Supplementary Training Modules on

Good Manufacturing Practice

Water for Pharmaceutical Use
Nc s dng trong SX thuc

Part 2: (Phn 2)
Water purification and
engineering
(Tinh ch nc v k thut)
WHO Technical Report Series
No 929, 2005. Annex 3

Water | Slide 1 of 19 January 2006

 Water for Pharmaceutical Use
Objectives (Mc tiu)

To examine the basic technology and requirements for:

(Kho st cc k thut c bn v cc yu cu i vi:)

Water treatment systems (Cc h thng x l nc)

Storage and distribution requirements (Cc yu cu v tn tr

v phn phi)

Sampling and testing (Ly mu v th nghim)

Sanitization (S tit trng) 6.

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 Water for Pharmaceutical Use

General (Tng qut)

Part 1 reviewed types of water and water purification systems (Phn 1-
Xem xt cc loi nc v cc h thng tinh ch nc)
Water can be used directly, or stored in a storage vessel for subsequent
distribution to points of use (Nc c th c s dng trc tip hoc tn
tr trong bn cha phn phi ti cc im s dng)
Design appropriately to prevent recontamination after treatment (Thit k
ph hp ngn nga ti nhim sau khi x l)
Combination of on-line and off-line monitoring to ensure compliance with
water specification (Kt hp gim st trc tuyn v ngoi tuyn bo
m s tun th theo tiu chun cht lng nc)

6.1

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 Water for Pharmaceutical Use
WPU system contact materials (Cc vt liu tip xc
vi h thng nc dng cho sn xut thuc)
Contact materials include: (Cc vt liu tip xc bao gm)
Pipes (ng dn)
Valves and fittings (Van v ch ni)
Seals (Vng m kn)
Diaphragms and instruments (Mng chn v cc thit b)
Tanks (Bn cha)
Pumps, etc. (Bm...)
Proper selection to ensure these are suitable (Chn la ng m bo cc vt
liu ny l ph hp)

6.2

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 Water for Pharmaceutical Use
WPU system contact materials (2) (Cc vt liu tip
xc vi h thng nc dng cho sn xut thuc (2))
Factors to consider (including components) (Cc yu t cn quan tm (bao gm
cc thnh phn))
Compatibility and leaching effect (Tnh tng thch v nh hng thm)
Corrosion resistance (Chng n mn)
Smooth internal finishing, ease of jointing (Mt trong phng, d kt ni)
Hygienic / sanitary design (Thit k v sinh/sch)
Documentation (H s ti liu)
Materials of construction (MOC) - (including original/certified copies of material
certificates (Vt liu xy dng-bao gm bn gc/bn sao c chng nhn ca chng
ch vt liu) 6.2

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 Water for Pharmaceutical Use
WPU system contact materials (3) (Cc vt liu tip xc vi h
thng nc dng cho sn xut thuc (3))
Compatibility (Tnh tng thch)
With temperature and chemicals used in the system (Vi nhit v ha cht dng
trong h thng)

Leaching effect (nh hng thm)

Non-leaching at temperature range (Khng thm qua phm vi nhit hot ng)

Corrosion resistance (Chng n mn)

PW, HPW, WFI highly corrosive (Nc tinh khit, nc siu tinh khit, nc pha
thuc tim c tnh n mn cao)
Stainless steel Grade 316L to be used (S dng thp khng g lai 316L)
System passivated after installation and modification according to SOP (H thng
c oxy ha chng g sau khi lp t v iu chnh ty theo SOP)
6.2

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 Water for Pharmaceutical Use
WPU system contact materials (4) (Cc vt liu tip xc vi h
thng nc dng cho sn xut thuc (4))
Smooth internal finish (B mt bn trong phng)
Biofilms and microbial contamination ( nhim vi sinh v mng sinh hc)
Crevices and roughness result in problem areas associated with contamination
and corrosion (ng nt v s g gh dn ti cc khu vc c vn lin
quan ti nhim v n mn)
Internal finish to have arithmetical average surface roughness not greater than
0.8 micrometer arithmetical mean roughness (Ra) (B mt bn trong c g
gh trung bnh khng qu 0,8 m)
Mechanical and electropolishing needed when stainless steel is used (Cn
nh bng bng in v c hc khi dng thp khng g)
6.2

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 Water for Pharmaceutical Use
WPU system contact materials (4) (Cc vt liu tip xc vi h
thng nc dng cho sn xut thuc (4))
Joints (Ch ni)
System materials easily jointed, e.g. by welding (Cc vt liu ca h thng
phi c th c kt ni d dng, th d: bng cch hn)
Process controlled including requirements such as: (Qu trnh c kim sott
gm cc yu cu nh:)
Qualification of operator (Nng lc ca ngi thao tc)
documentation of welder set up (Thit lp h s ti liu ca th hn)
work session test pieces (Kim tra cng tc)
weld logs (Nht k hn)
visual inspection of defined proportions of welds (Kim tra bng mt cc
phn xc nh ca mi hn)
6.2

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 Water for Pharmaceutical Use
WPU system contact materials (6) ) (Cc vt liu tip xc vi h
thng nc dng cho sn xut thuc (6))
Suitable materials include: (Cc vt liu thch hp bao gm)
Stainless steel Grade 316 L (low carbon) (Thp khng g lai 316L (cacbon
thp))
Polypropylene (PP)
Polyvinylidenedifluoride (PVDF)
Perfluoroalkoxy (PFA)

Unplasticized polyvinylchloride (uPVC) used for non-hygienic designed water

treatment equipment such as ion exchangers and softeners (uPVC dng cho thit
b x l nc thit k khng hp chun v sinh nh ct trao i ion v thit b lm
mm nc)

6.2

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 Water for Pharmaceutical Use
System sanitization and bioburden control (S tit
trng h thng v kim sot gii hn vi sinh vt)
Systems in place to control proliferation of microbes (Cc h thng thch hp
kim sot s tng sinh ca vi khun)

Techniques for sanitizing or sterilization (Cc k thut tit trng hoc v trng h
thng sau khi bo tr hoc thay i)

Consideration already during design stage then validated (S quan tm n k

thut s dng trong thit k h thng v hiu nng c thm nh)

Special precautions if water not kept in the range of 70 to 80 degrees Celsius (Cc
lu c bit nu nc khng trong khong 70-80o C)

6.3

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 Water for Pharmaceutical Use
Storage and distribution - Storage vessels (Tn tr v phn
phi- Bn cha)
Design and size important (Thit k v kch thc l quan trng)
Serves as buffer between generation and use (ng vai tr l vng m gia sn xut v s
dng)
Avoid inefficiencies and equipment stress during frequent on-off cycles (Trnh tt-m thng
xuyn lm thit b hot ng khng hiu qu v b stress)
Short-term reserve in case of failure (D tr nc trong thi gian ngn khi thit b trc trc)

Contamination control consideration (Quan tm kim sot nhim)

Headspace (kept wet with spray ball / distributor device) (Vng kh trn mt nc (Gi t bng
qu cu phun/thit b phun))
Nozzles (no dead zone design) (Ming vi (thit k khng c c vng cht))
Vent filters (type, testing, use of heat) (Cc lc thng kh (loi, th nghim tnh nguyn vn, vic
s dng nhit)
Pressure relief valves and burst discs (sanitary design) (Cc van gim p v a n (thit k v
sinh))
6.4

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 Water for Pharmaceutical Use
Storage and distribution Pipes and heat exchangers
(Tn tr v phn phi-ng dn v b tn nhit)
Continuous circulating loop needed (Nc tun hon lin tc trong ng nhnh)

Filtration not recommended in loop and take-off point (Khng lc nc trong ng

nhnh v im ly nc)

Heat exchangers: (B tn nhit)

Double tube plate or double plate and frame type (Kiu bn kim loi hnh ng
kp hoc bn kim loi v khung kp)
Designed to ensure no stasis of water (Thit k sao cho khng c ng nc)

Where water is cooled before use, done in minimum time, and validated process
(Nc c lm ngui trc khi s dng phi trong thi gian ti thiu v quy trnh
phi c thm nh)
6.5, 6.5.1

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 Water for Pharmaceutical Use
Storage and distribution Circulation pumps (Tn
tr v phn phi - Bm hon lu)

Sanitary design with appropriate seals (Thit k kiu bm sch vi

cc vng m kn thch hp)

Standby pumps (Bm d phng)

Can be used (C th c s dng)
Configured or managed in a way to avoid trapped dead zones
(Cu hnh hoc c iu khin sao cho trnh cc vng nc
ng)
6.5.2

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 Water for Pharmaceutical Use
Typical water storage and distribution schematic (Biu tn tr v phn phi nc in hnh)
(Nc ngun
(Lc kh k nc
t
& a n)
DI hay RO)
Hydrophobic air filter
Feed Water & burst disc
from (Li lc1 m)
DI or RO Cartridge
filter 1 m Spray ball
(Qu cu phun)
(Nc phi
Water must Optional (Lc chn thm lun tun
in-line filter 0,2 m)
be kept 0,2 m hon)
circulating UV light (n UV)
(u ra)
Outlets

(B tn nhit) Heat Exchanger

Air break (Van x kh)
(My sinh ozon) Ozone Generator (Bm sch) Hygienic pump
to drain

Water | Slide 14 of 19 January 2006

 Water for Pharmaceutical Use
Biocontamination control techniques (K thut kim
sot nhim sinh hc)
Continuous turbulent flow circulation (Dng tun hon xo ng lin tc)
Specified velocity proven (qualification), and monitored (Tc ch ra c
nh gi v theo di)

Avoid dead legs (Trnh cc on cht)

Hygienic pattern diaphragm valves (Van kiu mng chn sch)

Shortest possible length of pipe work (ng ng ngn nht c th)

Pipe work of ambient temperature systems, isolated from hot pipes (ng ng
thuc cc h thng c nhit mi trng tch bit khi cc ng nng)
6.5.3

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 Water for Pharmaceutical Use
Biocontamination control techniques (2) (K thut kim sot
nhim sinh hc (2))
There should be no dead legs (Khng c c on cht)

D
Flow direction arrows
on pipes are important
(Mi tn ch hng dng
trn ng l quan trng)
Dead leg section (Mt ct
on cht)
If D=25mm & distance X is X >1.5D
greater than 50mm, we have
a dead leg that is too long
(Nu D=25mm v khong cch X
Ln hn 50mm, on cht l qu di)
Sanitary Valve (Van sch)
Water scours dead leg (on cht sc nc)

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 Water for Pharmaceutical Use
Biocontamination control techniques (3) K thut kim sot
nhim sinh hc (3))
1. Ball valves are unacceptable (Khng chp nhn van bi)

2. Bacteria can grow when

the valve is closed (Vi khun c
th pht trin khi van ng kn)

3. The water is contaminated as it passes

through the valve (Nc b nhim khi Stagnant water
chy qua van) inside valve (Nc t
ng bn trong van)

Water | Slide 17 of 19 January 2006

 Water for Pharmaceutical Use
Biocontamination control techniques (4) K thut
kim sot nhim sinh hc (4))
Pressure gauges separated from system membranes (ng h p sut tch bit khi
cc mng ca h thng)

Pipe work laid to fall (slope) allows drainage (ng dn phi dc- cho php nc
chy)

Maintain system at high temperature (above 70 degrees Celsius) (Duy tr h thng

nhit cao (trn 70o C))

Use UV radiation (S dng bc x UV)

Flow rate, life-cycle of the lamp (Tc dng, vng i ca n)

Suitable construction material (Cht liu xy dng thch hp) 6.5.3

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 Water for Pharmaceutical Use
Biocontamination control techniques (5) (K thut
kim sot nhim sinh hc (5))
Periodic sanitization with hot water (Tit trng nh k bng nc nng)

Periodic sanitization with super-heated hot water or clean steam (nh k tit trng
bng nc siu nng hoc hi nc sch)
Reliable (Tin cy)
Monitoring temperature during cycle (Theo di nhit trong chu k)

Routine chemical sanitization using, e.g. Ozone (Tit trng bng ha cht thng
xuyn, th d ozon)
Removal of agent before use of water important (Lai b tc nhn tit trng trc
khi s dng nc l quan trng)
6.5.3

Water | Slide 19 of 19 January 2006