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Water types

Here you will find answers to the following questions:

  • What are the different types of pharmaceutical water?
  • What are they used for in pharmaceutical production?
  • What microbiological and physico-chemical requirements are described in the pharmacopoeia?

There are essentially four types of water that are of interest for the pharmaceutical industry: Potable water, purified water, water for injection and highly purified water. Figure 1 gives an overview of the different, common designations. Below is a list of the requirements from the European pharmacopoeia for these four main water qualities for the pharmaceutical industry.

Figure 1 Designations of water types

Designations of water types

In accordance with pharmacopoeia (Ph. Eur.)

Synonyms

Potable water

Feed water, public water supply, service water, city water

Purified water

Demineralised water, deionised water

Water for injection (WFI)

Aqua ad iniectabilia, ultra pure water, distilled water

Highly purified water

Aqua valde purificata, low endotoxin water, reverse osmosis water

1 Potable water

Potable water is the first stage in water purification, it is the starting material from which the other three water qualities are produced. For this reason, potable water must be handled as a raw material and must therefore be subject to goods receipt control. In many cases, only certificates from the water supply companies are used to prove the quality of potable water. This is never sufficient. Council direction 98/83/EC (dated 3.11.1998) on the quality of water intended in human consumption. As water handover at the plant entrance takes place at the water meter, but the water quality in accordance with § 8 has to meet the limits "at the outlet of any tap connection used for withdrawal of water for human consumption", the contractor, in particular with large loops for purified water on the company premises, is obligated to guarantee the water quality. Accordingly, the potable water must be subject to an internal investigation.

Potable water quality is defined by the Primary Drinking Water Regulations TVO (Revised Version 2003). The microbiological quality of the potable water is an important parameter. The following limits apply for the microbiological quality: Escherichia coli, coliform organisms and faecal streptococci (replaced with enterococci in the new TVO) must not be detectable in 100 ml water. This requirement is deemed to be satisfied for coliform organisms if these organisms are not detectable in 95% of at least 40 investigations, i.e. the above-mentioned organisms must not be detectable in 38 of 40 samples (this interpretation note is omitted from the new TVO).

Guideline

Colony count at 20 °C ± 2 °C per ml

<100

Colony count at 36 °C ± 1 °C per ml

<20

The new TVO contains microbiological requirements regarding the total microbial count only for water used for human consumption, which is intended to be filled in bottles or other containers to be dispensed:

Limit

Colony count at 22 °C per ml

<100

Colony count at 36 °C per ml

<20

For heavy metals, organic compounds and other physical parameters such as temperature, there is a wide range of guidelines and limits. Details can be found in the Primary Drinking Water Regulations. In practice, it can be sufficient to check selected chemical and physical parameters for the respective application of the potable water. These parameters can be nitrates and heavy metals, for example (figure 2).

Figure 2 Application of potable water

Application of potable water

Preliminary stage for water purification

Rinsing of equipment and containers

In addition to the preliminary stage for water purification, potable water can be used to rinse equipment or containers in washing cycles. However, this use is often prevented by the hardness of the potable water.

2 Purified water

The terms specified in figure 1 are common for purified water, although they also technically describe other water qualities in part. The pharmacopoeia provides for purified water in bulk for the production of preparations that do not have to be sterile or pyrogen-free (see figure 3).

Figure 3 Application of purified water in bulk

Application of purified water (in bulk)

  • Manufacturing for category 2, 3 and 4 products
  • Manufacturing of WFI
  • Manufacturing of highly purified water
  • Cleaning of facilities
  • Cleaning of containers for category 2, 3 and 4 products
  • Rinsing of equipment and containers for category 1 products*
  • Autoclave cooling (only cooling jacket)
  • Autoclave cooling (touching container)**
  • Blue bath solution

* See also the CPMP requirements (EMEA) for highly purified water (figure 4).

** With stricter limits for the microbial count.

The pharmacopoeia names the testing parameters and acceptance limits listed in figure 4.

Figure 4 Requirements of purified water in bulk  

Requirements of purified water in bulk

Testing parameter

Specification

Properties

Clear, colourless, no odour or taste

Microbial count

Not more than 100 CFU (colony-forming units) per ml*

Specified micro-organisms**

Pseudomonas aeruginosa and Escherichia coli not detectable in 100 ml

Nitrates not more than 2 ppm

Conductivity

Not more than 4.3 mS cm-1 at 20 °C

Heavy metals

Not detectable (0.1 ppm)

TOC

Not more than 0.5 ppm or 500 pb per litre

* The microbiological quality is verified by monitoring. The value is a recommended action limit.

** No pharmacopoeia requirement, verification only as part of monitoring

The pharmacopoeia does not explicitly stipulate tests for specified micro-organisms. However, without information on this it is hardly possible to pass an inspection by the authorities. For certain applications and depending on the quality of the water purification, additional organism-reducing measures may be necessary when storing the purified water (e.g. hot storage).

If purified water is filled into containers for dispensing, it is a final product. In this case, additional tests for purity must be carried out. The specifications for purified water, filled in containers apply. Purified water filled in containers must also pass the following tests: Test for acidic or alkaline substances, oxidising substances, chloride, sulphate, ammonium, calcium/magnesium, residue on evaporating (0.001 percent).

The microbial purity is a specification and not an action limit. The permissible microbial count is 102 CFU/ml, with a theoretical maximum permissible microbial count of 5 x 102 CFU/ml.

The American pharmacopoeia USP also distinguishes sterile purified water. In addition to the chemico-physical parameters, this water must also pass the test for sterility.

If purified water is used as autoclave cooling water (touching the container), significantly stricter limits must be followed. An action limit of 10 CFU/1000 ml is not unusual.

3 Water for injection

The pharmacopoeia prescribes water for injection in bulk for the production of medicinal products for parenteral application which are dissolved in water (see figure 5).

Figure 5 Application of water for injection in bulk

Application of water for injection (in bulk)

  • Manufacturing of parenterals
    (aseptic manufacturing)
  • Manufacturing of parenterals
    (final sterilisation)
  • Final rinsing of equipment, containers and caps for category 1 products

The pharmacopoeia names the testing parameters and acceptance limits listed in figure 6.

Figure 6 Requirements of water for injection in bulk

Requirements of water for injection in bulk

Testing parameter

Specification

Properties

Clear, colourless, no odour or taste

Microbial count*

Not more than 10 CFU/100 ml (for aseptically processed Injectable drug products - stricter limits may be required)

Specified micro-organisms**

Pseudomonas aeruginosa not detectable in 100 ml

Nitrate

Not more than 2 ppm

Aluminium (only when used for production of dialysis solutions)

Not more than 10 mg/l

Heavy metals

Not detectable (0.1 ppm)

Conductivity

Not more than 2.1 mS/cm at 20 °C

TOC

Not more than 0.5 ppm/l corresponding to 500 ppb/l

Bacterial endotoxins

Less than 0.25 I.E./ml

*The microbiological quality is verified by monitoring. The value is a recommended action limit. **No pharmacopoeia requirement, verification only as part of monitoring

Sterilised water for injection is a final product. To this end, the pharmacopoeia contains further requirements (figure 7).

Figure 7 Requirements of sterilised water for injection  

Requirements of sterilised water for injection  

Testing parameter

Specification

Properties

Clear, colourless, no odour or taste

Sterility

Must pass test for sterility

Bacterial endotoxins

Less than 0.25 I.E./ml

Nitrate

Not more than 2 ppm

Heavy metals

Not detectable (0.1 ppm)

Acid or alkaline reactive substances

Not detectable

Oxidising substances

Not detectable

Chloride

Not detectable (0.5 ppm)

Residue on evaporating
(nominal volume up to 10 ml)

Not more than 0.004 percent

Residue on evaporating
(nominal volume over 10 ml)

Not more than 0.002 percent

Conductivity
(nominal volume up to 10 ml)

Not more than 25 mS/cm

Conductivity
(nominal volume over 10 ml)

Not more than 5 mS/cm

Particles: Container with more than 100 ml content; particle limits per ml

Not more than 25 particles greater than or equal to 10 mm

Not more than 3 particles greater than or equal to 25 mm

Particles: Container with 100 ml or less content; particle limits per ml

Not more than 6000 particles greater than or equal to 10 mm

Not more than 600 particles greater than or equal to 25 mm

The Ph. Eur. 5 also contains [15O] water-injection solution as special water for injection. Special tests are intended for this water for diagnostic purposes.

The American pharmacopoeia USP also distinguishes between the following types of water for injection, unlike the European pharmacopoeia:

  • Sterile water for injection,
  • Bacteriostatic water for injection
  • Sterile water for inhalation
  • Sterile water for irrigation

4 Highly purified water

Highly purified water is provided for by the pharmacopoeia for the production of preparations that require a high biological quality, except when water for injection is prescribed. There are initial handling instructions from CPMP (EMEA) for this water, which has been newly added to the pharmacopoeia (see figure 8).

Figure 8 Application of highly purified water

Application of highly purified water

  • Manufacturing of ophthalmic products
  • Manufacturing of sterile nose/ear preparations
  • Manufacturing of sterile preparations for cutaneous use
  • Final rinsing of equipment, containers and covers for sterile parenterals, if a later depyrogenisation step is carried out.

The pharmacopoeia names the testing parameters and acceptance limits listed in figure 9.

Figure 9 Requirements of highly purified water  

Requirements of highly purified water

Testing parameter

Specification

Properties

Clear, colourless, no odour or taste

Microbial count*

Not more than 10 CFU/100 ml

Specified micro-organisms**

Pseudomonas aeruginosa not detectable in 100 ml

Nitrate

Not more than 2 ppm

Heavy metals

Not detectable (0.1 ppm)

Aluminium (only when used for production of dialysis solutions)

Not more than 10 mg/l

Conductivity

Not more than 1.1 mS/cm at 20 °C

Bacterial endotoxins

Less than 0.25 I.E./ml

* The microbiological quality is verified by monitoring. The value is a recommended action limit. ** No pharmacopoeia requirement, verification only as part of monitoring

Summary

The European pharmacopoeia describes requirements of purified water, water for injection and highly purified water (new since 2001).



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