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The Studyofofthe
theDesign
Design
ofofProduction
ProductionSystems
Systems
ofofPurified
Purified Water for
thePharmaceutical
the Pharmaceutical Industry
Industry
By I. Lerin Riera,
R. Salazar Macian,
J.M. Suñé Negre,
and J.R. Ticó Grau
University of Barcelona
O
Part I on the design (description of func-
c tioning) is carried out for each of
W
ater used in the phar- them, together with a report on the
maceutical industry, design.
especially water used to
manufacture drug products (puri- General Considerations
fied water and water-for-injection)
is vital to the manufacture of these The chosen pharmaceutical plants
products and, therefore, should be have been labeled Pharmaceutical
considered as a raw material that Plant A, Pharmaceutical Plant B, and
needs to comply, at a minimum, Pharmaceutical Plant C.
with specifications set out in Pharm- The study for each of the three
acopeia. plants has been separated into two
Presently, validation is essen- d distinct sections:
tial to ensure the reliability of any
system to produce water of phar- 1. Study of the design: A descrip-
maceutical quality. The first step to ensure the cor- tion of the functioning of the system. To examine the
rect functioning of the system is that each instru- design of each production system of Purified Water,
ment, each component, all the building materials, the study has been divided into two phases:
and all other considerations in the design of these
systems should comply with ruling Pharmacopeias Production and storage of purified water
and the current Good Manufacturing Practice Distribution of purified water to points of use
(cGMP).
This study examines the design of the production 2. Report on design: Contains recommendations
systems of purified water for the pharmaceutical for each point of improvement* (both critical and
industry in three pharmaceutical plants where a study noncritical) detected by the study in the design.
Figure 1
Production System for Purified Water Design Diagram:
Pharmaceutical Plant A
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Glossary R1 R2 R3
1. Chlorination 9. Ionic exchange
storage tank resins
2. Sand filter 10. UV lamp 16
3. Decalcification 11. 2 micrometer
equipment and 0,22
4. Intermediate micrometer filters
storage tank 12. Purified storage
(adding of sodi- tank R1: Recirculation 1
um hipochloride) 13. UV lamp
5. Carbon filter 14. 0,22 micrometer R2: Recirculation 2
6. Intermediate filters R3: Recirculation 3 (Distribution loop)
storage tank 15. Heat exchanger
7. Reverse 16. Distribution ring
Osmosis to points of use
8. Osmotic water
storage tanks
R2
Glossary
1. Chlorination storage 7. Reverse Osmosis
13
tank 8. Osmotic water
2. Adding of flocculant storage tanks
3. Dechlorination by 9. Ionic exchange resins R1
means of sodium 10. 1 and 0.22 micrometer
bisulfate filters
4. 10 micrometer filter 11. Heat exchanger R1: Recirculation 1
5. Adding of chelating 12. Purified storage tank R2: Recirculation 2 (Distribution loops)
agent 13. Distribution loop to
6. 5 micrometer filter points of use
Study of the Design: the two installations for demineralizing. In this way,
Description of the functioning of the system possible microbiological contamination in the inner
layers of resin is diminished when the equipment does
Production of Purified Water not produce water, whether there is no need for con-
Sand filter – decalcification equipment – chlo- sumption or simply because it is in reserve.
rination – Flocculation – adding of bisulfite – 10 • The microbiological quality of the water that
µm filtration – adding of abductor – 5 µm filtra - goes into the purified water tank and comes from the
tion – reverse osmosis – intermediate storage ionic exchange resins is ensured first by a 0.22 µm
tanks – ionic exchange resins – 1 µm filtration – filter and later by the heat exchanger. The water is
0.22 µm filtration – Heat exchanger – Purified stored at 80ºC in the heat-resistant storage tank,
Water storage tank. which is made of AISI 316 L stainless steel.
7 13
7 R1
Glossary
1. Adding of flocculant 11.a.Reverse Osmosis 14.b
2. Adding of chloride 11.b.Double reverse osmosis
3. Silex – anthracite filter 12. Purified water storage
4. Carbon filters tank R1: Recirculation 1: Distribution loops
5. 5 micrometer filter 13. UV lamps
6. Decalcification equipment 14.a.Distribution loop 1:
7. Ozonation Production
8. 5 and 1 micrometer filters 14.b.Distribution loop 2:
9. UV lamp Laboratory
10. UV lamp
• In this plant, water is also purified in two leave residual compounds, add odor or flavor, nor
stages, but differently from the other plants and, does it attack the membranes in the ionic exchange
because of the low conductivity of feed water, it is nor those in the osmosis stage. In this sense there
carried out through double reverse osmosis. should be no concern regarding the elimination of
• Dechlorination of the water is carried out using ozone after treating the water. However, it does have
two carbon filters in a parallel installation. a drawback when compared to chloride: Its effect is
• Note that from the moment the decalcified not as lasting, which implies that the water should be
water is obtained, its microbiological quality is treated later with chloride at a smaller dose (as a
ensured by the combined treatment of ozone (bacte- result of the prior treatment with ozone) or, as in this
ricidal and oxidizing agent) and of ultraviolet tech- case, repeat treatment along the entire system to en-
nology. sure the bacteriological quality of water thus treated.
• Throughout the system, the water is ozonated Nevertheless, it is well known that UV wavelengths
several times, specifically at the entry points to the employed in water treatment are 254 nm and 185
purified water storage tank, at the entry point com- nm; 254 nm UV light is employed in disinfection
ing from the production plant, and in all the returns and ozone destruction applications.
in the two distribution loops. Water is also ozonated
when it leaves the tank of purified water before the Storage and Distribution of Purified Water to
water enters each of the two loops, just prior to the Points of Use
last treatment with ultraviolet lamps. Purified Water storage tank – ozonation – UV
lamp – distribution loop – ozonation – Purified
Keep in mind that the use of ozone as a bacterici- Water storage tank
dal agent is far more convenient than treatment with
chloride; the effect of the ozone is not influenced by The design shows two independent distribution
the pH in the medium. On the other hand, it does not loops from a sole tank of purified water. The micro-
After studying the design of Pharmaceutical Plant 2. Carbon filters: To avoid the problems of micro-
C, it can be said that it is correct to achieve water of biological contamination and maintenance these
microbiological and chemical quality as set out in systems require, it is preferable to remove them and
the norms for purified water to be used in the phar- obtain dechlorinated water by means of a system of
maceutical industry. bisulfite dosage with its corresponding controls. It is
Note that there are two differences between the advisable to:
design of the Pharmaceutical Plant C and that of the
Pharmaceutical Plants A and B. a) Strictly record the cleaning and sanitization
The first difference is that once the water has been processes, which should be carried out at least
decalcified, ozone is used together with ultraviolet once a week. Experience will suggest the most
technology to assure microbiological quality. The other adequate frequency to ensure that the microbi-
difference lies in the double-sequenced reverse osmo- ological levels are within limits.
sis treatment, which enables correct conductivity of the b) Check the microbiological level of the water
water. The high quality level of the water obtained by twice a week at the point it leaves the carbon
double osmosis makes the ionic exchange resins in the filter.
system unnecessary, thus avoiding the drawbacks they
represent in the regeneration of same. 3. Ozonation: Bear in mind that, in this plant, the
Keep in mind that the application of double- ozone and UV treatments are used consecutively.
reverse osmosis is recommended only for water with Although apparently this is contradictory to previ-
low conductivity (under 600 (s/cm), as an increase ous statements; as a general rule, a UV dosage of
of concentration will overcome the retention capac- 90,000 (W-s/cm2 is required to completely destroy 1
ity of the reverse-osmosis, thus causing the water ppm (1 mg/l) of residual ozone.
leaving the osmosis modules to have a conductivity The bactericidal treatment of water by using
over the limits. ozone is a technologically correct option, but it is far
Should the water have a high conductivity too expensive. Therefore, it is recommended to
(600–1500 (s/cm), employ ionic exchange resins or replace this treatment with one less expensive, such
electrodeionization equipment (CDI), as these meth- as ultraviolet lamps, as these represent much lower
ods have a greater power of retention than that of maintenance costs.
reverse osmosis. Points of improvement are understood to be those
There are several points where improvements can points where the final quality of the product as well
be made. as the productivity of the process might be affected.
These points of improvement are divided into criti-
Recommendations cal and noncritical points.
1. Recirculation between the purified water storage Critical points are those which affect or might
Figure 5
Optimized Design (Plan 1/2)
Production of Purified Water Clean
Steam
Vent
7
FIlter
3 Silex- 5 µm
Anthracite Filter
6
1 2 Filter 3 4 5
Chloride 8
1 Detector Decalcified
Chlorination Water
Feed Tank Storage
Water Tank
2 Adding of 5 Dechlorination
Flocculant 10
Through
Return from the 4 Decalcification Bisulfite
Distribution Loop Clean Equipment
14 UV
Steam
TOC Sterile Vent
FIlter HEPA
R1: Recirculation 1
12 15
Purified
Water 11 9 8 7 6
Storage 10
Distribution
Tank 13 UV C 11 UV Reverse 9 UV
Loop
Osmosis
12
CDI: Electrodeionization C: Conductivity meter on-line
Equipment
TOC: (Total Organic Carbon)
TOC measurer on-line
19 UV
R2: Recirculation 2 HEPA Sterile
Clean TOC
Steam Vent Filter
15 11
Points of Use 18 Distribution Loop Purified
Water
Storage From
Tank Production
15 14 13 12 Plant
17 UV
16
Heat TOC: (Total Organic Carbon)
Exchanger TOC measurer on-line
When leaving the tank, the flocculant is added to tank, it flows through a 5 µm filter to retain parti-
cause a flocculation of solid matter, easing its elimi- cles which might break away from the decalcifica-
nation through filtration by silex-anthracite, the func- tion equipment.
tion of which is to retain suspended solids. The water enters the decalcified water storage
The water, once filtered, goes through decalcifica- tank, which is sterilized by clean steam.
tion equipment, which retains calcium and magne- After the water leaves the decalcified water tank
sium in the water. The equipment is made up of a and prior to it flowing into the reverse osmosis, the
double cationic resin in sodium cycle, with the aim of water flows through an ultraviolet lamp to ensure its
carrying out an automatic regeneration of resins, i.e., microbiological quality before entering the reverse
when one of these goes into a regeneration period, osmosis modules.
the other column starts functioning. This means that Water is driven by two autonomous high-pressure
it is not necessary to stop the production of purified sanitary pumps (15/20 atmospheres) into the
water to allow for the regeneration of these resins. polyamide membranes of the reverse osmosis mod-
Once the water has gone through the decalcification ules to carry out the first stage of deionization, elim-
equipment and just before it enters the decalcified water inating 95 – 97% of the salts in the water, thus
storage tank, dechlorination of the water takes place by allowing the desired quality to be attained in an eco-
injecting bisulfite into the system, avoiding the chloride nomical way.
attacking the membranes of the reverse osmosis.
As chloride, even at low concentrations, could dam- Purification of Osmotic Water
age the membranes of the reverse osmosis module, Into Purified Water
there is a chloride detector after the dechlorination mod-
ule and just before the entry of water into the decalcified Reverse osmosis – W lamp – electrodeioniza-
water storage tank. This ensures that the process is tion (CDI) – Wlamp – Purified Water storage tank.
stopped should there be a high level of chloride in the
water and thus preventing it from entering the tank. Once it has gone through the reverse osmosis, the
Prior to the water entering the decalcified water water passes the ultraviolet lamp, ensuring its micro-
Figure 7
Optimized Design (Plan 2/2) Storage and Distribution of
Purified Water to Points of Use – Heated Water to 80ºC
HEPA Sterile
Recirculation of
Clean TOC Vent Filter
Purified Water
Heated to 80ºC Steam
RS
Figure 8
Recirculation 1
Water Coming
from the
Decalcification 8
Equipment Decalcified 10
Water 9 UV Reverse 11 UV
Storage Osmosis
Tank
R1 Recirculation
14 UV
Vent 12 CDI
Filter
HEPA
Conductivity
C
15 Meter
Distribution Purified
Water 13 UV
Loop
Storage
Tank
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142 Special Edition: Utilities Qualification
carbon filt ers need a strict and continu ous mainte- The general recirculation R I, whi ch includes
nance program. reverse osmos is and the electrode ioni zation equip-
me nt, helps ensure that, should there be a stoppage,
2. Usi ng electrode ioni zation equ ipment (COl) to the poss ibi lity of problems as a result of mi crobio-
rep lace the ionic exchange resins presents econom- logical contamination are reduced to a minimum in
ic, sa fety, and environmental advantages, as elec- the osmosis membranes and electrodeionization re-
trodeioni zation avo ids the use of the chemical solu- sins, as the water is rec ircul ating through thi s equip-
ti ons empl oyed to regenerate the resi ns of ionic ment.
exchange. Constant recircu lation of the water in R2 prevents
water from becoming stagnant in the distribu tion
3. The combined use of reverse osmos is and e lec- loop, avoiding the possib le risk of microbiol ogical
trodeionization technology full y ensures the chemi - contamination.
cal and microb iological quality of purified water
obtained in an operati ve and inex pensive way. 6. Chlorine is eliminated before the water enters
the tank of decalcified water because of R I reci rcu-
4. The use of ultraviolet lamps as di sinfectant lation. In thi s way, when recirculation is started aft er
along the system assures the microbiological quality a stoppage of the system, there is no need to dech lo-
of the water at all times. In addition, thi s method rinate constantly.
creates an advantage over the use of high-efficiency
filt ers for thi s purpose when it comes to mainte- 7. The heat exchanger has two functio ns: peri od-
nance, clean ing, and sanitization. High-efficiency ical saniti zations and regulating the water tempera-
filters have to be sterili zed periodi cally to avoid pos- tu re (not hi gher than 22°C).
sible microbiological contamination; therefore their
mainten ance makes the production of purified water 8. Note the on- line control of the conducti vity of
more ex pensive. the water when it leaves the e lectrodeioni zation
equipment. If the conductivity is over the limit set
5. Regarding the recircul ation s in the system: by the USP 23, it stops the system.
Figure 11
Microbiological Critical Points 1, 4, 5, 6, 7, 8, 9,10,11,12,15,16,17
and Points of Use
. . . . Determinations and Specifications
1 Entry of feed water into system Total aerobic at 32°C «200 CFU/ml) and
no traces of total fecal colifoms in 100 ml
4 Entry to decalcified water storage tank (8)
5 Exit of decalcified water storage tank (8)
6 Entry to reverse osmosis
7 Exit from reverse osmosis Total aerobic 50-100 CFU/ml. No traces in
100 ml of E. coli and Ps. aeruginosa
8 Ent ry into the electrodeionizalion equipment (COl)
9 Exit from electrodeionization equi pment
10 Entry into tank (8) from recirculation R1
11 Entry into purified water storage tank (15)
12 Exit from purified water tank (15), prior to UV lamp (17)
15 Entry into distribution loop, after UV lamp (17) Total aerobic 10-20 CFU/ml. No traces in
100 ml of E. coli and Ps. aeruginosa
16 Return of distribution loop, prior to UV lamp (19)
17 Return to purified water tank (15), after UV lamp (19)
Note: The fower limit IS the alert limit and the higher one IS the action limit.
Figure 13
Weekly Sampling Criterion (Microbiological)
Points in the Total Monday Tuesday Wednesday Thursday Friday Total Points
System Points Sampled
A. Pre-Treatment 11 2 2 2 2 3 11
B. Points in Loop:
B.1 Control Points 6 1 1 1 1 2 6
B.2 Points of Use 40 8 8 8 8 8 40
In such a way that:
• Every week all the pre-treatment points and all points in the distribution ring are sampled.
• At the end of the 4 week’s validation period, four samples from each point will have been taken
Total Aerobic at
32"C (in CFUlml) <200 <100 <100 50-100 50-100 50-100
Total Coliforms No traces
in 100 ml
Faecal No traces
in 100 ml
E. coli No traces No traces No traces No traces No traces
in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml
Ps. aeruginosa No traces No traces No traces No traces No traces
in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml
( .) When two values are shown in the specifications, the first one is the alenlimit and the second one is the
action limit.
Total Aerobic at
32°C 50-100 50-100 50-100 50-100 10-20
E. coli No traces No traces No traces No traces No traces
in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml
traces traces
in 100 ml in 100 ml in 100 ml in 100 ml
1 recircula tion.
Figure 16
Points of Use of the Distribution Loop:
Determination and Specifications
B. 1 - Contro' Sampling Points
Total Aerobic at
32"<: (in CFU/ml) 10-20 10-20 10-20 10-20 10-20 10-20
E. coli No traces No traces No traces No traces No traces No traces
inl00ml in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml
Ps. aeruginosa No traces No traces No traces No traces No traces No traces
in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml in 100 ml
B.2 - Points of Use
Determination Points of Use: Specifications
Total Aerobic at 32"C (in CFU/ml) 10-20
E. coli No traces in 100 ml
Ps. Aeruginosa No traces in 100 ml
Figure 17
Weekly Sampling Criterion (Chemical)
Points in the
System
A. Pre-Treatment 4 4
B. Points in Loop:
B.l Control Points 2 1 1 2
B.2 Points of Use 40 8 8 8 8 8 40
a way
• Each week all the critical pre-treatment and all the critical points in the distribution loop will be sampled .
• At the end of the 4 weeks of the I will have been taken at each i.
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146 Special Edition: Utilities Qualification
Figure 19 Determinations and spec ifi cation s.
B.I Control sampling points
Points of Use of the Distribution
Loop: Determinations Discussion
and Specifications
B. 1. - Control Sampling Points The novelties presented in this optimized design are:
Elimination of sterili zing filt ers, which are very
efficient but expensive 10 maintain, can somelimes
cause "accidents" by blockage, raising the microbi-
ologicallevel of the water (bioburden).
Introduct ion of a decalc ified and dechlorinated
Aspect Transparent Transparent water storage tank, which ensures that water enter-
ing the reverse osmosis equipment will always be
Color Colorless Colorless
chlorine-free and have a very low mkrobiallevel.
Odor Odorless Odorless Rl recirculation circuit: The decalcified water
TOe 350-500 ppb 350-500 ppb tank is the center of the R I recirculation circuit,
which ensu res that water in pretreatment wi ll con-
Conductivity 0.5-1.3 )ls/cm 0.5-1 .3 )ls/cm
stantly have a very low microbial level, which in
B.2. - Points of Use practice means obtaining purified water with a
Delenmnal10ns POints of Use: SpeCificatIOns microbial level under 5 CFU/ml.
Aspect Transparent
Presently, the function ing and control of water pro-
Color Colorless
duction systems are regulated on-line by means of spe-
Odor Odorless ci fi c software through a PLC (Programmable Logic
TOe 350-500 ppb Controller) .
Conductivity 0.5-1.3 !ls/cm
Conclusion
II. Entry into the purified water storage tank
The proposed design is easy, economical to main-
B. Points along the distribution loop tain , and ecological because it has no high-efficien-
8. 1. Control sampling points: (2) cy filters, eli minating the constant regeneration of
15 . Entry into the distribution loop, after UV lamp the ionic exchange resins. It should also be pointed
17. Return 10 the Purified Water storage tank, out that stainless steel tanks for decalc ified and puri-
after UV lamp fi ed water can be sterili zed easi ly and regularly by
B.2. Points of use: A ll (40) means of clean steam.
Therefore, validation of the system will ensure
Sampli ng is to be earned out according to the cri- the production of water will be dependable and with-
terion set oul in the follo wing table: in the specified limi ts. In this case it will be easy 10
prove that the price of the purified water will be
• Each week all critical pretreatment points and competitive and , in practice, less expensive then
all cri tical points in the distribution loop are other water-producing systems. 0
sampled .
• At the end of the four weeks of validation , four
samples will have been taken at each point.
Resource…
edition, Associazione Farmaceutici del’industria, Roma, 1991.
3. Collentro W., Angelucci L., “Coordinating Validation Re-
quirements for Pharmaceutical Water Purification Systems,”
Pharmaceutical Technology, Sept 1992, pp. 68-78.
4. Good Manufacturing Practices for Pharmaceutical Products,
Annex: Guidelines on the Validation of Manufacturing Processes.
WHO Expert Committes on Specifications for Pharmaceutical Glossary of Computerized
System and Software
Preparations, Thirty-second Report, Genova, 1992.
5. Guide of Correct Norms for the manufacture of medicine in
the European Community, Ministry of Health and Con-
sumption, General Management of Pharmacy and Sanitary
Products, General Sub-management of Pharmaceutical Development Terminology
Control, Madrid, 1992.
6. FDA, Guide to Inspections of High Purity Water Systems, July
1993. This document serves
7. Berry I.R., Nash R.A., Pharmaceutical Process Validation, as a glossary of terminol- AN
SERVICE
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UM U
Second Ed. Marcel/Dekker Inc. Cap 9: Ward Journal,
SA
&
F HEALTH
Validation of Water Systems for Sterile and Non Sterile ogy applicable to soft-
TO
Products, 1993: 299-317. ware development and
EN
M
RT
8. Gibes S., The Second European Pharm Tech Conference, DEPA