A NOVEL, COMBINATION REVERSE OSMOSIS EDI WATER PURIFICATION SYSTEM FOR THE PHARMACEUTICAL INDUSTRY


Blue Spring Corporation manufactures edi-based pharmaceutical USP water systems

For details, specifications for Blue Spring WFI-EDI system, click here
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Water-quality plays an important role in the manufacture of pharmaceutical products. Process water is used to compound products, to wash containers, and for steam-sterilization. There are two basic grades of water1 popularly used in the pharmaceutical industry:  (a) Purified Water and (b) Water-for-Injection (WFI). Purified Water is meant for formulation of non-injectable OTC products, that do not contact blood. It must be chemically pure, because chemicals in water do get absorbed into our body through the digestive tract, but it does not have to be biologically ultra-pure, because our intestines are capable of filtering out most, but not all of the harmful biological contaminants. Water-for-injection meets the chemical purity requirements of Purified Water and in addition, must meet stringent biological purity requirements, because the water enters the blood-stream directly. The biological purity requirements are expressed in terms of two standards: bacteria-count and endotoxin-content. Bacteria are responsible for causing diseases. Endotoxins are by-products of bacteria that cause fever almost immediately, which is why they are called "pyrogenic" matter 2.

The United States Pharmacopoeia (USP) is the bible of the pharmaceutical industry that defines how things are done there. The pharmaceutical water standards have always evolved around the contemporary water purification technologies. Table 1 lists the technologies for pharmaceutical water purification that dominated during certain era, and the applicable USP standards. Until USP Vol. 22, the chemical purity of  Pharmaceutical water called for total dissolved solids (TDS)  of  <10 mg/L, which corresponds to electrical conductivity of approx. 16 microS/cm. This was easily achievable by conventional ion-exchange (IX) process, reverse osmosis (RO), or distillation. Beginning with  Vol. 23, USP abandoned the TDS standard in favor of electrical conductivity measurement together with Total Organic Carbon (TOC) standard (please refer to Table 1). The current conductivity standard of 1.3 mS/cm essentially makes the older water purification systems obsolete, creating new opportunities for new technologies to come up with new design technologies.
TABLE 1.  SPECIFICATIONS FOR USP GRADE WATER
 
  Before USP Vol. 20
(prior to 1984)
  USP Vol. 20-22
(Circa 1984-1998)
  USP Vol. 23-27
(Circa 1999-2003 )
  USP Vol. 28 and later
(Circa 2004 )
 
Purified
Water
Water for
Injection
Purified
Water
Water for
Injection
Purified
Water
Water for
Injection
Purified
Water
Water for
Injection
TDS
10 mg/L
10 mg/L
10 mg/L
10 mg/L
-
-
-
-
Electrical
Conductivity
-
-
-
-
1.3
microS/cm
  1.3
microS/cm
1.3
microS/cm
1.3
microS/cm
TOC
-
-
-
-
500 ppb
500 ppb
500 ppb
500 ppb
pH
5.0-7.0
5.0-7.0
5.0-7.0
5.0-7.0
5.0-7.0
5.0-7.0
-
-
Chlorides
500 ppb
500 ppb
500 ppb
500 ppb
-
-
-
-
Ammonia
300 ppb
300 ppb
300 ppb
300 ppb
-
-
-
-
Sulfate
Qualitative
Qualitative
Qualitative
Qualitative
-
-
-
-
Calcium
Qualitative
Qualitative
Qualitative
Qualitative
-
-
-
-
Heavy
Metals
Qualitative
Qualitative
Qualitative
Qualitative
-
-
-
-
Oxidizables
Qualitative
Qualitative
Qualitative
Qualitative
-
-
-
-
Carbon
dioxide
Qualitative
Qualitative
Qualitative
Qualitative
-
-
-
-
Bacteria
Max
EPA 40CFR
141.14;141.21
  EPA 40CFR
141.14;141.21
  EPA 40CFR
141.14;141.21
  EPA 40CFR
141.14;141.21
EPA 40CFR
141.14;141.21
  EPA 40CFR
141.14;141.21
EPA 40CFR
141.14;141.21
EPA 40CFR
141.14;141.21
Bacteria
Alert
(FDA)
100 cfu/ml
10 cfu/ml
100 cfu/ml
10 cfu/ml
100 cfu/ml
  10 cfu/100ml
100 cfu/ml
  10 cfu/100ml
Pyrogens
-
Rabbit Test
-
-
-
-
-
-
Endotoxins
-
-
-
LAL Clotting
-
0.25 EU/ml
-
0.25 EU/ml
Final
Purification
Process
Any
Distillation
Any
Distillation,
Reverse
Osmosis
Any
  Distillation,
Reverse
Osmosis
Any
Any
Popular
Water
Systems
Distillation,
Ion-Exchange
Distillation, Ion
Exchange+
Distillation
  Distillation,
Ion-Exchange
RO+RO, Ion
Exchange+RO,
Distillation, Ion-
Exchange+
Distillation
RO+EDI,
Ion-exchange
RO+EDI+RO,
RO+EDI+
Distillation, Ion-
Exchange+
Distillation
RO+EDI,
Ion-exchange
RO+EDI+RO,
RO+EDI+
Distillation, Ion-
Exchange+
Distillation
The Water-for-Injection (WFI) has additional requirements of  bio-purity. The endotoxin-content must be less than 0.25 Endotoxin Units (EU) per ml. Typical municipal water contains 200-1,000 EU/ml level of endotoxins. Currently, the alert level for bacteria content is 10 colony forming units (cfu) per 100 ml which is 2,000-4,000 times stricter than the generally accepted guideline of 200-400 cfu/ml adopted by most municipalities. These pharmaceutical bio-standards are difficult to attain without the help of definitive water purification processes; such as, distillation and reverse osmosis. One of the USP requirements for Water-for-Injection until Vol. 28 was that the final water purification process must be either distillation or reverse osmosis, both of which are true water purification processes, as opposed to water treatment processes.  Even though USP does not specify the method of water purification, it is difficult to achieve the endotoxin standards for the Water-for-Injection, without using either distillation or reverse osmosis as the final process.

In pharmaceutical industry, the water purification system must be definitive and consistent, particularly with respect to bio-purity of water. The legendary pharmaceutical water system during the distillation era was a complex mixture of water softeners, carbon beds, IX resin beds, multi-stage distillation columns, polished stainless steel tanks, water heaters and coolers, distribution pumps, UV-light sanitizers, bacteria filters and monitoring instrumentation, all of which occupied space, and cost anywhere from $250,000 to $2 million. In comparison, the modern pharmaceutical water purification system that achieves ten-fold improvement in performance, costs ten-fold less and occupies ten-fold less space is exemplified by Blue Spring System WFI-EDI, which is a double-pass reverse osmosis system incorporating EDI enhancement.

Reverse osmosis (RO) offers simplicity, high output flow capacity, compactness, and low cost. RO-based WFI installations also eliminate the need for:  storage tanks for WFI, re-circulation pumps, bacteria filters, UV-lights, and the associated maintenance costs. RO process is also far more efficient, in removal of pyrogenic endotoxins from water than distillation. One problem with the RO process is that with typical municipal water measuring 300-600 mg/L TDS, the RO membranes can barely achieve the older <10 mg/L TDS USP standard. To meet this standard on a consistent basis, a double-pass RO in which the output of the first RO is further purified by a second RO, was commonly used in the industry. The best the double-pass RO could do was 1-2 mg/L for most city waters. But this is not good enough for the current USP XXVII, which calls for electrical conductivity of  <1.3 mS/cm, which is equivalent to TDS of  <0.82 mg/L. Help is needed from another de-ionizing technology.

Electro-de-ionization (EDI) is the process of removal of ionic impurities from water, by the passage of  electric current. It started in 1984 with O'Hare patent (U.S. 4,465,573) but it was not commercially developed until the late 1990s. Since then, there have been several exciting developments in the EDI technology that make EDI the path of the future for de-ionization of water. For example, the latest, spiral-wound EDI module design3 is leak-proof, serviceable and cost-effective, in comparison with the original flat-stack design.

Modern EDI uses a pair of ion-permeable membranes4 to separate the ions from the water, under the influence of DC electric current. The EDI cell is filled with ordinary mixed-bed IX resin to enhance  removal of ions and to lower electrical power consumption. The electric current also produces H+ and OH- ions by splitting water molecules. These ions effect in situ, continuous regeneration of the IX resins. EDI is environmentally friendly, because it uses no chemicals for regeneration. EDI is a continuous process, which means the equipment is on-line 24/7. Conventional IX equipment is intermittent, due to periodic regeneration requirements. EDI provides water of consistent purity, as opposed to conventional IX process, which exhibits cyclic swings in water purity. The capital cost of the EDI equipment is higher, but the operating costs are lower. EDI is more suitable for pharmaceutical water processing than conventional IX, because EDI offers consistency of output water quality, which the conventional IX process lacks.

One big disadvantage of EDI process is that it requires pre-purification of water to a conductivity level below approximately 25 mS/cm. It is common practice in the EDI industry to use a reverse osmosis (RO) unit as pre-treatment for EDI feed water, to meet this pre-requisite. Direct use of the EDI output is suitable as Purified Water category per USP, but it must undergo further purification, either by reverse osmosis or by distillation to qualify it as WFI. This is because EDI is not capable of removing organics and biological impurities with any consistency, and may actually add these impurities to water.

Combining EDI and RO technologies can overcome the limitations of either technology. The most logical system configuration consists of two RO units and an EDI unit in-between. Initially, the municipal water is pre-treated to remove hardness and chlorine, before entering the RO/EDI system. The first RO unit serves as pre-treatment for the EDI unit. The EDI output may be used directly in Purified Water applications. The second RO unit upgrades the output of the EDI unit to WFI level, per USP requirements. A typical RO/EDI system producing 6 gpm of WFI quality water occupies only 6'x7' space and costs an order of magnitude less than an equivalent distillation-based system, in terms of capital costs, operating costs, and maintenance costs.

Typical service requirements of the RO/EDI installation in the pharmaceutical industry include:  weekly replenishment of salt for the water softener; semi-annual replacement of activated carbon beds; weekly cleaning and sanitizing of the RO membranes; periodic changing of cartridge filter elements; replacement of RO membrane elements every 2-5 years; and replacement or servicing of the EDI modules, when required. There are also electro-mechanical service items like pumps, valves, piping, system instrumentation and EDI power supply.

References:
1. Satish Desai, "EDI in Manufacture of Pharmaceuticals", Water Technology, March 2004,  p 74-76
2. Satish Desai, "Dialysis Induced Fever",  Nephrology News & Issues, March  (1989), p 11.
3. Jeff Tate, "An Introduction to Spiral-wound EDI", Water Technology, Jan. 2003.
4. "Ion Permeable Membranes", by T.A. Davis, J. D. Genders and D. Pletcher, Alresford Press, 1997