H&E-Purified Water System PDF

Innovative Production of
Water for Pharmaceutical Use

JJ Pharmatec Technical Seminar
28. August - 1. September 2006
Kuala Lumpur - Jakarta - Bangkok

Overview
Current Guidelines and Requirements on

Water for Pharmaceutical Industry
Innovative Generation of Purified
Water and Highly Purified Water
with Membrane Technologies
- Reverse Osmosis
- Membrane degasification
- Electrodeionisation
- Ultrafiltration
Professional Raw Water Treatment
Qualification of PW-Systems
JJ Pharmatec Technical Seminar, August/September 2006 2

Requirements on Water for Pharmaceutical Use
Regulations and Guidelines for Design and

Processing of Water Treatment Systems: European Pharmacopeia EP 5.6 (valid from 1.06.2006)
US Pharmacopeia USP 29 (valid from 1.01.2006)
Japanese Pharmacopeia JP 15
Water quality and analytical methods
Note for Guidance on Quality of Water

EMEA (European Medicines Agency) for Pharmaceutical Use“
FDA (U.S. Food and Drug Administration) Guide to Inspection of high purity water systems
21 CFR 210/211, 21 CFR Part 11, 21 CFR 177
European Commission (EG) Guide to Good Manufacturing Practice (1991)
PIC/S (Pharmaceutical Inspection Convention) Guide to Good Manufacturing Practice for

Medicinal Products (2003)
GAMP-Forum GAMP 4.0 (2003)

Guide for Validation of Automated Systems
ISPE (Intern. Society for Pharmaceutical Eng.) BASELINE Pharmaceutical Engineering Guide
Volume 4 Water and Steam Systems (2001)
Special requirements of the client

Requirements EP 5.0 / USP 29
Purified Water (PW) EP USP

TOC < 500 ppb < 500 ppb
or Oxidisable Substances < 3,2 ppm KMnO4/l
Electrical Conductivity < 5,1 µS/cm (25 °C) < 1,3 µS/cm (25 °C) Stage1
Bacteria < 100 CFU/ml < 100 CFU/ml
Nitrate < 0,2 ppm -
Heavy Metals < 0,1 ppm -
WFI (as PW before, but) EP USP

Electrical Conductivity < 1,3 µS/cm (25 °C) Stage1 < 1,3 µS/cm (25 °C) Stage1
Bacteria < 10 CFU/100 ml < 10 CFU/100 ml
Bacterial Endotoxins < 0,25 EU/ml < 0,25 EU/ml
Highly Purified Water (HPW) EP

as WFI before

Methods for Generation of Water
for Pharmaceutical Use
Highly Purified Removal of Bacteria and Water for Injection

Water Pyrogens
Distillation
Ultrafiltration
only EP only USP/JP
Purified Water Desalination / Pure Steam

(Aqua Purificata) TOC-Reduction Generator
Electrodeionisation
Reverse Osmosis
Ion Exchange
Drinking Water

Generation of PW and HPW
PW-Generation-History
Before 1990 Ion Exchange Systems

Since an ion exchange system is not able to remove
Bacteria, Endotoxins and Organica (TOC)
1990 – 2000 Two-Pass Reverse Osmosis
Since publication of USP23 it is required to check the water quality by means of
measuring of the water conductivity instead of wet-chemistry testing in the
laboratory. Two-pass RO is not able to achieve a conductivity clearly below the
new limit (1,3 µS/cm). Typical quality after 2-pass-RO approx. 1 µS/cm.
Since 2000 Reverse Osmosis / EDI
Excellent Pure Water Quality, clearly below the required limit values
El. Conductivity ~ 0,2 µS/cm
TOC ~ 20 ppb
Bacteria ~ 5 CFU/ml

Generation of PW und HPW
Prefilter Ultrafiltration (only for WFI/HPW-

Softener or Antiscalant- Production)
Dosing Equipment for Sanitization with
Reverse Osmosis (RO) Chemicals or Hot Water
Membrane degasification Switch Cabinet for fully
(only for high CO2-content) automated operation
Electro-Deionisation (EDI)
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water
CF PU HEX RO MDG EDI UF

• Pre-Filter
• Softener or Antiscalant-Dosing
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

Function Filtration/Softening
Pre-filtration
The Prefilter (approx. 100 µm) serves for removal of rough particles
from the drinking water network as a protection for the downstream
Water Treatment System
Antiscalant-Dosing
To avoid scaling of hardness on the RO membranes a small amount of
Antiscalant Chemical is dosed into RO feed water.
Softening
In the softener ion exchanger resin causes hardness elements (such
as Calcium and Magnesia) to be replaced by an equivalent amount of
sodium ions. For regeneration of the softener the resin bed has to be
charged with brine (concentratred salt dilution) periodically.

PHARMASOFT / ECOSOFT
Characteristics
Reliable and permanent protection of the

downstream RO and EDI against precipitation
Minimised risk of microbiological contamination

due to serial operation (continuous flow)
Polisher minimizes the risk of

hardness breakthrough
Automatic chemical disinfection at every

umpteenth regeneration
Options
ECOSOFT minimizes Water and Salt

consumption (Counter-current regeneration)
ECOSOFT TS with hot brine sanitization
Residual Hardness Control

ECOSOFT TS Hot Brine Sanitization
Highest Sanitization effect due to

the combination of elevated temperature
with brine regeneration
Fully Automatic Sanitzation during

Regeneration without interruption
of Water Generation
No corrosion problems due to

complete plastic design
(Maximum temperature 65 C)

Prefilter
Softener connected in series
• Reverse Osmosis (RO)
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

Functional Description Reverse Osmosis
Water ingredients (salt ions, particles, colloids, Bacteria,

endotoxins) are held back at the surface of a semipermeable RO-
membrane, almost pure water is filtered through the membrane.
Removal
- Salt ions approx. 98-99%
- Organics > 90%
Permeate conductivity 5-10 µS/cm

depending on raw water quality

Characteristics of Reverse Osmosis Systems
No removal of dissolved gases (e.g. CO2)
Production of 75-80% demineralized water (permeate)
approx. 20-25% concentrated waste water (concentrate)
Lifetime of modules
approx. 5 years

Technologies - Reverse Osmosis
∆p

Prefilter
Reverse Osmosis (RO)
• Membrane degasification
(only for high CO2-content)
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

Function membrane degasification
Liquid Out
Gas
In Gas
Functional Principle
Installation of a partial pressure gradient
over the membrane
Diffusion of the on the water side dissolved

carbonic acid (CO2) through the membrane
Discharge of carbon dioxide (CO2) on the gas side pLiquid pLiquid

with dry, oil free compressed air or nitrogen pGas
Gas
Out
Gas
Liquid In + CO2

Technologies - Membrane Degasification
Characteristics and
advantages
Chemical-free CO2-removal
No risk of bacterial contamination
Easy Sanitization (Chemical or Hot water)
Low required space
Modular system
Low operation costs

Prefilter
Membrane degasification
• Electro-Deionisation (EDI)
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

EDI - Functional principle
Ultrapure Concentrate Ultrapure Concentrate

Product Recycle Product Recycle
Cation Membrane
Anion Membrane
Na+ CI- Na+ CI-
Feed Diluting Concentrating Feed Diluting Concentrating

Compartment Compartment Compartment Compartment
(D Chamber) (C Chamber) (D Chamber) (C Chamber)


Cation Membrane
Anion Membrane
Anion Membrane
CATHODE Na+ ANODE
Cl- Na+
Cl-
H+
Cl-
H+
+
Na+
OH- OH-
Anion
Cation
Resin
Resin
Na+ CI- Na+ CI-
Electrolyte Electrolyte
Feed Diluting Concentrating Feed Diluting Concentrating
Compartment Compartment
Compartment Compartment Compartment Compartment
(E Chamber) (E Chamber)
(D Chamber) (C Chamber) (D Chamber) (C Chamber)


Cation Membrane
Anion Membrane
Anion Membrane
CATHODE Na+ ANODE
Cl- Na+
Cl-
H+
Cl-
H+
++
Na+
OH- OH-
Anion
Cation
Resin
Resin
Na+ CI- Na+ CI-
Electrolyte Concentrating Electrolyte

Feed Diluting Concentrating Feed Diluting
Compartment Compartment Compartment
Compartment Compartment Compartment
(E Chamber) (C Chamber) (E Chamber)
(D Chamber) (C Chamber) (D Chamber)

Functional Description Electrodeionisation
Combination of Membrane- and Ion Exchanger technology
Under the influence of an electrical DC voltage field, ions (salts)

are moving over the very good conductive resin surface through
semipermeable membranes out of the process chamber into the
concentrate chamber
Chemical free, continuous regeneration of the ion exchanger

through splitting of the water on the resin grains

Functional description Electrodeionisation
Pure water conductivity approx. 0,1- 0,2 µS/cm
Reduction of TOC, Bacteria and Endotoxins
Necessary voltage approx. 100 - 400 V
Necessary operating pressure approx. 3 bar
Lifetime of modules approx. 5 years

CDI-LX Exploded View
O-ring seals
Anion membrane
Cell spacer
Tie rods
Cation membrane
End plate

Special features of our EDI-Design
Advantages of Plate Design compared to Spiral-Wound Design
Longer average lifetime of EDI-modules 5 years

No need of concentrate recycle to increase conductivity leads to
- No risk of scaling and chlorine build-up in concentrate
compartment
- No risk of microbiological contamination
- Concentrate Compartment incl. in hot water sanitization cycle
Higher stability against pressure and temperature fluctuations
Safety valve upstream EDI to avoid pressure hammers
EDI-Stack with FDA-declaration of conformity

Prefilter • Ultrafiltration (only for

Softener connected in series HPW-Production)
Membrane degasification
Electro-Deionisation (EDI)
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

HPW through Ultrafiltration
Function
- Continuous Filtration through hollow-fibre membranes
- Membrane bundle fixed in Epoxy Resin blocks
- Selectivity 6000 Dalton (corresponds to approx. 0,01 µm)
- Filtrate recovery 90%
Characteristics
- Certificated retention of Bacteria
and Endotoxins
- Sanitisation by hot water 80 C
- Maximum Leakage Protection
- Integrity test

Prefilter Ultrafiltration (only for HPW-

Softener connected in series Production)
• Equipment for Sanitization
Membrane degasification with Chemicals or Hot Water
(only for high CO2-content) • Switch Cabinet for fully
Electro-Deionisation (EDI) automated operation
HPW
ROCEDIS HPW-TS
Air
- +
Soft-Water

Automatical Hot Water Sanitization
TapWater
PW
ROCEDIS PW-TS
AIR
- +
Pre-Filter Softening Brine Tank 5µ-Filter Pump Heater Reverse Osmosis Membrane Elektro
Degassification eionisation

ROCEDIS PHARMA
Plug and Play-Compact system to PW- and HPW-production
ROCEDIS Pharma
Production of Highly Purified Water
Hot water sanitisation

Plug and Play - Compact System
Pre-assembled
- Completely pre-assembled on one rack
Ready for connection

- Connections for raw water, purified water and waste water
Tested
- Test run with water in our workshop,
all operational steps are tested (FAT)
Pre-qualified
- Installation and Operational Qualification

ROCEDIS PHARMA - Features
Large Capacity Range from 500 l/h

Excellent Pure Water Quality,
clearly below the required limit values of USP/EP
- El. Conductivity ~ 0,2 µS/cm
- TOC ~ 20 ppb
- Bacteria ~ 5 CFU/ml
Integrated Equipment for automatic Sanitisation
by Chemicals or Hot Water 80 C
Easy Extension from PW to HPW-Generation
by an additional Ultrafiltration
Qualified Remote Maintenance and Control

Plant Design acc. to GMP
GMP - Good Manufacturing Practice
Material 316L, orbitally welded
Surface roughness Ra < 0,8 µm
Aseptic Fittings, Sample Points

and connections as CLAMP
Measuring devices with calibration certificate
free of dead-legs
Seals acc. to FDA requirements
Fully Drainable
Sanitisable

Professional Raw Water Treatment
Raw water standards
European Pharmacopeia (EP):

- Purified Water, Highly Purified Water, and Water for Injection (Bulk):
“is obtained from water that complies with the regulations on water
intended for human consumption laid down by the competend
authority.” (Or WFI is obtained from purified Water)
United States Pharmacopeia (USP):

- Purified Water and WFI: “is prepared from water complying with the
U.S. Environmental Protection Agency National Primary Drinking
Water Regulations or comparable regulations of the European Union
or Japan. It contains no added substances.”

Feed Water Requirements
for PW-Generation with Reverse Osmosis/Electrodeionisation
Critical Inlet Parameter Unit RO EDI
Iron and Manganese Fe/Mn mg/l < 0,05 < 0,01

Calcium and Magnesium Ca/Mg ppm CaCO3 <1 < 0,5
Colloids SDI15 <3 <1
Silicic Acid SiO2 ppm < 30 * < 0,05
Strong Oxidants Chlor/O3 ppm < 0,1 < 0,05
Conductivity (Salinity) µS/cm < 1000 < 10-30 **
Free Carbonic Acid CO2 ppm < 5 **
* depending on Temperature and pH-Value

** independent of the Module construction and hydraulic load

Professional Pre-Treatment
If the raw water hardness is lower than 50 ppm CaCO3 an

Antiscalant-Dosing for Stabilisation of Hardness is sufficient as
pretreatment. If raw water hardness is higher than 50 ppm
CaCO3, softening by means of ion exchange is recommended.
If the content of carbon dioxide is higher than 5 ppm, removal
via Membrane Degasification or NaOH-Dosing is required.
If the silica content is higher than 30 ppm, an Antiscalant-
Dosing, NaOH-Dosing for pH-increase or reduction of RO-
recovery is required.
If other substances exceed the specified values,
additional pretreatment steps are required
- for example: Multi-Layer Filtration, Activated Carbon Filtration,
Microfiltration, Ultrafiltration, Sulfite-Dosing, UV-irradiation

Pre-treatment for Membrane Technologies
Raw water-
Colloidal matter
Bacteria (KBE)
Impurities
Calcium and
Chlorine and
magnesium
substances
Barium and
manganese
strontium
Iron and
Organic
Technologies
(SDI15 )
(TOC)
(SIO2 )
ozone
Silica
for Pre-treatment
Softening
Decarbonization
Multi-layer filtration
Activated carbon filtration
Precoat filtration
Microfiltration
Ultrafiltration
Antiscalant-Dosing
Acid dosing (HCl, H2 SO4, CO2 )
Sulfite dosing
UV-irradiation
very well, nearly complete removal
well, conditions for application have to be checked
contingently suitable, at very low loads
no effect

Classification of Membrane Technologies
$ # ' (
%
! &
' (
"#

Ultrafiltration Mode - Filtration
Filtration: 30 min
Feed Water
BF10
Backwash Tank
UF membrane
PAC

Ultrafiltration Mode - Backwash
Backwash: 35 sec
BF10
Backwash Tank
UF membrane
Waste

Ultrafiltration Mode - Chemical Backwash
Backwash: 35 sec
Chemical affect: 5 min
Rinse: 35 sec
BF10
Backwash Tank
UF membrane
HCl
NaOCl
Neutralisation

Qualification
Qualification of Water Plants
Document templates for protocols, reports and SOPs

for DQ, IQ, OQ
Proven in similar projects
Well suited for water plants
Scope based risk analysis
Successive checks during qualification steps
DQ, IQ, OQ
Coherent concept
Execution according to GMP and
(on option) GAMP

Staff for Execution of Qualification Works
Qualification Manager
prepares protocols and reports
prepares and maintains all relevant SOPs
is responsible for any qualification activities
during project execution
is the person to contact for any questions
during qualification
Checks are executed by:

engineers of different disciplines:
- electric and software by electrical engineers
and software specialists
- check of welding seams by
European Welding Specialist
Design Qualification (DQ) - Optional
DQ comprises the following checks:
user requirement specification,

functional specification, risk analysis
inspection of PI&Ds
inspection of piping and layout plans
inspection of functional description
inspection of wiring diagram
inspection of component list
inspection of limit switch list
DQ is not requested by CFR 21 part 210,

however, recommended by ISPE-Guide

Installation Qualification (IQ)
IQ comprises the following checks:
Document check:
- mill certificates EN 10204 3.1
- FDA compliance certificates for product-wetted polymers
- certificates on initial calibration for critical instruments
- welding documentation
- operating and maintenance instructions
for the components

Mechanical check of the plant
check on completeness against PI&Ds and Component list

mechanical check (installation, accessibility, 3d-rule, slope)
against P&IDs and layout-plan
inspection of drainability
inspection of welding seams
(according to SOP)
labor safety inspection
check of labeling
leak test (according to SOP)
further checks on option

Electrical check of the plant
Acceptance-test of switch board at

supplier’s site
software registration
electrical line test

Operation Qualification (OQ)
OQ comprises the following checks:
check of documentation in as-built status

(operating and maintenance instructions)
check of supply media (raw water, compressed air, regeneration
salt, steam, ...)
check of filters and membrane elements
(RO, EDI, UF)
adjustment of process parameters
for hot-water sanitisable plants:
check of sanitisation

Check of automation
check of direction of motor rotation

check of limit switches and
accessibility test
software test (plant is connected)
- check against functional description
pass-word tests
stress test (power outage, cut-off of compressed air,
recovery)

OQ comprises the following checks:
performance test (water flow rate, conductivity,

TOC, colonies, if applicable: ozone)
documentation of operator training
on option: calibration of critical instruments
on site according to SOPs

Change Control Procedures
Changes are documented in DQ-/IQ-/OQ- Report and approved

on this document by the client
Alternatively, the following procedure can be agreed upon:
Each change will be

- Documented
- assessed for GMP-relevance
- approved by the client
- realization is documented

Documentation and Reporting
all qualification checks are documented GMP-conform

for each qualification step a Qualification Report is filled-in
(DQ-, IQ-, OQ-Report) with documentation of
- changes
- deviations and
corresponding Operation
corrective actions
documents in English language

Qualification of Water Plants
ISPE Guide Commissioning and Qualification

recommends:
„In many cases, the supplier or contractor will have their

own system. Where this is the case, the usual practises
of the contractors or contractor should be integrated
within Qualification effort owned by End-User.
(chapter 2.5.2)“

Many thanks for you attention!
Jochen Schmidt-Nawrot
Dipl.-Ing. Process Engineering
Key Account Manager Pharmaceutical Industry
jochen.schmidtnawrot@he-water.com
Tel. + 49 711 7866-213

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Innovative Production of

Water for Pharmaceutical Use

Kuala Lumpur - Jakarta - Bangkok

Current Guidelines and Requirements on

JJ Pharmatec Technical Seminar, August/September 2006 2

Regulations and Guidelines for Design and

Note for Guidance on Quality of Water

European Commission (EG) Guide to Good Manufacturing Practice (1991)

PIC/S (Pharmaceutical Inspection Convention) Guide to Good Manufacturing Practice for

GAMP-Forum GAMP 4.0 (2003)

JJ Pharmatec Technical Seminar, August/September 2006 3

Purified Water (PW) EP USP

WFI (as PW before, but) EP USP

Highly Purified Water (HPW) EP

JJ Pharmatec Technical Seminar, August/September 2006 4

Highly Purified Removal of Bacteria and Water for Injection

Purified Water Desalination / Pure Steam

JJ Pharmatec Technical Seminar, August/September 2006 5

Before 1990 Ion Exchange Systems

JJ Pharmatec Technical Seminar, August/September 2006 7

Prefilter Ultrafiltration (only for WFI/HPW-

CF PU HEX RO MDG EDI UF

JJ Pharmatec Technical Seminar, August/September 2006 8

CF PU HEX RO MDG EDI UF

JJ Pharmatec Technical Seminar, August/September 2006 9

JJ Pharmatec Technical Seminar, August/September 2006 10

Reliable and permanent protection of the

Minimised risk of microbiological contamination

Polisher minimizes the risk of

Automatic chemical disinfection at every

ECOSOFT minimizes Water and Salt

ECOSOFT TS with hot brine sanitization

Residual Hardness Control

JJ Pharmatec Technical Seminar, August/September 2006 11

Highest Sanitization effect due to

Fully Automatic Sanitzation during

No corrosion problems due to

JJ Pharmatec Technical Seminar, August/September 2006 12

• Reverse Osmosis (RO)

CF PU HEX RO MDG EDI UF

JJ Pharmatec Technical Seminar, August/September 2006 13

Water ingredients (salt ions, particles, colloids, Bacteria,

Permeate conductivity 5-10 µS/cm

JJ Pharmatec Technical Seminar, August/September 2006 14

No removal of dissolved gases (e.g. CO2)

Production of 75-80% demineralized water (permeate)

approx. 20-25% concentrated waste water (concentrate)

JJ Pharmatec Technical Seminar, August/September 2006 15

JJ Pharmatec Technical Seminar, August/September 2006 16

CF PU HEX RO MDG EDI UF

JJ Pharmatec Technical Seminar, August/September 2006 17

Diffusion of the on the water side dissolved

Discharge of carbon dioxide (CO2) on the gas side pLiquid pLiquid

JJ Pharmatec Technical Seminar, August/September 2006 18

No risk of bacterial contamination

Easy Sanitization (Chemical or Hot water)

Low required space