METHODS OF PRODUCING WATER FOR INJECTION

Primary methods to produce Water for Injection via distillation

A safe way: the change of state

As agreed in the main pharmacopoeias, recognized by the FDA and Ph.Eur., Water for Injection can be produced through distillation systems or through membrane systems. 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 technologies for the water distillation. 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.

WFI 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).

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WFI via Multi Effect Distiller

Multiple-effect stills (MED 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.

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Can condensed Pure Steam meet WFI standards?

The answer is yes: the pure steam produced by a generator such as the Bram-Cor CPSG meets all the requirements set by the pharmacopoeias. However, while not cost-effective for large-scale production, it can be useful for having both pure steam and compendial water production capabilities available. (USP, Ph. Eur., JP, …). Producing Pure Steam - PS Generator

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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

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.

More on Further notes about the phase change in this page

The alternative way is membrane-based, with Reverse Osmosis + Ultrafiltration

Membrane-based WFI via Ultrafiltration (UF)

We do not believe that Reverse Osmosis system is the safest method to produce Water for Injection (WFI) everywhere, unless the feed water is truly excellent. Above all, with the availability of more technologically advanced membranes, we can produce "cold" WFI by adding customized pre-treatment techniques upstream and a second Ultrafiltration unit downstream. This enable us to produce cold WFI that meets all the parameters required (USP, Ph. Eur., JP, …). 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.

See the related page about Reverse Osmosis+UF on this site. You can read the PDF in which the EMA addressed the "Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies" in 2016. The latest ISPE guide on this topic was published in 2022: "Good Practice Guide: Membrane-Based WFI Systems"

Further references

You can also read a "Guideline on the quality of water for pharmaceutical use" from EMA (European Medicines Agency)

https://www.ema.europa.eu/en/documents/other/questions-and-answers-production-water-injections-non-distillation-methods-reverse-osmosis-and-biofilms-and-control-strategies-final_en.pdf

For further information on this topic, we recommend "The ISPE Baseline Guide® Water and Steam Systems (Third Edition, 2019) that aims to assist with the design, construction, operation, and lifecycle management of new and existing water and steam systems". A more recent ISPE publication (2025), however, deals with "Approaches to Commissioning and Qualification of Pharmaceutical Water and Steam Systems (Third Edition)"

You can discover more national and international pharmacopoeias and references at this section (Page: What is Water for Injection?)

Further notes about the phase change

What happens huring 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.

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.

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;
- absence of contaminants in accordance with the requirements set out in the pharmacopoeias.

In laboratory and industrial systems, distillation achieves 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. 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 contaminants? 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.