period. At necropsy after the 14th day, there were no gross abnormalities found. Therefore, the single dose acute dermal LD50 of Swish Silver Supreme is greater than 5,000 mg/kg of bodyweight.3.2.5 Conclusion
Overall, the microbiology and toxicological studies provided in support of Swish Silver Supreme are considered suitable. All studies conducted showed favourable results in the efficacy of Swish Silver Supreme as a broad spectrum antimicrobial disinfectant. The studies conducted for possible eye and skin irritations did demonstrate that Swish Silver Supreme may irritate eyes and be slightly irritating to skin. Precaution statements have been placed on the product label to address the identified safety concerns.
3.3 Clinical basis for decision
Given the product is a hard surface disinfectant, Section 3.3 Clinical Basis for Decision does not apply.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The microbiological efficacy studies conducted demonstrate that Swish Silver Supreme is an effective broad-spectrum antimicrobial disinfectant and can be used as a hard surface disinfectant for non-porous surfaces which may contain bacteria, fungi, and viruses.
The toxicity studies showed that Swish Silver Supreme may irritate eyes and be slightly irritating to skin. A precautionary statement has been placed on the product label suggesting to avoid direct contact with eyes or skin. Furthermore, detailed conditions for use of Swish Silver Supreme are clearly described on the product label.
Overall, the data presented in this application demonstrate that Swish Silver Supreme has a favourable benefit to risk profile for use in accordance with the proposed labelling. Considering the public health need for effective broad-spectrum antimicrobial disinfectants to inactive the growth of bacteria, fungi and viruses, Swish Silver Supreme meets this need.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Swish Silver Supreme is favourable for use on hard non-porous surfaces which may contain bacteria, fungi, and viruses. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Swish Silver Supreme
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-09-17 |
| Submission filed | 2008-03-26 |
| Screening | 2008-04-02 |
| Screening Acceptance Letter issued: | 2008-04-30 |
| Review | |
| Comprehensive Evaluation completed: | 2009-09-21 |
| Quality Evaluation completed: | 2009-09-18 |
| Labelling Review completed: | 2009-09-21 |
| Notice of Compliance (NOC) issued by Director General: | 2009-10-13 |