Water is used in larger quantity than any active ingredient. Here is how poor water quality can reduce drug stability, efficacy and safety.
INTRODUCTION
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As a pharmacist, we check its dose, its purity and its stability. However, there is another material which is used in larger quantity than any active ingredient, and that is water.
Every dosage form needs water. Tablets need water for granulation. Syrups need water as a vehicle. Injections need water as a solvent. Cleaning of equipment also needs water. Because of this wide use, water quality has a direct impact on drug quality. If water quality is poor, the final product quality will also be poor, even if the active ingredient is of high quality. Therefore it is important to understand whether water can change drug efficacy. The answer is yes, it can.
ROLE OF WATER IN PHARMA MANUFACTURING
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Water is used in four major areas in a pharmaceutical plant.
• It is used as a raw material in formulation. Oral liquids made up of half amount of water. Injections and infusions almost made up of water. Creams and lotions also contain purified water to form emulsion base.
• It is used as a solvent in synthesis of active pharmaceutical ingredient. Many chemical reactions require water to dissolve reactants.
• It is used for cleaning and rinsing of manufacturing equipment, tanks, pipes and primary packing materials. If cleaning water is contaminated, it will leave residues that contaminate the next batch.
• It is used in quality control laboratory for preparation of reagents, dilution of samples and microbiological media preparation.
Due to this high consumption, a medium size manufacturing unit requires 50,000 to 100,000 liters of treated water per day. This makes water a critical utility, not just a general utility.
TYPES OF WATER USED IN PHARMACEUTICAL INDUSTRY
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Pharmaceutical industry does not use tap water directly for manufacturing. It converts it into different grades.
Figure 1: Flow chart showing types of water, purification steps and effects of impure water on drug efficacy
HOW WATER QUALITY AFFECTS DRUG EFFICACY
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Few mechanisms of impure water Effect efficacy and safety of drugs.
1. EFFECT OF CHEMICAL IMPURITIES
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Tap water contains inorganic salts such as calcium, magnesium, sodium, chloride, sulfate and trace heavy metals like iron and lead. These ions can interact with active ingredients.
For example, calcium and iron form chelation complexes with tetracyclines and fluoroquinolones. Chelated drug is not absorbed from gastrointestinal tract, so bioavailability decreases and therapeutic effect is reduced. Heavy metals also act as catalysts for oxidation and hydrolysis. They accelerate degradation of drug, leading to loss of potency and short shelf life. A product that should be stable for 24 months may fail assay within 12 months due to metal catalyzed degradation.
2. EFFECT OF ORGANIC IMPURITIES
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Organic impurities are carbon based dirt that comes in water from natural and human sources. Natural source is dead plants and leaves that dissolve in ground water. Human source is pesticides sprayed on crops, oil leakage, factory waste and household chemicals. Syrup made with such water can change color to brownish and give bad odor. Cream can give rancid smell. Patient will refuse to take it.
Preservative is added in syrup to stop germ growth. Organic matter consumes preservative and makes it weak. After some weeks germs start growing, sugar is fermented and drug efficacy goes down.
3. EFFECT OF MICROBIAL AND ENDOTOXIN CONTAMINATION
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Microbial contamination is the most serious issue. Biofilm is resistant to normal disinfection. When such water is used for syrup manufacturing, total microbial count of product increases. Microorganisms consume sugar and preservative and also degrade the active ingredient. Product becomes turbid and loses efficacy.
When such water is used for injection manufacturing, risk is higher. Filtration removes bacteria but does not remove endotoxin. If endotoxin containing water is used, final injection will be pyrogenic. After intravenous administration, patient may develop fever, chills, hypotension and in severe cases shock. In this case, active ingredient is within specification, but water has made product unsafe and ineffective.
4. EFFECT OF pH AND HARDNESS
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Most drugs are weak acids or weak bases and their solubility is pH dependent. If pH of manufacturing water is not controlled, drug may not dissolve completely, leading to non-uniform distribution in liquid dosage forms. Hardness due to calcium and magnesium salts causes physical instability in emulsions and creams, leading to phase separation. In injections, hardness can cause crystals.
WATER PURIFICATION TECHNOLOGIES
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To prevent these problems, pharmaceutical companies install water treatment plants.
Common steps include multimedia filtration to remove suspended particles, water softening to remove hardness, activated carbon filtration to remove chlorine and organic matter, reverse osmosis to remove 95 percent dissolved salts and organics, electrodeionization to remove remaining ions, distillation to produce Water for Injection, and ultraviolet disinfection to kill microorganisms.
Storage and distribution are also critical. Purified water and Water for Injection are stored in SS tanks with sanitary fittings and are kept in continuous circulation loop. Water for Injection loop is maintained at certain temperature to prevent microbial growth. Stagnant water allows rapid microbial proliferation, therefore continuous circulation is essential. If any parameter is out of specification, production is stopped until corrective action is taken.
REGULATORY REQUIREMENTS
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All major pharmacopeias including United States Pharmacopeia, European Pharmacopeia, British Pharmacopeia and Indian Pharmacopeia have specific monographs for Purified Water and Water for Injection. Good Manufacturing Practice guidelines of World Health Organization and US Food and Drug Administration state that water is a critical utility. Failure of water system can lead to product recall, warning letter and import alert.
During regulatory audits, water treatment plant and water testing trends are checked first, because water system reflects overall quality management of company.
RELEVANCE TO ZONE IV-A COUNTRIES
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Pakistan belongs to Zone IV-A which is hot and humid. High temperature and humidity favor microbial growth in water storage tanks and distribution loops. In Karachi, ambient temperature can reach 40 degree C to 42 degree C in summer. Therefore companies operating in Zone IV-A require more frequent sanitization with hot water or ozone and strict temperature control. Without proper control, problems such as discoloration of syrups, assay failure of tablets and pyrogenic reactions in injections increase.
CONCLUSION
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In conclusion, water used in pharmaceutical manufacturing can definitely change drug efficacy. Pure water does not increase efficacy beyond its intended value, but impure water can decrease efficacy, reduce stability and compromise safety through chemical interactions, catalyzed degradation, microbial contamination and pH effects.
Investment in water purification, storage and monitoring is essential to ensure product quality and patient safety. For pharmacy students, understanding water system is as important as understanding active ingredient, because quality of water is propositional to determines quality of medicine.
REFERENCES
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1. United States Pharmacopeia National Formulary 2024 Water for pharmaceutical purposes monographs.
2. World Health Organization 2021 Good manufacturing practices Water for pharmaceutical use WHO TRS 1033.
3. University of Texas at Arlington 2020 Research could improve pharmaceuticals testing Science Daily.
4. European Pharmacopoeia 2023 Water purified and Water for Injections Edition 11.