METHODS OF PRODUCING WATER FOR INJECTION

TWO MAIN METHODS TO PRODUCE WATER FOR INJECTION

The safe way: the change of state

As agreed in the main pharmacopoeias, Water for Injection can be produced through Vapor Compression or Multiple Effect distillation or through Reverse Osmosis system with a downstream unit of ultrafiltration. Within these several methods for producing Water for Injection (WFI), we consider distillation-based methods, which involve a change of state, to be safer.

Multiple Effect (MED) and Vapor Compression (VCD) Distillation are also the two primary methods recognized by the FDA and Ph.Eur. Both are established methods, offering different advantages depending on the proposed application. BRAM-COR employs these two different technologies in some versions and with many water pretreatment options to obtain compendial WFI, the worldwide standard for pharmaceutical applications, I.V. fluids and parenteral solutions.

Methods of producing water for Injection

WFI generation via Vapor Compression Still

VC distillation system is also known as thermocompression / vapor recompression or thermal / mechanical vapor compression. It is a technology similar to the evaporation systems used for the water desalination (vapor compression is also a common term in the refrigeration industry).

Furthermore, the VC distillation system can be powered by either steam or electric heating, and has minimal feed water quality requirement due to lower operating temperature.

WFI generation via Multiple Effect Distiller

Multiple-effect stills (ME System) are mainly characterized by their multiple column design which reuses steam energy through the process, requiring minimal moving parts, but requiring cooling water for final distillation of product.

In case of low required capacities (since MED systems absorbing much energy and cooling water) you can also get WFI from Single Effect Distiller (BRAM-COR Mod. DPSG), that is both a Still and a Pure Steam Generator.

Membrane-based WFI via Ultrafiltration (UF)

As we have stated before, we do not believe that Reverse Osmosis system is the safest method to produce Water for Injection (WFI), unless the feed water is truly excellent. Above all, with the availability of more technologically advanced membranes, we can theoretically produce "cold" WFI by adding an Ultrafiltration unit downstream (pre-treatment techniques, such as water softening, descaling, pre filtration, degasification, nanofiltration, electro-deionisation, ozonation, UV treatment and micro-filtration, should all be considered, in relation to the feed water quality). This enable us to produce cold WFI that meets all the parameters required (USP, Ph. Eur., JP, …).

Therefore, Bram-Cor has no problem in designing a turnkey plant for the production of WFI from reverse osmosis. However, once in production, the RO system requires -unlike distillers- a continuous control on its efficiency, in terms of membrane degradation, biofilm prevention and microbial charges, with periodic sanitization and validation. If there are no obstacles in ensuring this constant monitoring, which must also concern distribution loops, the Reverse Osmosis system can offer a real advantage, reducing the energy demand.

You can also read a "Guideline on the quality of water for pharmaceutical use" from EMA (European Medicines Agency) (Site source: https://www.ema.europa.eu/en/homepage)

WHY DISTILLATION PURIFIES WATER: THE SCIENCE OF LIQUID-TO VAPOR PHASE CHANGE

The Importance of the Liquid-to-Vapor Phase Change

Water purification by phase change, particularly through evaporation and subsequent condensation (distillation), is one of the oldest and most scientifically robust methods for obtaining high-purity water. Regardless of whether it is for drinking water or pharmaceutical-grade water, as in our case, the effectiveness of this process is rooted in the fundamental physical properties of water molecules and in the selective nature of the liquid-to-vapor transition. Understanding what occurs at the molecular level during evaporation provides insight into why distillation is capable of removing a wide range of contaminants from water.

Molecular Structure and Intermolecular Forces in Liquid Water

A water molecule (H₂O) consists of one oxygen atom covalently bonded to two hydrogen atoms. Because oxygen is more electronegative than hydrogen, the molecule possesses a permanent dipole moment, making it highly polar.
In liquid water, individual molecules are not isolated; they are interconnected through a dynamic network of hydrogen bonds. Each molecule continuously forms and breaks hydrogen bonds with neighboring molecules on timescales of picoseconds. These intermolecular interactions are responsible for many of water's unique properties, including its relatively high boiling point, high specific heat capacity, and high latent heat of vaporization.
At any given temperature, water molecules possess a distribution of kinetic energies. Some molecules near the surface acquire sufficient energy to overcome the attractive forces exerted by neighboring molecules and escape into the gaseous phase.

What Happens During the Liquid-to-Vapor Transition?

When water is heated, energy is supplied to the liquid. This energy does not primarily break the covalent O–H bonds within the molecule; instead, it is used to overcome the hydrogen bonds and intermolecular attractions that hold the liquid together.

As evaporation proceeds:

1. Individual H₂O molecules gain kinetic energy.

2. Hydrogen-bond interactions are disrupted.

3. Molecules escape from the liquid surface and enter the gas phase.

4. The average distance between molecules increases dramatically.

In liquid water, molecules are separated by only a few angstroms and remain strongly influenced by neighboring molecules. In contrast, in water vapor the molecules move freely and independently, colliding only occasionally according to the principles of kinetic molecular theory.

Importantly, the chemical identity of the molecule remains unchanged. An H₂O molecule in steam is chemically identical to an H₂O molecule in liquid water; only its physical state and molecular environment differ.

Selective Separation of Contaminants

The purification capability of evaporation arises from differences in volatility between water and dissolved or suspended substances.Most contaminants present in natural or polluted water possess significantly lower vapor pressures than water and therefore do not readily enter the vapor phase. As water evaporates, these substances remain behind in the residual liquid.

Inorganic Salts, Heavy Metals and Suspended Particles

Dissolved salts such as:

• Sodium chloride (NaCl)

• Calcium carbonate (CaCO₃)

• Magnesium sulfate (MgSO₄)

• Potassium salts

exist in water as hydrated ions. These ions are nonvolatile under normal distillation conditions and remain entirely in the liquid phase.

This principle explains why seawater distillation produces freshwater while the dissolved salts are left behind as concentrated brine. Metal ions such as:

• Lead (Pb²⁺)

• Mercury (Hg²⁺)

• Cadmium (Cd²⁺)

• Chromium (Cr³⁺/Cr⁶⁺)

generally do not vaporize at the temperatures associated with water boiling. Consequently, they remain in the distillation residue. Solid particles including:

• Clay

• Silt

• Rust

• Microplastics

• Sediments

cannot transition into the vapor phase and are completely retained in the liquid residue.

Microorganisms

Biological contaminants such as:

• Bacteria

• Viruses

• Protozoa

• Algae

are likewise nonvolatile. Furthermore, the elevated temperatures involved in boiling often inactivate or destroy many microorganisms before separation occurs.

Volatile Compounds: An Important Exception

Not all contaminants remain behind.

Substances possessing appreciable vapor pressures may partially evaporate together with water. Examples include:

• Ammonia (NH₃)

• Certain solvents

• Some hydrocarbons

• Various volatile organic compounds (VOCs)

These compounds may be carried into the vapor stream and subsequently appear in the condensate. For this reason, advanced distillation systems often incorporate degassing stages, activated carbon treatment, or fractionation techniques to remove volatile impurities.

Thus, distillation is exceptionally effective against nonvolatile contaminants but may require supplementary treatment when volatile substances are present.

This is why all distillation processes for pharmaceutical use require a thorough analysis of the feed water as a preliminary step: based on the chemical analysis, the appropriate water pre-treatment systems will be identified and calibrated.

The Nature of Water Vapor

The vapor produced during evaporation consists predominantly of individual H₂O molecules dispersed throughout the gaseous phase.

Contrary to common perception, true water vapor is invisible. What is often observed above boiling water as a white cloud is actually a mist of microscopic liquid droplets formed when hot vapor cools and partially condenses in the surrounding air.

Pure water vapor possesses several notable characteristics:

• It is colorless.

• It is odorless.

• It contains molecules moving at high velocities.

• Its density is much lower than that of liquid water.

• The molecules are largely independent rather than hydrogen-bonded into an extended network.

If the source water contains only nonvolatile impurities, the resulting vapor is composed almost exclusively of H₂O molecules and is therefore substantially purer than the original liquid. Clean Steam (CS, a more familiar industrial term in the USA) and Pure Steam (PS, a more closely associated term with the pharmaceutical sector), are dry, saturated steams, suitable for sterilization of pharmaceutical production plants, for direct contact with Active Pharmaceutical Ingredients, for Parenteral and Non-Parenteral dosage form applications. See, in this website: pure-steam-and-cip-systems for further insights.

Condensation and Recovery of Distilled Water

In all cases (distillation for the production of drinking water or for the production of Pure Steam), the second stage of distillation is condensation.
When water vapor encounters a cooler surface, molecular kinetic energy decreases. Hydrogen bonds begin to reform, allowing molecules to aggregate once again into the liquid state.
The condensed liquid, known as the distillate, may contain:
- significantly reduced concentrations of dissolved salts, particulates, microorganisms and many inorganic contaminants in the case of distillation for the production of ‘pure’ drinking water;
- a total absence of contaminants in accordance with the requirements set out in the relevant pharmacopoeias for pharmaceutical use.

In laboratory and industrial systems, distillation achieves, in practice, different levels of water purity depending on the intended use (analytical chemistry, pharmaceutical production, semiconductor manufacturing, industrial CIP, etc.).

Thermodynamic Perspective

From a thermodynamic standpoint, evaporation and condensation constitute a highly effective separation process because they exploit differences in chemical potential and volatility.
The latent heat of vaporization of water is approximately 2,260 kJ/kg at atmospheric pressure. This substantial energy requirement reflects the strength of the intermolecular hydrogen-bond network that must be overcome during vaporization. The same energy is released when vapor condenses back into liquid water.
Because only molecules with sufficient energy can enter the vapor phase, the phase transition acts as a molecular-level selection mechanism, preferentially transferring water molecules while excluding most dissolved contaminants.

In pharmaceutical Water for Injection production, this molecular selectivity is particularly important because it allows the removal of dissolved salts, endotoxin-carrying particles, microorganisms and many contaminants, contributing to the extremely high purity required by international pharmacopoeias.

In summary: why does distillation remove contaminats?

Because most dissolved substances are non-volatile and remain in the boiling chamber while only water molecules enter the vapor phase.

In summary: why is phase change important for pharmaceutical WFI?

Because the liquid-to-vapor transition provides a powerful physical separation mechanism capable of removing salts, particles, microorganisms and many impurities.

Water for Injection systems by Vapor Compression distillation

The advantage of a higher efficiency

(low cost by quantity produced in comparison to MED)

BRAM-COR Vapor Compression Distiller Mod. STMC improperly called thermocompressor or thermal recompression still, produces Water for Injection, the reliable compendial distilled water for pharmaceutical applications. As a result, many products benefit from WFI, such as LVP or SVP (Large volume / Small Volume Parenteral), any injectable product as well as washing medias and special solutions where

quality factors (such as the sterility, elimination of the pyrogens and low molecular weight chlorine solvents)
economical factors (low running costs)

are critical to the success of the pharmaceutical process.

The STMC distiller can produce either cold or hot distillate with huge savings in energy costs and with no need for cooling water. STMC Vapor Compression Distillers operate with electrical heating (STMC EL) or plant steam heating (STMC ST) or even through both electrical and steam heating systems (STMC ES). Capacities range: from 20 to 20.000 lph with one/more blowers.

BRAM-COR STMC - Vapor Compression Distiller - function chart

BRAM-COR STMC – Vapor Compression Distiller – function chart

The design, construction and documentation of the STMC distiller is in strict compliance with GMP and FDA regulations, ensuring an easy certification by the relevant authorities.

In detail:

The Distiller is made of certified AISI 316L stainless steel
Any internal part in contact with the infeed water, the Pure Steam and the Distillate is mirror-polished
All hydraulic connections are sanitary tri-clamp or flange connection
Any gasket is made in PTFE / EPDM
All weldings are T.I.G
Vapor is compressed by a special blower.

The recognized benefit of the Vapor Compression technology

Low energy consumption
No need for cooling water to condensate the pure steam
No need for high quality inlet water (in some cases even softened water can feed the VC still)
Very high quality WFI due to strong degassing process
No need to pressurize the inlet water
WFI outflow at high pressure (1 – 1.5 bar) without any additional pump
Extremely safe process, with no risk of any cross contamination through plant steam or inlet water
Highest flexibility in terms of capacities and WFI temperatures
Reduced Maintenance

Producing WFI: the front view of a BRAM-COR STMC Vapor Compression system. Producing WFI: STMC Vapor Compression system with remote SCADA system

Note about evaporation

A vertically-mounted compressor will evaporate water on either a falling film or thin rising film principle for drier steam, whereas spray film units direct water over the horizontal surface area of the evaporation tubes for a more wetted surface. Since the separation of impurities from the steam is done by more of mechanical process (vs. multi-effect’s centrifugal action) a secondary separation system is in place. Commonly, a demister pad is used but a newer approach utilizes a baffle similar to those found in multiple-effect stills for a design which is considered more sterile as it is fully drainable. Therefore, a full automation ensures easy operation and total monitoring of critical parameters, by means of certified in-line instruments and of a careful alarm policy. Access policy and records can be managed according to 21 CFR PART 11.

Note about blower

A further enhancement of VCD has been the BRAM-COR multistage blower compressor which runs under 4000 rpm, significantly reducing operating noise level (below 65-70 dB) and maintenance. A standardized approach to mechanical seal design can also reduce the maintenance time typically associated with their changeover as well as prevent or minimize leakage over a longer operating period. The issue of non-condensable gas removal is as standard addressed by vapor compression designs by preceding the compressor with a deaerator.

Bram-Cor STMC - Vapor Compression Still_2107W

More on: Vapor Compression Distiller . See also Bram-Cor STMC reference website: vapor-compression-distiller.com

Water for Injection systems by Multiple Effect Distillation

The advantage of less moving parts

BRAM-COR Multi Effect Stills Mod. SMPT are designed and manufactured according to cGMP to produce compendial Water for Injection. Each unit contains a number of boiling columns (or effects) with the first column producing pure steam, which is condensed and re-distilled in subsequent columns to reduce operating costs. Heating for evaporation and cooling for condensation processes are performed by double tube sheet (DTS) exchangers. Condensation is achieved using thin-film technology. The process is repeated in each column: the higher the quantity of columns the lower overall the consumption of the unit. The number of columns therefore has no effect on the quality or performance of the system.

Note about preheaters and evaporators

Preheaters will make the Multiple Effect still operate more efficiently in regards to steam and water consumption, but are not always a standard feature. A preheater can be installed prior to the first column for additional benefit, or prior to all columns for maximum benefit. Evaporators will be located internal or external to the column.

The evaporators bear the brunt of varying pressures and temperatures. If there is any severe failure to the still, it will most likely be with the evaporator. For this reason, the first evaporator should have a double-tube sheet design; it should be decided in the specification process if all evaporators should be of double tube-sheet design since this is not a standard with all manufacturers.

The quality of Bram-Cor construction

A special labyrinth-separator installed at the top of each column separates the steam generated by the evaporation process from entrained substance in the steam itself. The result is a pure, “dry”, pyrogen-free steam, condensed in compendial Water for Injection. The first column of the Still may be used to produce also Clean Steam alternatively or even at same time. Pressure vessels are designed according to ASME and PED regulation and the equipment features:

Double tube sheet heath exchangers
Certified AISI 316L stainless steel mirror-polished and passivated product contact surfaces
AISI 304 frame, jackets and control board
PTFE gaskets
Pneumatic valves with Teflon membranes and AISI 316 L SS polished body
ASTM C-795 – compliant insulation.

Capacities range: from 50 to 15.000 lph with three to ten columns.

Bram-Cor SMPT ST 5 - Multi Effect Still W

More on: Multiple Effect Distiller Operating system in this site

See also Bram-Cor SMPT reference website: www.multiple-effect-water-distiller.com

Water for Injection production from Single Effect Distillation

The advantage: both a Still and a Pure Steam Generator

BRAM-COR Single Effect Distiller Mod. DPSG is both a Still and a Pure Steam Generator. The production process consists in PW water evaporation followed by pure steam separation and condensation. The steam is purified using centrifugal and gravity separation methods. This equipment produces dry, saturated steam to be used as sterilizing agent.

Naturally, the Pure Steam, when condensed through a Double Tube Sheet condenser, meets the requirements of international pharmacopoeias for Water for Injection. The system can therefore provide a simultaneous production of Pure Steam and Water for Injection.

Methods of producing water for incjection- single effect still

Note about Pure Steam Generator

BRAM-COR CPSG, Pure Steam Generator, produces dry and saturated steam: this steam, when condensed, meets USP requirements for Water for Injection (WFI) (see the relevant page on this site).

See also the Bram-Cor CPSG reference website pure-steam-generator.com