Water is key in making drugs. The WHO rules make sure water used in Good Making Practice (GMP) places is very pure to keep people safe and make sure products work well. Here's what you should know:
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4 Water Types: WHO sets four levels of water purity:
- Drinking Water: Basic type for usual needs.
- Purified Water (PW): For cleaning tools and products not for shots.
- Highly Purified Water (HPW): For steps needing more pure water than PW.
- Water for Injection (WFI): The most pure water, used in shots and clean products.
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Key Quality Tests:
- Microbial Limits: Hard control of germs.
- Conductivity: Checks salt dirt.
- Total Organic Carbon (TOC): Finds organic bad stuff.
- Endotoxins: Very important for WFI to block bad toxins.
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System Build & Care:
- Use tough stuff like 316L stainless steel.
- Keep surfaces smooth to stop germs from growing.
- Keep water moving and clean often to dodge dirt.
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Testing Process:
- Systems go through three test parts: hard watching (2-4 weeks), working tests (2-4 weeks), and long-term check (1 year).
- Often care and watching are key to keep up good quality.
- New Changes: WHO now says it's okay to make WFI with reverse osmosis (RO) instead of the old way, making it use less power.
Why it counts: Following these rules makes sure drugs are safe and top-notch for people, while fitting with world rules.
Pharmaceutical Water Types Explained: WFI, Purified Water, PW | Complete Guide
WHO Water Quality Rules
The World Health Organization (WHO) sets key water quality rules to make sure that drug making follows them. These rules lay out levels of water purity, with each level for a certain use and tougher needs. Picking the right water level is key because water quality impacts the safety and work of products. These rules guide decisions on how to design and check water systems.
4 WHO Water Levels and Their Uses
The WHO puts water into four main levels, from drinkable water to very pure water for clean uses:
- Drinking Water: This level meets WHO drinkable water rules and is the basic water type in drug places. It is right for some steps, but many steps need purer water.
- Purified Water (PW): Often used in non-shot products and for cleaning tools between making batches, this level gets rid of most dirt.
- Highly Purified Water (HPW): Used in steps that need less organic and microbe dirt than PW but do not need the tough rules of Water for Injection (WFI).
- Water for Injection (WFI): The purest level, WFI is made for shot products and other clean uses. It must meet the strictest rules for microbes and endotoxins, making it key for shot drugs and clean drug products.
The European Medicines Agency (EMA) also backs this group system, giving detailed needs for water levels, even those used to make extracts, to fit with certain drug steps.
Needed Water Quality Parts
To keep each water level right, tough quality parts are checked. These include watching microbe counts, how well it carries power, Total Organic Carbon (TOC), and endotoxin levels. Each part helps make sure the water reaches its pure goals.
- Microbial Colony Forming Units (CFU): This part counts living tiny life forms. Each water level has set CFU limits, with WFI needing the toughest germ control.
- Conductivity: This is a quick check of salt contamination, which can be watched all the time. Changes in how well water carries power often point to possible problems, like endotoxins or microbe dirt.
- Total Organic Carbon (TOC): TOC numbers show organic dirt. The U.S. Pharmacopeia (USP) sets a TOC max of 500 µg of Carbon/L for both Purified Water and WFI. Watching TOC in real-time gives early signs of dirt.
- Endotoxin Levels: Very key for WFI, endotoxin checks keep patients safe by stopping harm from bad germ poisons.
The WHO stresses the need for these parts in its quality rules, saying:
"Above all, manufacturers must not place patients at risk due to inadequate safety, quality or efficacy. For this reason, risk assessment has come to play an important role in WHO quality assurance guidelines." [3]
Makers should set up clear rules for the physical, chemical, tiny life forms, and toxin levels that fit their own needs. For water used in the last steps of getting and making clean non-sterile Active Pharmaceutical Ingredients (APIs) - mainly if made for sterile drug making - these rules are key.
To keep checks right, it's key to often set gear right. Experts say a full set-right process that includes checks before changes, making changes, and checks after changes is needed to make sure the numbers are trusted.
What We Need for a Good Water System
A strong water system needs the right stuff and a good plan that keeps dirt out and lasts long. The World Health Organization (WHO) says there are specific rules makers must follow so the water stays clean as long as the system is used.
Stuff and Parts Rules
What we put in a water system is big for how it works and if it fits WHO rules. For example, 316L stainless steel is chosen for places that follow GMP (Good Making Practice) because it does not rust and it can stand up to very hot cleanings. This steel can deal with wash force up to 1,500 psi and heat up over 300°F, which makes it great for drug making.
How smooth the surfaces are is also key. To keep bacteria away, systems should have a roughness average (Ra) under 0.4 micrometers. Inside surfaces shouldn't be rougher than 0.8 micrometers to cut down the risk of bugs growing.
Electropolishing makes surfaces even smoother, which stops rust and helps with better cleaning and making sure things are germ-free.
All parts must fit tight clean design rules, like those in ASME BPE and FDA guides, to be okay for drug making. These guides help make sure water stays up to WHO quality rules.
As Better Engineering puts it:
"Ensuring food safety requires food and beverage processing and handling equipment to be designed, constructed, and installed according to sanitary design principles is the goal of this organization." [4]
Now, we look at how to build storage and systems to share out water. These are key to keep clean water safe from new dirt.
How to Build Storage and Sharing Systems
Where we keep and share water is a big deal. If not done right, clean water can get dirty again. WHO rules say we must mix these systems well with water cleaning parts to keep water good.
To share water well, we need to keep it moving all the time. Pipes must make water run fast (1–2 m/s) to stop slimy layers from forming, and there should be no dead-end pipes where water sits still and germs grow. All joins should drain well and be easy to clean.
Keeping systems hot, over 65°C (149°F), cuts down on germ risks. Heat changers must be built well to stop dirt from mixing between the hot part and clean water.
Tanks for holding water also need smart design to lower risk of dirt. This means picking the right size, making sure there's enough space at the top, and having vents with filters that trap germs and can be tested right there.
Using UV light, keeping the heat up, and cleaning with chemicals then washing it all out makes sure no cleaning stuff hurts the water quality. Clean design for pumps and smart placing of pipes, valves, and spots to get in help make it easy to keep clean and fix, all while keeping the system working right and safe.
Water System Check and Upkeep
Check your water system to make sure it keeps working well and stays clean. The World Health Organization says it's very important to have a good check process. This keeps your system working right and clean, not only the first time but all the time.
The method stops bad stuff from getting in on purpose. It uses regular small life form tests and checks gear. The Parenteral Drug Association points out:
"Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function." [5]
3 Main Steps to Check a Water System
Water system checks happen in three main parts. Every part helps make sure the system can make top-notch water in different cases.
- Step 1 (Close Watch, 2–4 weeks): This step looks closely at the system. Taking samples every day after each clean-up step helps set work ranges and lock in plans, which includes setting warning and action levels.
- Step 2 (Steady Use, 2–4 weeks): In this step, the system is run in real job settings while still being watched closely. This checks that the methods set in Step 1 keep making great water during actual use.
- Step 3 (Long Run, 1 year): This step tests how well the system works over time, seeing changes across seasons. Regular checks are done, but with fewer samples, based on the methods set earlier.
| Phase | Duration | Focus | Key Activities |
|---|---|---|---|
| 1 (Intensive Watching) | 2–4 weeks | Check the system | Check each day, plan steps, set alert level |
| 2 (Steady Work) | 2–4 weeks | Ready to make | Watch while making to keep quality same |
| 3 (Year-Long Outcome) | 1 year | Trust over seasons | Keep an eye on it often, judge how it does each year |
After checking, always watching and caring well are key to keep water good for a long time. For example, one firm found out that they had a repeat issue with bad stuff growing because water did not move in a pump part. By putting a drain at the bottom part of the pump, they fixed it [5].
How to Watch and Keep Up
When the check is done, watching and caring all the time are big in keeping water clean. Rules say you must keep it tight: for clean water, any rate over 100 CFU/mL is too much, and for Water For Injection, it must be under 10 CFU/100 mL [5].
You should have a care plan ready after the Site Test ends. Do what the maker says, like:
- Swap rubber seals and parts each year
- Change softening stuff every 3–5 years
- Put in new reverse osmosis layers, filter things, and EDI pieces every 3–5 years
- Get new UV lights every 8,000 hours or 12 months [7]
Real cases show why this matters. A drug place in India had slime build up in its pipes, causing dirt. They got it right by making cleaning better, changing pipes to cut out still spots, and bettering how they train people, which cut down time lost [9]. Likewise, a firm in Egypt saw rising organic stuff and power in water because a key part was bad. By changing it, making their watch system better, and fixing check files, they made the water meet the needed marks [9].
Look at alarms often, best each year, setting points from check results to find issues early. As WHO notes:
"If drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feed-water for the production of higher qualities of WPU, then testing should be carried out periodically by the water user's site to confirm that the quality meets the standards required for drinking-water." [8]
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2020 WHO Guideline Updates for WFI Production
In May 2020, the World Health Group (WHO) put out an update of its rules, called "Good Manufacturing Practices: water for use in drugs." They asked for feedback [1]. This change came after the European drug rules group in 2017 said you could make Water for Injection (WFI) in ways other than heating to make steam [1].
The new rules, called "Making water for injection without heating to make steam", show WHO's plan to match new ways to make things [1]. So, the worldwide drug set of rules needs to change its "Water for Injection" text to add these new ways [1]. The new tips talk about other ways to make WFI, like taking out ions, filtering small and very small things, cleaning off scale, taking out gas, and using UV light[1].
This change makes WHO's rules like those of the US and Japan, who already said okay to these new ways [11]. This move comes from more than ten years of proof that water cleaned by pushing it through small spaces is safe and good [10].
First, in April 2017, the European rules group changed text 0169 to say WFI can be made through cleaning ways like steam [11]. The 2020 version also mixes WFI with very clean water [10], underlining it’s key to keep water good while using new ways to make it.
How pushing water through small spaces changed WFI Making
One big update in these new rules is using reverse osmosis (RO) more for making WFI. RO is a cheap and less energy-using choice instead of old steam ways [10][11].
In RO, they push water that’s been cleaned a bit through a special wall under squeeze. This wall stops big bits and bad stuff but lets clean water go through [10]. RO setups can block 99% of rocks, dirty bits, and germs in water [11], mostly saving about 80% of it [10].
Unlike steam methods, which use high heat, RO works in normal heat [10]. This uses less power, but it could also let germs grow. To stop this, RO setups must be cleaned often with steam, heat, or air and light [10].
Now, many places use a two-pass RO with ion switch and ultra filter[11]. This mix, sometimes called "Membrane WFI" or "room-heat WFI", has a step that takes out nearly all endotoxins and pyrogens [11]. Many setups also have running electrodeionization (CEDI), which cleans bits without dirty chemicals [11].
The new WHO rules are strict about using RO systems. The rules say:
"All parts of the system should be suitable for routine sanitization, including reverse osmosis membranes." [12]
Also, firms have to show that their cleaning way is as good as or tops boiling:
"It shall be demonstrated that the purification process of distillation is comparable or better." [12]
RO systems need to be checked often. These checks include testing the membranes and keeping an eye on things like how well it carries electric current, how much living stuff it has, and how much organic stuff is in it.
No matter how it is made, WFI has to meet tough quality rules: less than 1.3 µS/cm of conductivity at 77°F, less than 10 CFU/100 mL of bacteria, less than 0.25 international units/mL of endotoxins, and less than 0.5 mg/L of TOC.
Rules show why these standards matter. In 2021, the FDA told off a U.S. drug maker because its WFI system had too many germs and could dirty the drugs you inject. Also, in 2022, the European Medicines Agency warned a company making bio drugs because it did not check its RO system well enough and did not keep testing for bad toxins.
For firms switching to RO, they must fully check and approve the design, set-up, work, and outcomes to meet all rules and quality needs before they start making anything. This tough process makes sure the systems are checked well and are safe for making top-quality WFI.
Meeting WHO Water Rules for GMP Rules
To meet WHO water rules, you need careful plan making, system checks, and keep-up work. GMP sites must use strong ways to make sure their water systems always make water that is good for drug making.
The rule process starts with a clear check plan, which has four main steps: Design Check (DQ), Install Check (IQ), Work Check (OQ), and Work Show (PQ). These steps make sure the system gives out the same water quality, even when water changes through the year[13][14].
The Job of Keep-up in Rules
Right keep-up plans are key to keep rules. Set times to check things should be picked in the design step, seeing how key each part is. These rules must be set before the start and check steps. By the time the Site OK Test (SAT) is done and the drug company takes over, there should already be a plan for the start work and keep-up[7]. This base helps keep an eye on and care needed to keep water clean.
Plan checks before problems are key to keep the system whole and stop issues like biofilm build. By aiming at how key parts are, sites can make sure all system parts work as they should.
Watching and Bug Control
Often watching is key to keep rules. For systems that stay at room heat, often checks and clean-outs are needed to keep bug levels down[14]. Changes in heat and bug life over the year should lead the watch plan. Testing water at the use point is key to find dirt in the pipes[6].
Action and warn levels, based on check info, must be set low to find big changes from normal work[6]. To deal with bug dirt, sites should often clean their systems with heat, air, or chems[2].
Real Use: MASI Longevity Science
MASI Longevity Science shows how key it is to stick to WHO water rules in drug-grade making. Their top aging slow-down bits - like NMN, Resveratrol, Fisetin, and Spermidine - are made in Germany with strong water quality rules. Each bit is checked in Switzerland to make sure it's clean, safe, and works well. This strong rule has made the trust of over 352,000 people in their world long life group, showing how key water quality is in making trusty and strong bits.
Handling Changes and Always Getting Better
When bringing in new stuff or changing old systems, it’s key to write all changes in set rule methods or normal work methods (SOPs)[7]. This plan makes sure that sticking to WHO rules is kept up while also keeping product quality and safety over time.
FAQs
Why use reverse osmosis for making Water for Injection (WFI) under the new WHO rules?
New WHO Rules and Reverse Osmosis for WFI Making
The World Health Organization's new rules now let us use reverse osmosis (RO) to make Water for Injection (WFI). This brings many good things for GMP places. One big plus is how RO saves on power. Not like the old boil and cool ways, RO uses a lot less power - about 3 kWh per cubic meter of water made. This means big cuts in costs and less harm to the earth.
Another plus is that RO is easy to keep up. RO works with fewer parts and at lower push, which means it breaks less. Less break down means lower cost to fix and more trust in the system. By using RO, places can keep a good balance of working well and being green while still making clean water.
