10_design and performance qualification

7/27/2019 10_Design and Performance Qualification

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Design and Performance Qualification, of Pharmaceutical

Water Purification System for GMP Compliance.*Chemist :Soad Yacout

Q.C. Manager of Microbiological Control affair

European Egyptian pharmaceutical industries (EEPI)

Abstract

This article describes water purification system in pharmaceutical industries operating in

compliance with cGMPand also to meet the USP requirements for purified water. Detail ofthe design consideration and selection ,system description & system validation are presented.

Water test results from the system performance qualification are detailed. System deviations

for TOC and microbial monitoring are noted and action taken to resolve them are presented.

The European Egyptian pharmaceutical industries (EEPI) water purification system

components were chosen to control running cost, maximize validation performance, and

meet USP requirements for purified water.

Introduction

Purified water is one of the key components in most pharmaceutical manufacturing facilites

,and it is one of the most critical utility systems in a plant operating in compliance with Good

Manufacturing Practices (GMPs).The United States Pharmacopeia (USP), which sets

standards for different water qualities, states that Water for Injection (WFI) is intended for

use in the preparation of parenteral solutions.1 However, for other pharmaceutical

applications, the guidance is more general and intended to ensure that the user designs a

water system fit for the intended purpose. In many applications, a suitable water system can

be defined as providing water meeting the current USP monograph for purified water. This

definition allows the system designer to consider alternatives to the typical stainless steel

WFI system, while achieving the desired water quality in a more affordable and manageable

manner. 1

Water Purification System Design Considerations and Selection

The plant began with an assessment of an existing reverse osmosis/ Continuous deionization

(RO/CDI) water system for expansion and validation. The purified water is used for product

preparations equipment (indirect contact with the product) and facility cleaning purposes .

The water quality specification was set as described in USP 24 . The U.S. Pharmacopeia

(USP) dictates the purity of water used for manufacture of pharmaceuticals . The compendial

grades of water must meet a specification for conductivity and TOC . In order to meet these

specifications it is often necessary to use a membrane process such as RO in combination


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with an ion exchange process such as CDI .Using double-pass RO/CDI system .and a

location for the system was identified. The design take in consideration the selection of the

materials of construction for the water storage vessels and distribution loop, therefore

stainless steel piping systems .

The major components of the selected system are described below. The purification processis illustrated schematically in Figure 1. The actual system and a point of use are shown in

Figures 2 and 3, respectively.

Fig. 1-

Water

System

Schematic

The feed water from the city supply first passes through pretreatment including dosing with

coagulant and pass through sand and carbon filter cartridges and five micron prefilter and

passes through UV lamp before entering the Reverse Osmosis ( R.O.) station. The RO

system includes an additional integrated pretreatment with antiscalent for calcium hardness

and a 5 micron prefilter. This combination protect the reverse osmosis membrane from

damage due to fouling from particulates, chlorine oxidation, and formation of mineral scale

on the membrane surface. The antiscalent agent is a solid, long chain polyphosphate that

weakly binds calcium ions and minimizes calcium carbonate precipitation (scale formation ).

The use of the coagulant and antiscalent agent within the system pretreatment were

particularly important in the system design as this eliminated the need to use softening for

removing calcium hardness from the feed water supply; therefore, saving considerable space.

1-Reverse Osmosis Stage :

Pretreated water flushes through a high pressure pump that boosts water pressure before

entering the reverse osmosis membrane cartridge. The high pressured water through the reverse

osmosis membrane with contaminants being rejected by the membrane between 95 and 99%.

Water is rinsed continually along the upstream side to continually flush contaminants to drain.Approximately 70% of the feed water entering the system is processed through the membrane

as product water at a rate of 7 m3 per hour, providing


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the required ~ 80m3 per day. Reverse osmosis system performance is monitored

including feed and produced water conductivity and the calculated % of ionic rejection.The water leaving the reverse osmosis system requires additional purification to meet the

USP purified water quality requirements in term of conductivity.

2-Continuous Deionization Stage :The process of continuous deionization (CDI) uses ion-exchange membrane, ion-

exchange resin, and a DC electrical potential to ionizable materials from water. One of

the main advantages of the process is that it does not require chemicals to regenerate the

on exchange resins since the DC field regenerates the resins electrochemically. Another

advantage is that the electric field helps minimize bacterial growth in resin bed. The CDI

installed downstream of reverse osmosis system to remove ions that have not been (or

can not be) removed by the RO.

Fig.2 Purified water system ,Major component Fig.3 Point of use .

3- Storage and Distribution systems :

The purpose of the storage tank is to buffer the fluctuating demands of up to 8 m 3. The

goal when designing and operating the storage and distribution system is to keep the

water at these purity levels preventing any of three parameters listed below :

a- Prevention of ionic contamination ( Increase in water conductivity )

The storage tank, piping pumps and other components of the system in contact with the

purified water is made of mirror polished 316L stainless steel .

b- Prevention of contaminants like foreign particles and microorganisms

To prevent foreign particles and microorganisms contaminant from Storage and

Distribution systems

Sterilizing grade (0.22 micron) vent filter on the storage tank. The distribution piping & storage tank maintained with positive pressure. The system pumps used double mechanical seals ,using purified water as a

seal flush fluid.

Heat exchangers made of double tube sheets.


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c- Prevention of microbial growth

Microorganisms in purified water system usually form a biofilm on the internal surface

of the storage tank and piping2. For this reason several ways to prevent microbial growth

in purified water system.

1-

Periodically sanitize the system by heating up the water ( 85-90

o

C)

,andkeep it in the distribution system and piping circulating.

2- There are no "dead legs" (stagnant zones such as branch lines) in thepiping long enough to allow standing water to cool below 85 oC .

3- Circulation pumps are designed so that all parts in contact with waterremain hot.

4- Utilize an UV light installed in distribution loop to continuously sanitizethe water stream.

5- The vent filter on the storage tank is necessary both for microbial controland prevent moisture condensation.

6- The top head and wall of the storage tank will continuously flushed withcirculating hot water to remain clean.

7- Reduce temperature in piping and tank to (18-22 oC ) . The purified waterin ambient storage system is maintained at room temperature. The growth

of microorganisms and accumulation of endotoxines is prevented by

periodic sanitization of the heat water

8- The ambient temperature is not optimal for growth of mostmicroorganisms sanitizing a system (1-2 a week).

9- Piping sloped is carred out every of 1/8`` per foot (10mml /ml)to assurecomplete drainage of the system .

10-Liquid velocity of >5ft/fec. ( 1.5 m/sec) in circulation loop >3 ft/sec( 0.9m/sec) in return section of the circulation loop during peak usage .

Material Selection

Selection of proper materials of constructions for purified water system components is very

important issue.(2)

The material used are stainless steel ( typically 316 L) for all storage and distribution system

and pretreatment stage carbon filter cartridge wall and filtered water tank. The thermoplastic

material such as polypropylene and PVDF used in pretreatment stages such as feed water

buffer tank , sand filter cartridge wall. On the other hand ,thermoplastic in pretreatment

system are resistance to corrosion ,no potential for metallic contamination of fluids and

chemicals required for sanitation and extremely smooth internal surfaces without polishing.


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Water System Qualification

The typical three-stage qualification approach was followed, starting with the Installation

Qualification (IQ), transitioning to an Operational Qualification (OQ), and finishing with the

Performance Qualification (PQ). For the IQ and OQ .

As USP 25 specifies, the IQ stage should consist of instrument calibrations, inspections toverify that the drawings accurately depict the as-built configuration of the water system, and

where necessary, special tests to verify that the installation meets the design requirements.4

The vendor-provided IQ protocol package for each of the individual primary components

(reverse osmosis, continuous deionized system, and storage reservoir systems) was used to

provide verification of the hydraulic and electrical connections as well as the system drawings.

An internally generated IQ protocol collected the details of all reference documentation,

instrument and utilities verifications, spare parts verification, and drawing verification for the

entire system as a whole.

The vendor supplied OQ protocol was used to test the primary components to prove that they

were operating according to the design specifications. A validation master plan for a water

system typically includes an OQ stage consisting of tests and inspections to verify that the

equipment, system alerts, and controls are operating reliably.4 This included testing of the

equipment's controls and operation with both liquid path hydraulic and electronic tests. Specific

testing of the system operating alerts was performed by challenges the system by exceeding the

system limits using a calibrated instrument from the manufacturer. The internally generated OQ

protocol covered the overall system OQ, which verified system operation including the

distribution loop (point of use pressures, temperatures, and flow rates), water system generation,

storage system operation, and alarms.

The purpose of the Performance Qualification (PQ)was to demonstrate that the system produced

and maintained re-circulating water that meets the compendial requirements of USP purified

water over a suitable time period. The qualification period was chosen to strike a balance

between time and testing burden , the need to demonstrate a robust system (reliability), as well as

the knowledge that the system was intended and would continue to be monitored after

completion of the qualification testing . After considering these requirements, a ten-week

qualification period was approved.

A test schedule was prepared with samples drawn from all available point of use (23 POU). All

samples were tested for Total Organic Carbon (TOC), conductivity, and microbial analysis

(bioburden). The city feed water to the system also was tested for bioburden and coliform

bacteria.

Acceptance criteria for the system were based on USP 25. All ports in the system required a


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TOC result 500 ppb. Conductivity specifications with a range of 1.3 and 2.1 S/cm

corresponding to a "normal" room temperature range of 20 to 25C. The USP bioburden

requirement of


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Fig 6 Bioburden results for Point of use at 30-35oC Fig 7 Bioburden results for Point of use at 20-

25oC

Monitoring of using high or low incubation temperature or shorter or longer incubation time

were determined during the qualification period ( fig. 8 , 9)

time study Over the course of the next year, no further isolates of any nature were obtained

from this location, which underscored this event as isolated.

Feed water monitoring results were as expected for potable city water. Bioburden typically

Final evaluation of the system demonstrated consistently low TOC, conductivity, and

bioburden in the system. Following approval of the validation report in February 2003, the

system was considered acceptable for the manufacturing pharmaceutical products.

Water System Performance

Following the process validation, ongoing system monitoring and release of tested water is a

standard requirement for GMP water systems. Water was sampled and released on a dailybasis. The 10 points considered to be most critical, Test returned water ( the last point of use ).

The other point used for development and for equipment cleaning were sampled on a rotating

date

Totalbacte

rialcountat30-35

oC

544842363024181261

90

80

70

60

50

40

30

20

10

0

Variable

8-25C

11-25C

13-25C

14-25C

15-25C

16-25C

17-25C

18-25C

20-25C

21-25C

3-25C

23-25C

6-25C

Time Series Plot of point of used ( count at 30-35 oC)

Date

Totalbact

erialcountat20-25

oC

Variable

8-35C

11-35C

13-35C

14-35C

15-35C

16-35C

17-35C

18-35C

20-35C

21-35C

3-35C

23-35C

6-35C

Time Series Plot of point of used ( count at 20-25 oC)

100

80

60

40

20

0

544842363024181261

CDI water at 30-35 oC

0

10

20

30

40

50

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82

Date

talbac

unt

To

terialco

2 days

3 days

Linear (3 days)

Linear (2 days)

Fig 8Bioburdenresults at

30-35oC

CDI water at 22-25 oC

30

35

40

45

50

3 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109te

Totalbacterialcount

5 days

7 days

Linear (7 days)

Linear (5 days)

0

5

10

15

20

25

1 5 9 1Da

Fig 9Bioburden

results at

20-25oC


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basis every month. The city water also was tested on the weekly schedule to verify the absence

of coliform bacteria.The incubation temperature and time 30-35 oC for 72 hr and 20-25 oC for 7

day was selected.

Test results were compiled by the quality control and release certificate was attached to the lot

files for any drug product batches manufactured. As part of batch release, acceptable releaseresults were required from the sampling date prior to and after the used date of the water in the

drug product batch. This testing system was performed from the close of the validation in

February 2003 to 2007 with the resulting data set covering more years of system operation.

Bioburden results were, with two exceptions, always acceptable - Figure 6,7. The system limit

was set at < 100 CFU/mL based on USP criteria. Most daily results were negative for

bioburden, withoccasional single isolates and rare samples up to 10 CFU/mL.Conclusions

The European Egyptian pharmaceutical water system is designed ,installed, qualified and

monitored in accordance to USP purified water specification. . Use of standard components

also expedited the validation process as the vendor-supplied protocols covered the component

details and allowed simplification of the internally generated IQ/OQ protocols to focus

primarily on the system details.

The PQ was completed successfully and established all ports met the required water purity

requirements.

Post-validation system monitoring was performed for more than a year. Ongoing bioburdenmonitoring which typically exhibited zero bioburden in the daily test samples . The results all

results support the robustness of the purified water generation and distribution system

presented.

References

1- Joseph T., George K., Jeffrey D., and Sean M.2006. Design, Qualification, and Performance

of a Cost-Effective Water Purification System for a GMP Pilot Plant. . Pharmaceutical

Engineering July/August 2006, Vol. 26 No. 4.

2- Leoind S. 2001. Pharmaceutical purified water storage and distribution systems an

Engineering perspective. Pharmaceutical Engineering November /December 2001 pp.66-72.

3. Reference Part 9215.B, Standard Methods for the Examination of Water and Wastewater,

20th

Edition, American Public Health Association, 1998.4. USP 25; General Chapter 645 .& General Chapter 1231

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