Supplementary Training Modules on

Good Manufacturing Practice

Water for Pharmaceutical Use

Nc dng cho sn xut
thuc
Part 3: (Phn 3)
Inspection of water
purification systems (Thanh
tra h thng tinh ch nc)

WHO Technical Report Series

No 929, 2005. Annex 3

Water | Slide 1 of 30 January 2006

 Water for Pharmaceutical Use

Objectives (Mc ch)

To understand: ( hiu)

The specific requirements when inspecting water systems,

including associated documentation (Cc yu cu chuyn
bit khi thanh tra h thng nc, bao gm cc h s ti
liu c lin quan)

Water system inspection techniques and approaches (Cc

k thut v phng php thanh tra h thng nc)

Water | Slide 2 of 30 January 2006

 Water for Pharmaceutical Use

Prepare an aide-memoire for items to inspect:

(Chun b checklist thanh tra)
Schematic drawing review (Xem xt s bn v)
Changes to system since installation (Cc thay i ca h thng t khi lp t)
Sampling procedure and plan (Quy trnh v k hach ly mu)
Specifications, results and trends (Tiu chun cht lng, cc kt qu v xu
hng cht lng)
Out-of-specification results (Cc kt qu khng t)
Annual system review (Xem xt h thng hng nm)
Deviations (Cc sai lch)

8.

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 Water for Pharmaceutical Use

Prepare an aide-memoire for items to inspect (2):

(Chun b checklist thanh tra (2))
Results of system performance monitoring (Cc kt qu theo di hiu nng h
thng)
Out of limit results, failure investigations and alarms recorded (Kt qu nm ngoi
gii hn, iu tra khng t v cc cnh bo c ghi nhn)
Sanitization procedures and records (Cc quy trnh v sinh v cc bo co)
Maintenance and repairs logs/records (Bo co/nht k bo tr v sa cha)
Instrument calibration and standardization (hiu chun v tiu chun ha thit b)
Qualification and validation including DQ, IQ, OQ, PQ (nh gi v thm nh bao
gm DQ, IQ, OQ, PQ)
Requalification when appropriate, etc. (Ti nh gi khi cn...) 8.

Water | Slide 4 of 30 January 2006

 Water for Pharmaceutical Use
Where to start: (Bt u u:)
What is the water to be used for? (Nc dng lm g?)
sterile products (Sn phm v khun)
non-sterile products, e.g. oral liquid products, external applications (Sn
phm khng v khun, th d thuc ung nc, thuc dng ngoi)
solid dosage forms (Sn phm dng rn phn liu)
washing and rinsing (Dng lm nc trng v ra)

Start: Document review site verification followed by additional document

review (Bt u: Xem xt h s ti liu-Thm tra thc a-Tip tc xem xt b
sung h s ti liu

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 Water for Pharmaceutical Use

Verification: (Thm tra)

Start with document review (e.g. schematic drawing of the system, "water
quality manual" if available) (Bt u bng cch xem xt h s ti liu (th d:
s bn v h thng, S tay cht lng nc nu c)

Review change control (in case of changes after qualification and validation)
(Xem xt kim sot cc thay i (trong trng hp nhng thay i sau khi
nh gi v thm nh))
On site verification (system in accordance with the drawing) (Thm tra thc a
(h thng ph hp vi bn v))
Start source water supply (Ngun cung cp nc)
Pre-treatment and treatment systems (H thng tin x l v x l)

Water | Slide 6 of 30 January 2006

 Water for Pharmaceutical Use

Documentation should reflect information on: (H

s ti liu phi phn nh cc thng tin v:)
Pipeline (ng dn)
Valves (non-return type) (Van (Kiu mt chiu))
Breather points (Cc im thng hi)
Couplings (Cc ch ni )
Pipe slope ( dc ng dn)
Velocities (Tc dng chy)
Sampling points (V tr ly mu)
Drain points (Cc im tho nc)
Instrumentation (Thit b kim tra, gim st)
Flow rates (Lu lng)

Water | Slide 7 of 30 January 2006

 Water for Pharmaceutical Use
Documentation should reflect information on: (H s
ti liu phi phn nh cc thng tin v:)
Specification for each system element (Tiu chun cht lng ca mi thnh phn
trong h thng)
Standard procedures for use (Quy trnh chun vn hnh)
System changes (Cc thay i ca h thng)
Routine and non-routine maintenance (Bo tr thng xuyn v khng nh k)
Investigations and corrective action (iu tra v hnh ng khc phc)
Validation studies (Thm nh)
Chemical and microbiological specifications (Tiu chun cht lng v ha v vi
sinh)
Sampling instructions (Hng dn ly mu)
Test procedures (Quy trnh th nghim)
Responsible persons (Nhn vin c trch nhim)
Training requirements (Cc yu cu v o to)

Water | Slide 8 of 30 January 2006

 Water for Pharmaceutical Use

On site review and verification: (Xem xt vthm nh

thc a)
Walk through the system, verifying the parts of the system as indicated in the
drawing (i khp h thng, thm nh cc phn ca h thng nh ch trong bn v)
Review procedures and "on site" records, logs, results (Xem xt cc quy trnh v
cc bo co, nht k, kt qu ti thc a)
Verify components, sensors, instruments (Thm nh cc thnh phn, u d, thit
b)
Inspect the finishing, state, calibration status, labels, pipes, tanks etc as discussed
in previous parts of this module (Thanh tra , tnh trng hiu chun, ng dn, bn
cha...)
Start with source water supply follow whole system "loop (Bt u vi ngun cp
nc-tip theo ton b h thng ng nhnh)

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 Water for Pharmaceutical Use
Well water (Nc ging)
Inspect exposed parts of the well, depth of well (Thanh tra
cc phn phi nhim ca ging, su ca ging)

Check for nearby septic systems, hazardous materials

usage (pesticides, fertilizers, etc.) (Kim tra xc cc ng
vt gy nhim trng, vic s dng cc cht c hi (thuc
tr su, phn bn))

Well maintenance (Bo tr ging)

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 Water for Pharmaceutical Use
Raw water storage (Tn tr nc cha tinh ch)

May be required prior to pre-treatment (C th cn thit trc khi tin x l)

Check material of construction (Kim tra vt liu xy dng)
Concrete, steel are acceptable but check corrosion (B ton, thp c th
chp nhn nhng phi kim tra n mn)
Plastics or plastic linings may leach (Nha hay vi lt bng nha c th
thm)
Check cover (Kim tra np)
To keep out insects, birds and animals (Khng cho cn trng, chim chc,
sc vt i vo)
Check disinfection practices (Kim tra thc hin kh trng)

Water | Slide 11 of 30 January 2006

 Water for Pharmaceutical Use

Water treatment system inspection (1) (Thanh tra

h thng x l nc (1))

Checks may include: (Kim tra bao gm:)

dead legs (Cc im cht)
Filters (Cc lc)
pipes and fittings (Cc ng dn v ch ni)
Ionic beds (lp kh ion)
storage tanks (Cc bn cha)
by-pass lines (Cc ng nhnh)

Water | Slide 12 of 30 January 2006

 Water for Pharmaceutical Use

Water treatment system inspection (2) (Thanh tra h

thng x l nc (2))
Checks may include: (Kim tra bao gm:)
Pumps (Bm)
UV lights (n UV)
sample points (im ly mu)
reverse osmosis (Thm thu ngc)
Valves (Van)
heat exchangers (B trao i nhit)
Instruments, controls, gauges, etc. (Thit b, b iu chnh, ng
h o...)

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 Water for Pharmaceutical Use

Other checks (1) (Kim tra khc (1))

Stainless steel PVC and most plastics not recommended (Thp khng g-
Khng khuyn khch dng PVC v hu ht cc loi cht do)

Weld quality (Cht lng hn)

Hygienic couplings (Ch ni hp chun v sinh)

Passivation (th ng hoa b mt tip xc)

Air breaks or Tundish (Nt gi van x)

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 Water for Pharmaceutical Use

Other checks (2) (Kim tra khc (2))

Pipes and pumps (ng v bm)

hygienic couplings (Ch ni sch)
welded pipes (ng c hn)
hygienic pumps (Bm sch)
hygienic
sampling points (Ch ly mu hp v sinh)
acceptable floor (Sn sch s)
no leaks (Khng c r r)

Water | Slide 15 of 30 January 2006

 Water for Pharmaceutical Use

Other checks (3) (Kim tra khc (3))

Check condition of equipment (Kim tra tnh
trng thit b)
Staining on
water storage
tanks (Vt bn
trn thng ng
nc)

Corrosion on plates of heat exchangers

indicates possible contamination (n mn cc
tm kim lai ca b tn nhit cho thy c th
do nhim)
Water | Slide 16 of 30 January 2006
 Water for Pharmaceutical Use
Other checks (4) (Kim tra khc (4))
Maintenance records, maintenance of pump seals and O rings
(Kim tra h s bo tr, kim tra vic bo tr vng m kn ca
bm v vng O)

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 Water for Pharmaceutical Use

Other checks (5) (Kim tra khc (5))

Air filters (Lc kh)

Integrity testing, sterilization
and replacement frequency
(Th tnh ton vn, s tit
trng v tn sut thay th)
Check burst discs (Kim tra
van an ton)

Water | Slide 18 of 30 January 2006

 Water for Pharmaceutical Use

Other checks (6) (Kim tra khc (6))

By-pass lines ng r
Softened water
out to deionizer
By-pass valve Van r
Nc lm Carefully check by-pass valves
mm i ra b and lines (Cn thn kim tra van r v
phn kh ion
ng r)
These sometimes leak or are
inadvertently left open (Cc b phn
ny i khi c th b r r hoc h
do v )
A blanking piece is better
Thit b lm mm nc bng
nha Zeolite trao i Ca v
during operation phase (Cc b phn
Mg vi Na
Zeolite water softener
ny c bt kn trong giai on hot
exchanges Ca and Mg for Na ng l tt nht)

Water | Slide 19 of 30 January 2006

 Water for Pharmaceutical Use

Other checks (7) (Kim tra khc (7))

Activated carbon bed sanitization (V sinh lp than hat)

Temperature-compensated conductivity meters (My o dn c b nhit)

Influence of plastic pipe adhesive on TOC (nh hng ca cht lm dnh ng

nha trn ch tiu TOC)

Non-condensable gases in pure steam (Kh khng ngng t trong hi nc tinh

khit)

Water | Slide 20 of 30 January 2006

 Water for Pharmaceutical Use

Other checks (8) (Kim tra khc (8))

Polypropylene welding inspection (Thanh tra mi hn bng polypropylen)
checking pin holes (Kim tra l inh)

Retrospective validation of WFI system (Thm nh hi cu h thng nc

pha thuc tim)

Rouging of WFI storage systems (G st h thng tn tr nc pha thuc

tim)

Spray ball efficacy (Hiu nng qu cu phun)

Water | Slide 21 of 30 January 2006

 Water for Pharmaceutical Use

Other checks (9) (Kim tra khc (9))

UV light monitoring performance and lamp life and intensity (n UV-theo di hiu
nng v gi s dng v cng )

Validating ozone dosage (Thm nh liu ozon)

Specifications for acids, alkalis for DI and sodium chloride for water softener (Tiu chun
cht lng ca acid, kim i vi nc kh ion v natri clorid lm mm nc)

Normally open and normally closed valves (Cc van thng ng, thng m)

Water | Slide 22 of 30 January 2006

 Water for Pharmaceutical Use
Then review additional documentation (Xem xt h s ti
liu b sung)

Qualification protocols and reports ( cng thm nh v bo co)

Change control request (where applicable) (Yu cu kim sat thay i)

Requalification (where applicable) (nh gi li)

QC and microbiology laboratory: (Phng kim nghim v vi sinh)

SOP for sampling (SOP ly mu)

Procedures and records (Cc quy trnh v h s)

Water | Slide 23 of 30 January 2006
 Water for Pharmaceutical Use

Sampling (1) (Ly mu (1))

There must be a sampling procedure (Phi c quy trnh ly mu)

Sample integrity must be assured (Phi m bo mu nguyn
vn)
Sampler training (Hun luyn cho ngi ly mu)
Sample point (im ly mu)
Sample size (C mu)

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 Water for Pharmaceutical Use

Sampling (2) (Ly mu (2))

Sample container ( ng mu)
Sample label (Nhn mu)
Sample transport and storage (Vn chuyn v bo qun mu)
Arrival at the laboratory (a mu n phng kim nghim)
Test method (Phng php th)
When is the test started? (Khi no bt u th)

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 Water for Pharmaceutical Use
Testing (Th nghim)

Review method verification (Xem xt thm nh phng php)

Chemical testing (Th nghim ha hc)
Microbiological testing (Th nghim vi sinh)
test method (Phng php th)
types of media used (Loi mi trng s dng)
incubation time and temperature (Thi gian v nhit )
objectionable and indicator organisms (Vi sinh vt khng chp nhn v vi
sinh vt ch th)
manufacturer must set specifications (Nh sn xut phi xy dng tiu
chun cht lng)

Water | Slide 26 of 30 January 2006

 Water for Pharmaceutical Use
Suggested bacterial limits (CFU /mL) (Gii hn vi khun (CFU/mL))

Sampling location Target Alert Action

(V tr ly mu) (Mc tiu) (Cnh bo) (Hnh ng)
Raw water (Nc cha tinh ch) 200 300 500
Post multimedia filter (Sau lc hn hp) 100 300 500
Post softener (Sau thit b lm mm nc) 100 300 500
Post activated carbon filter (Sau lc than) 50 300 500
Feed to RO (Nc ngun cho thm thu 20 200 500
ngc)
RO permeate (Mng thm thu ngc)) 10 50 100
Points of Use (Cc im s dng) 1 10 100

Water | Slide 27 of 30 January 2006

 Water for Pharmaceutical Use
Pyrogens and endotoxins (Cht gy st v ni c t vi khun)
Any compound injected into mammals which gives rise to fever is a Pyrogen (Bt k
cht no chch vo ng vt c v gy st gi l Cht gy st)

Endotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments (Ni
c t vi khun c tnh gy st, c ngun gc t cc mnh v thnh t bo vi khun
Gram m)

Detect endotoxins using a test for lipopolysaccharides (LPS) (Pht hin ni c t vi

khun bng th nghim tm lipopolysaccarid)
rabbit test detects pyrogens (Th nghim trn th pht hin cht gy st)
LAL test detects endotoxins (LAL test pht hin ni c t vi khun)

Ultrafiltration, distillation and RO may remove pyrogens (Lc qua thit b siu lc, chng
ct hay thm thu ngc c th loi tr cc cht gy st)

Water | Slide 28 of 30 January 2006

 Water for Pharmaceutical Use
Group Session
You are given a schematic drawing of a water system to discuss. List any
problems and their solutions

IN CO RRECT WA TER TREA TM EN T PLA N T

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 Water for Pharmaceutical Use

Group Session

M O DIFIED WA TER TREA TM EN T PLA N T

Water | Slide 30 of 30 January 2006