World Health Organization

INTRODUCTION:

This guide to local production of WHO-recommended hand rub formulations is separated into two discrete but interrelated sections:

• Part A provides a practical guide for use at the pharmacy bench during the actual preparation of the formulation. Users may want to display the material on the wall of the production unit.
• Part B summarizes some essential background technical information and is taken from WHO Guidelines on Hand Hygiene in Health Care (2009). Within Part B the user has access to important safety and cost information and supplementary material relating to dispensers and distribution.

PART A: GUIDE TO LOCAL PRODUCTION

Part A is intended to guide a local producer in the actual preparation of the formulation.

             Materials Required (small volume production)

REAGENTS FOR FORMULATION 1:

1. Ethanol 96%
2. Hydrogen peroxide 3%
3. Glycerol 98%
4. Sterile distilled or boiled cold water

REAGENTS FOR FORMULATION 2:

1. Isopropyl alcohol 99.8%
2. Hydrogen peroxide 3%
3. Glycerol 98%
4. Sterile distilled or boiled cold water

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• 10-litre glass or plastic bottles with screw-threaded stoppers (1), or
• 50-litre plastic tanks (preferably in polypropylene or high density
• polyethylene, translucent so as to see the liquid level) (2), or
• Stainless steel tanks with a capacity of 80–100 litres
• (for mixing without overflowing) (3, 4)
• Wooden, plastic or metal paddles for mixing (5)
• Measuring cylinders and measuring jugs (6, 7)
• Plastic or metal funnel
• 100 ml plastic bottles with leak-proof tops (8)
• 500 ml glass or plastic bottles with screw tops (8)
• An alcoholometer: the temperature scale is at the bottom and the ethanol concentration (percentage v/v) at the top (9, 10, 11)

NOTE:

• Glycerol: used as humectant, but other emollients may be used for skin care, provided that they are cheap, widely available and miscible in water and alcohol and do not add to toxicity, or promote allergy.
• Hydrogen peroxide: used to inactivate contaminating bacterial spores in the solution and is not an active substance for hand antisepsis.
• Any further additive to both formulations should be clearly labelled and be non-toxic in case of accidental ingestion.
• A colorant may be added to allow differentiation from other fluids, but should not add to toxicity, promote allergy, or interfere with antimicrobial properties. The addition of perfumes or dyes is not recommended due to risk of allergic reactions.

METHOD: 10-LITRE PREPARATIONS

These can be prepared in 10-litre glass or plastic bottles with screw-threaded stoppers.

Recommended Amounts of Products:

FORMULATION 1

• Ethanol 96%: 8333 ml
• • Hydrogen peroxide 3%: 417 ml
• • Glycerol 98%: 145 m

FORMULATION 2

• Isopropyl alcohol 99.8%: 7515 ml
• • Hydrogen peroxide 3%: 417 ml
• • Glycerol 98%: 145 ml

Step by Step Preparation:

Final Products

Final concentrations:

FORMULATION 1

Ethanol 80% (v/v),

Glycerol 1.45% (v/v),

Hydrogen peroxide 0.125% (v/v)

FORMULATION 2

Final concentrations:

Isopropyl alcohol 75% (v/v),

Glycerol 1.45% (v/v),

Hydrogen peroxide 0.125% (v/v)

Quality Control

1. Pre-production analysis should be made every time an analysis certificate is not available to guarantee the titration of alcohol (i.e. local production). Verify the alcohol concentration with the alcohol meter and make the necessary adjustments in volume in the preparation formulation to obtain the final recommended concentration.
2. Post-production analysis is mandatory if either ethanol or an isopropanol solution is used. Use the alcohol meter to control the alcohol concentration of the final use solution. The accepted limits should be fixed to ± 5% of the target concentration (75%–85%for ethanol).
3. The alcohol meter shown in this information pamphlet is for use with ethanol; if used to control an isopropanol solution, a 75% solution will show 77% (± 1%) on the scale at 25°C.

General Information

Labelling should be in accordance with national guidelines and should include the following:

• Name of institution

• WHO-recommended hand rub formulation

• For external use only

• Avoid contact with eyes

• Keep out of the reach of children

• Date of production and batch number

• Use: Apply a palmful of alcohol-based hand rub and cover all surfaces of the hands. Rub hands until dry

• Composition: ethanol or isopropanol, glycerol and hydrogen peroxide • Flammable: keep away from flame and heat

Production and Storage Facilities:

• Production and storage facilities should ideally be air conditioned or cool rooms. No naked flames or smoking should be permitted in these areas.

• WHO-recommended handrub formulations should not be produced in quantities exceeding 50-litres locally or in central pharmacies lacking specialised air conditioning and ventilation.

• Since undiluted ethanol is highly flammable and may ignite at temperatures as low as 10°C, production facilities should directly dilute it to the above-mentioned concentration. The flashpoints

of ethanol 80% (v/v) and of isopropyl alcohol 75% (v/v) are 17.5°C and 19°C, respectively.

• National safety guidelines and local legal requirements must be adhered to the storage of ingredients and the final product.

• Additional safety information is presented in Part B of this Guide.

PART B: SUPPLEMENTARY TECHNICAL, SAFETY AND COST INFORMATION

Part B contains important safety and cost information and incorporates information from the WHO Guidelines on Hand Hygiene in Health Care (2009).

The case for alcohol-based hand rubs in health care

At present, alcohol-based hand rubs are the only known means for rapidly and effectively inactivating a wide array of potentially harmful microorganisms on hands.

WHO recommends alcohol-based hand rubs based on the following factors:

1. Evidence-based, intrinsic advantages of fast-acting and broad-spectrum microbicidal activity with a minimal risk of generating resistance to antimicrobial agents;
2. Suitability for use in resource-limited or remote areas with
3. lack of accessibility to sinks or other facilities for hand hygiene (including clean water, towels, etc.);
4. Capacity to promote improved compliance with hand hygiene by making the process faster, more convenient and immediately accessible at the point of patient care;
5. Economic benefit by reducing annual costs for hand hygiene, representing approximately 1% of extra-costs generated by health care-associated infection
6. Minimization of risks from adverse events because of increased safety associated with better acceptability and tolerance than other products.

Background to WHO Alcohol-based Hand Rub Formulations

According to the available evidence on efficacy, tolerability and cost- effectiveness, WHO recommends using an alcohol-based hand rub for routine hand antisepsis in most clinical situations. Health-care facilities currently using commercially-available hand rubs, liquid soaps and skin care products sold in disposable containers should continue this practice, provided that the hand rubs meet recognized standards for microbicidal efficacy (ASTM or EN standards) and are well accepted/ tolerated by the health-care workers. It is obvious that these products should be regarded as acceptable, even if their contents differ from those of WHO-recommended formulations described within this document. WHO recommends the local production of the following formulations as an alternative when suitable commercial products are either unavailable or too costly.

To help countries and health-care facilities to achieve system change and adopt alcohol-based hand rubs, WHO has identified formulations for their local preparation. Logistic, economic, safety, cultural and religious factors have all been carefully considered by WHO before recommending such formulations for use worldwide.

Efficacy

It is the consensus opinion of a WHO expert group that WHO-recommended hand rub formulations can be used both for hygienic hand antisepsis and for pre-surgical hand preparation.

Hygienic Hand Rub

The microbicidal activity of the two WHO-recommended formulations was tested by WHO reference laboratories according to EN standards (EN 1500). Their activity was found to be equivalent to the reference substance (isopropanol 60% v/v) for hygienic hand antisepsis.

Pre-surgical Hand Preparation

Both WHO-recommended hand rub formulations were tested by two independent reference laboratories in different European countries to assess their suitability for use for pre-surgical hand preparation, according to the European Standard EN 12791. Although formulation I did not pass the test in both laboratories and formulation II in only one of them, the expert group is, nevertheless, of the opinion that the microbicidal activity of surgical antisepsis is still an ongoing issue for research as due to the lack of epidemiological data there is no indication that the efficacy of n-propanol (propan-1-ol) 60% v/v as a reference in EN 12791 finds a clinical correlate. It is the consensus opinion of a WHO expert group that the choice of n-propanol is inappropriate as the reference alcohol for the validation process because of its safety profile and the lack of evidence-based studies related to its potential harmfulness for humans. Indeed, only a few formulations worldwide have incorporated n-propanol for hand antisepsis.

Considering that other properties of WHO recommended formulations, such as their excellent tolerability, good acceptance by health-care workers and low cost are of high importance for a sustained clinical effect, the above results are considered acceptable and it is the consensus opinion of a WHO expert group that the two formulations can be used for surgical hand preparation. Institutions opting to use WHO- recommended formulations for surgical hand preparation should ensure that a minimum of three applications are used, if not more, for a period of 3–5 minutes. For surgical procedures of more than 2 hours duration, ideally surgeons should practice a second hand rub of approximately 1 minute, even though more research is needed on this aspect.

Many settings around the world successfully undertook local production of the two WHO-recommended formulations. Throughout Part B, additional information is presented where relevant, in table form, based on feedback from 11 sites located in Bangladesh, Costa Rica, Egypt, Hong Kong SAR, Kenya, Mali, Mongolia, Pakistan (two sites), Saudi Arabia, and Spain. Further, detailed information is available within the WHO Guidelines on Hand Hygiene in Health Care (2009)

Composition of Alcohol-based Formulations for In-house/local Production

The choice of components for WHO hand rubs takes into account both cost constraints and microbiological efficacy. The procurement of raw ingredients will be influenced by the availability of sub-standard materials on the market and it is important to select local sources with care.

The following two alcohol-based hand rub formulations are recommended for preparation in-house or in a local production facility, up to a maximum of 50 liters:

Formulation 1

To produce final concentrations of ethanol 80% v/v, glycerol 1.45% v/v, hydrogen peroxide (H2O2) 0.125% v/v.

Formulation 2

To produce final concentrations of isopropyl alcohol 75% v/v, glycerol 1.45% v/v, hydrogen peroxide (H2O2) 0.125% v/v:

Only pharmacopoeial quality reagents should be used (e.g. The International Pharmacopoeia) and not technical grade products.

Raw Materials:

While alcohol is the active component in the formulations, certain aspects of other components should be respected. All raw materials used should be preferably free of viable bacterial spores. The raw materials for inclusion/consideration are listed below:

1. H2O2

The low concentration of H2O2 is intended to help eliminate contaminating spores in the

bulk solutions and recipients and is not an active substance for hand antisepsis.

H2O2 adds an important safety aspect, however the use of 3–6% for the production might be complicated by its corrosive nature and by difficult procurement in some countries.

Further investigation is needed to assess H2O2 availability in different countries as well as the possibility of using a stock solution with a lower concentration.

2. Glycerol and other humectants or emollients

Glycerol is added as a humectant to increase the acceptability of the product.

Other humectants or emollients may be used for skin care, provided that they are affordable, available locally, miscible (mixable) in water and alcohol, non-toxic, and hypoallergenic.

Glycerol has been chosen because it is safe and relatively inexpensive. Lowering the percentage of glycerol may be considered to further reduce stickiness of the hand rub.

3. Use of proper water

• While sterile distilled water is preferred for making the formulations, boiled and cooled tap water may also be used as long as it is free of visible particles.

4. Addition of other additives

It is strongly recommended that no ingredients other than those specified here be added to the formulations.

In the case of any additions, full justification must be provided together with documented safety of the additive, its compatibility with the other ingredients, and all relevant details should be given on the product label.

5. Gelling agents

•  No data are available to assess the suitability of adding gelling agents to WHO-recommended liquid formulations, but this could increase potentially both production difficulties and costs, and may compromise antimicrobial efficacy.

6. Fragrances

• The addition of fragrances is not recommended because of the risk of allergic reactions.

***All hand rub containers must be labelled in accordance with national and international guidelines.

Production and Storage

Manufacture of WHO-recommended hand rub formulations is feasible in central pharmacies or dispensaries. Whenever possible and according to local policies, governments should encourage local production, support the quality assessment process, and keep production costs as low as possible. Special requirements apply for the production and stock piling of the formulations, as well as for the storage of the raw materials.

Because undiluted ethanol is highly flammable and may ignite at temperatures as low as 10°C, production facilities should directly dilute it to the concentrations detailed within this guide. (Refer to Summary table of risks and mitigation measures concerning the use of alcohol-based hand hygiene preparations)

WHO is exploring the development of additional guidance on large-scale production to facilitate scale-up.

Storage Volumes:

Special requirements are applicable for the production and storage of the formulations, as well as the storage of the primary products. The quantity of locally-produced WHO hand rub should not exceed 50 liters, or possibly less if regulated by local and/or national guidelines and regulations.

Cleansing and disinfection process for reusable hand rub bottles:

1. Bring empty bottles to a central point for reprocessing by standard operational protocols;
2. Wash bottles thoroughly with detergent and tap water to eliminate any residual liquid;
3. If heat-resistant, thermally disinfect bottles by boiling in water. Whenever possible, thermal disinfection should be chosen in preference to chemical disinfection. The latter may increase costs and introduces an extra step to flush out the remains of the disinfectant. Chemical disinfection should include soaking the bottles in a solution containing 1000 ppm of chlorine for a minimum of 15 minutes and then rinsing with sterile/cooled boiled water;
4. After thermal or chemical disinfection, leave bottles to dry completely upside-down in a bottle rack. Dry bottles should be closed with a lid and stored, protected from dust, until use.

Quality Control:

If concentrated alcohol is obtained from local production, verify the alcohol concentration and make the necessary adjustments in volume to obtain the final recommended concentration. An alcohol meter can be used to control the alcohol concentration of the final use solution; H2O2 concentration can be measured by titrimetry (oxydo-reduction reaction by iodine in acidic conditions). A higher level quality control can be performed using gas chromatography and the titrimetric method to control the alcohol and the hydrogen peroxide content, respectively. Moreover, the absence of microbial contamination (including spores) can be checked by filtration, according to the European Pharmacopeia specifications.

Distribution

To avoid contamination with spore-forming organisms, disposable bottles should preferably be used although reusable sterilizable bottles may reduce production costs and waste management. To prevent evaporation, containers should have a maximum capacity of 500 ml on ward and 1 liter in operating theaters, and ideally fit into a wall dispenser. Leakage-free pocket bottles with a capacity of no more than 100 ml should also be available and distributed individually to health-care workers, but it should be emphasized that the use of these products should be confined to health care only. The production or re-filling unit should follow norms on how to clean and disinfect the bottles (e.g. autoclaving, boiling, or chemical disinfection with chlorine). Autoclaving is considered the most suitable procedure. Reusable bottles should never be refilled until they have been completely emptied and then cleansed and disinfected.

Cost Issues:

The costs of WHO handrub formulations may vary according to country, resources and labour costs; studies to evaluate costs and resource

use are necessary. As a comparison, examples of actual prices of commercially available alcohol-based handrubs in different countries are detailed within the Guidelines.

Safety Standards

With regard to skin reactions, hand rubbing with alcohol based solutions is better tolerated than hand washing with soap and water. In a recent study conducted among ICU health-care workers, the short-term skin tolerability and acceptability of WHO-recommended hand rub formulations were significantly higher than those of a reference product. Any additive should be as non-toxic as possible in case of accidental or intentional ingestion.

General Safety Issues:

The main safety issues relate to the flammability of alcohol-based hand rubs and the adverse effects associated with accidental or deliberate ingestion. These are summarized in the Summary table of risks and mitigation measures concerning the use of alcohol-based hand hygiene preparations.

Flammability – Flash-points:

The flash points of ethanol 80% (v/v) and isopropyl alcohol 75% (v/v) are 17.5°C and 19°C, respectively, and special attention should be given to proper storage in tropical climates. Production and storage facilities should be ideally air-conditioned or cool rooms. Open flames and smoking must be strictly prohibited in production and storage areas. Pharmacies and small-scale production centers supplying WHO- recommended hand rub formulations are advised not to manufacture locally batches of more than 50 liters at a time.

Accidental Ingestion:

In general, it is not recommended to add any bittering agents to reduce the risk of ingestion of the hand rubs. Nevertheless, in exceptional cases where the risk of ingestion might be very high (paediatric or confused patients), substances such as methylethylketone and denatonium benzoate, added to some household products to make them less palatable, may be added to alcohol-based hand rubs in order to reduce the risk of accidental or deliberate ingestion. However, there is no published information on the compatibility and deterrent potential of such chemicals when used in alcohol-based hand rubs to discourage their abuse. It is important to note that such additives may make the products toxic and add to production costs. In addition, the bitter taste may be transferred from hands to food being handled by individuals using handrubs containing such agents. Therefore, compatibility and suitability, as well as cost, must be carefully considered before deciding on the use of such bittering agents.

A colorant may be incorporated to differentiate the handrub from other fluids as long as such an additive is safe and compatible with the essential components of the handrubs. However, the H2O2 in the handrubs may tend to fade any colouring agent used and prior testing is recommended.

Summary Table of Risks and Mitigation Measures Concerning the Use of Alcohol-based Hand Hygiene Preparations: