METHODS OF PRODUCING WATER FOR INJECTION

Primary methods to produce Water for Injection:

distillation and membrane-based systems

A safe way: the change of state

Water for Injection (WFI) may be produced by distillation or, where permitted by the applicable pharmacopoeia and regulatory framework, by other suitable purification technologies. USP and Ph. Eur. admit the production of WFI by distillation or by a purification process equivalent to distillation. For the Ph. Eur. (monograph 0169), non-distillation processes are accepted from 2017, with prior notification to the competent authority (see What is Water for Injection?).

The selected process must be designed, qualified and controlled to consistently meet the applicable WFI quality requirements. The suitability of each approach depends on the feedwater characteristics, system design, contamination-control strategy and operating conditions.Distillation is generally regarded as the more robust route because the liquid-to-vapor phase change acts as a physical barrier against endotoxins and microorganisms.

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.

See Further notes about the phase change in this page

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).

See the Vapor Compression Distiller page on this site

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.

See the Multi Effect Distiller page on this site.

Can condensed Pure Steam meet WFI standards?

The answer is yes: the pure steam produced by a generator such as the Bram-Cor CPSG can meet all the requirements set by the pharmacopoeias (the compliance of the steam depends on the pretreatment methods employed for feed water, the management of condensate, and the verification of applicable requirements). 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).

See the Pure Steam Generator page on this site.

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

Membrane-based WFI via Ultrafiltration (UF)

In reverse osmosis there is no phase change, so protection of the product depends on a validated multi-barrier design: customized pre-treatment, a downstream ultrafiltration stage, continuous monitoring of membrane integrity, biofilm control and periodic sanitization, which must also cover the distribution loops. When this monitoring can be guaranteed, the membrane route can reduce 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: "Guideline on the quality of water for pharmaceutical use" from EMA (European Medicines Agency) and some clarifications regarding non distillation methods

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

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.

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.

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

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.

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.