Benefits of Membrane Filtration Systems for Ambient WFI Production

向基于膜的WFI生产的转变可以大大减少公用事业的使用，缩小设施足迹的要求并帮助实现公司可持续性目标。金博宝怎么注册

Water for injection (WFI) is typically the highest quality, low-bioburden bulk water used in the production of active pharmaceutical ingredients, parenteral drug substances and drug products. As defined by the FDA and the EMA, WFI bioburden levels are orders of magnitude lower than purified water.

For nearly a century, WFI has been produced by distillation, which ensures a significant reduction of all ions, microbes, and endotoxins. Distillation boils and condenses feedwater using multiple effect or vapor compression stills, both requiring large amounts of energy to operate.

2017年，欧洲药房加入了美国药房和许多其他全球药物（中国除外）生成WFI的替代方法that produce water of an equivalent quality. This opened the door for ambient WFI production, which doesn’t require distillation. These membrane-based techniques include reverse osmosis (RO), electrodeionization (EDI), and ultrafiltration (UF), which have the potential to reduce utility use, decrease facility footprints, and enhance sustainability for biopharma companies.

The downsides of WFI by distillation

While WFI by distillation maintains a stronghold in biopharma due to its traditional place in the market, traditional does not necessarily make it the best. Many of the benefits of ambient WFI (AWFI) production are realized in the shortcomings of the WFI by distillation process.

1.对公用事业的需求量很大

Distillation typically uses natural gas to generate steam to boil bulk water and produce vapor, which is then condensed using cooling water. WFI is then heated again and continuously circulated at high temperatures—ISPE guidelinessuggest 65°C is sufficient for self-sanitizing—to limit microbial growth, and later needs to be cooled just prior to use. Each step in this process adds considerably to the facility’s energy load. If we remove steam needs for major users like WFI, we can more easily accommodate alternative heating sources (e.g., electricity).

As an example, a 1.1-million-square-foot pharma facility we recently evaluated dedicates as much as half its heating and cooling needs to WFI production. The facility (designed before 2013) leverages vapor compression distillation, a technique that uses less steam than multiple effect distillation but far more electricity, and requires more cooling and pretreatment than membrane filtration. The pie graph below provides similar data from a different site, clearly showing that WFI production accounts for the bulk of the campus’ natural gas (steam) consumption.

Membrane-based alternatives that heat the water once—or not at all—use far less energy. Additionally, membrane-based WFI generation systems inherently reject less water as waste when compared to distillation systems due to reduced feed water pretreatment requirements.

This heavy natural gas consumption and water waste makes WFI by distillation a prime target forresource reduction measuresand improving utility inefficiencies, and an opportunity forsustainability efforts。

2. Not environmentally sustainable

The fuel of choice for producing steam in a pharma plant is typically natural gas, which generates a larger carbon footprint than asustainable electric generation option。蒸馏的广泛能源需求迅速使蒸汽成为任何脱碳作用的敌人。即使设施放弃了天然气，使用电动锅炉蒸馏支撑WFI所需的能量仍在继续造成资源的压力 - 一种足够大，以至于对于较大的WFI生成系统的需求可能是不切实际的。此外，由于蒸馏过程中产生的纯蒸汽的相变，蒸馏技术固有地需要大量的冷却水。这不仅包括由于机械制冷而导致的能源消耗，还包括冷却塔的排污和蒸发损失。

In contrast, ambient WFI production avoids significant temperature changes, incurs lower utility costs, and is all aroundmore sustainable。This is important forthe vast majority of life sciences companies—biopharma, startups, and CDMOs—with formalized sustainability goals.

3. Facility size

Membrane-based equipment can often fit into tighter spaces as it tends to be smaller than distillation stills. Shrinking the footprint intensifies the productivity of each square foot, reduces the energy load of heating, cooling, and lighting a larger building, and can free up space for other functions or future expansions.

4. Safety

The hot water continuously circulated through stainless steel pipes for WFI distillation poses a burn hazard to operators. Ambient WFI eliminates this concern as storage and distribution occur at room temperature, mitigating the burn hazard by reducing the time the system is required to be hot (i.e., during sanitization). Alternatively, the use of ozone for WFI system sanitization is in vogue for ambient and cold systems, which eliminates the burn hazard but introduces a less severe safety concern—personnel exposure during sanitization.

Pharmaceutical manufacturing facilities that have high-purity water on site, and are distilling it to make WFI, will try to minimize the use of WFI to only the processes that demand it, such as many CIP (clean-in-place) cycles. Risk analyses point to where you can use purified water for such things as cleaning solutions and ancillary uses. This allows you to limit the volume of expensive-to-produce WFI and thereby limit the capital and operating expenses associated with higher volumes of WFI.

How is membrane-based WFI generated?

Membrane-based reverse osmosis systems for WFI productionuse ambient processes to generate WFI of a similar quality to distillation.

Ambient WFI pretreatment

无论是蒸馏还是膜过滤，WFI都需要高质量的馈送水。必须预先考虑去除可能会损坏或犯规设备以及下游WFI设备的氯，硬度和其他离子（尤其是RO膜）。在水进入静止状态之前，蒸馏系统可能具有预处理。具有讽刺意味的是，这种RO预处理水的质量通常满足汇编WFI的要求，但需要根据过去的EMA法规进行蒸馏。

Feedwater, which must be potable, is fed into a series of pretreatment steps to remove solids, hardness, media and silt, and chlorine and organics. The softener step that removes hardness relies on brine. In some jurisdictions (e.g., Southern California), the large amount of salt generated by this process cannot be added to wastewater and has to be trucked offsite, incurring additional costs.

Ambient WFI final treatment

The pretreated water may be stored in a break tank, after which it undergoes double-pass RO filtration, deionization, and ultrafiltration on its way to the WFI storage tank and facility distribution system. The WFI in this loop can be sanitized with ozone or heat, and is typically treated with UV light for ozone destruct, general disinfection, or TOC reduction before being stored and distributed.

Reverse osmosis followed by ultrafiltration

The gold standard membrane systems use double-pass RO; however, in many cases WFI quality water can be achieved using single pass RO in addition to EDI and UF polishing.

RO membranes have the propensity to gather biofilms, which will shed endotoxin. To mitigate that risk, multiple safety steps are added to the system to prevent biofilm build-up.

• 内部热水消毒：在RO滑雪中停机期间，热水被杀死大多数微生物。在某些单位中，这伴随着紫外线处理。热水是使用蒸汽或电力产生的，对于那些寻求减少能源负荷并提高其可持续性性能的人来说，电力是首选。金博宝怎么注册

• Clean-in-place: Some RO membrane skids have a clean-in-place (CIP) capability. This is not a normal part of operations but can provide an annual preventive maintenance option to prevent biofilm build-up.

• Ultrafiltration: Ultrafiltration (UF) is the final barrier against endotoxin. RO membranes can remove particles in the size range of endotoxin; however, since RO membranes can also generate endotoxin due to its inherent design, a terminal or cross-flow UF module can be used.

Ambient WFI systems provide faster loop sanitization

传统的蒸馏系统将WFI保持在储罐和分配环中的80C，以最大程度地减少微生物的生长。然后，这些系统在从出口阀中释放出来之前冷却WFI。环境系统可以使用臭氧注射而不是热量来杀死微生物并减少TOC（即细菌食物），从而降低了内毒素产生的风险。然后在WFI从储罐中释放到分配环之前，紫外线将去除臭氧。

Storage and distribution loops can be sanitized using either heat or ozone. For example, CRB worked with a client to工程师一个环境WFI系统，依赖于臭氧储罐和电加热作为备用。这次现场环境WFI代替了购买桶装的WFI产生的异地，并释放了仓库内大量的存储空间。

Transitioning a facility from WFI by distillation to membrane filtration

If a facility already uses RO and EDI to make adequate amounts of purified water, it may be possible to replace aging distillation WFI equipment with a membrane-based WFI system by tacking on a UF unit and bypassing the need for steam heat.

However, switching from a distillation system to ambient WFI production is a potentially more complex undertaking. Given that the industry has only begun to accept membrane systems over recent years, more time is needed before we see facilities making that leap—but those facilities will come, particularly if they’re incentivized by the space and utility constraints of distillation. ATMP manufacturers and animal health companies are strong candidates for switching from distillation to AWFI.

Case study: A cost-benefit comparison of distillation and ambient WFI generation

Client needs

Our biopharma client wanted to market their injectable drug in Turkey, China, Russia, and South America, creating multinational regulatory complications because of differences in compendial requirements for WFI production.

They partnered with us to design an addition to their existing facility to produce this drug product, which required a new WFI generation system. The existing facility generated WFI with multiple effect stills but supplying the buildout with distilled WFI had disadvantages.

我们比较了他们的尝试蒸馏系统的相对优点，并有机会安装基于环境的膜系统。

Current WFI generation used multiple effect distillation

While the plant’s multiple effect stills were reliable, had few moving parts, were self-sanitizing, and recognized by pharmacopeias worldwide, they presented certain disadvantages:

• High feed water requirement
• Highest utility consumption
• Higher lifecycle cost than membrane-based
• High-pressure steam requirement

The last point—the need for 120 psi steam—meant steam would have to be piped over to the new space, yet there was no campus distribution to get it there. It was going to cost ~$500,000 to run one line to power a new multiple effect still. We suggested looking at alternatives.

替代WFI生产方法

Vapor compression

These systems are also recognized by all global pharmacopeias, can have lower utility consumption than membrane systems at higher generation capacities, and have a low pretreatment requirement. Their disadvantages include:

• High capital and life cycle costs
• Require regular maintenance

Membrane

Ambient WFI generation has low life cycle and capital costs and uses less energy. Its disadvantages include:

• Does not comply with the Chinese Pharmacopeia
• Potential for membrane failure
• Requires cleaning and sanitization
• Membranes need to be replaced

We decided to run a side-by-side comparison of the three equipment selections approximating their WFI needs, looking at utility use, space requirements and capital cost. For each category, we identified which method was the best option.

Utility use

Membrane filtration came out on top in terms of electricity used, cooling needs, and pretreatment (Figure 3). Vapor compression has lower steam requirements than membrane since the client’s process requires WFI to be heated prior to the storage and distribution loop. Still, membrane filtration slashes steam use by almost one-third compared to the client’s current multiple effect stills.

Space needed

The buildout was a new building with a premium square footage. Both distillation systems occupy more than twice the square footage than membrane filtration equipment (Figure 4).

Capital cost

The cost of pretreatment for both distillation options would drive this client’s capital costs far beyond that of ambient WFI generation systems, which include pretreatment in the process (Figure 5). In fact, membrane filtration is roughly half the price of the other options, even before factoring in the steam and other utilities that would have to be piped over from the existing facility.

结论：膜过滤是明显的赢家

This analysis quantified the advantages of installing a membrane filtration WFI system from an energy, space, and capital cost perspective. CRB installed a 40 gpm membrane WFI system—one of the largest available generation capacities offered at the time.

Ambient WFI systems are gathering steam in biopharma

Many pharmaceutical companies installed large distillation WFI systems fewer than 10 years ago and are unlikely to scrap these legacy systems for new equipment. It comes down to evaluating their manufacturing constraints, how reliable andefficienttheir current WFI setup is, and the regulatory requirements for their drug products.

适应新技术可能需要时间，但是毫无疑问，膜过滤是一种新兴的人。最高的采用率是合同制造商，初创公司以及该行业新手和建立新设施的产品。当他们寻求增加利润率时，他们对风险的兴趣往往会有所不同。另外，环境WFI是一个合乎逻辑的选择，尤其是如果您的过程从头开始并且不需要热水。CRB最近完成了ATMP GMP manufacturing facilitythat is completely electrified, without steam distribution, which includes an ambient WFI system. While this is in a mild climate, it points to the potential energy savings amortized over the life of the equipment using this innovative technology.

If you want to explore the many advantages offered by installing an ambient WFI system, our engineers can help.