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53 views24 pagesPag 8122-8144
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© © All Rights Reserved
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/ 24
wt General Information (1231) 8121
(1231) WATER FOR PHARMACEUTICAL PURPOSES
TABLE OF CONTENTS
DUCTION
1 aie WATER CONSIDERATIONS
SED FOR PHARMACK
sare Meribbed ela ae MANUFACTURING AND TESTING PURPOSES
3.1.1 Purified Water
3.1.2 Water for Injection
3.13 Water for Hemodialysis
3.1.4 Pure Steam
4.2 Stele Monographed Waters
5.211 Stele Purified Water
312.2 Sterile Water for Injection
312.3 Bacteriostatie Water for Injection
3.2.4 Sterile Water for iigation
3.25 Stelle Water for Inhalation
3.3 Nonmonographed Waters
331 Drinking Water
3.3.2 Other Nonmonographed Waters
33.3 Ammonia.Free Water
334 Carbon Dioxide-ree Water
3.3.5 Distled Water
3.346 Freshly Distilled Water
3.3.7 Deionized Water
3.38 Deionized Distiled Water
33,9 Filtered Water
33.10 High-Purity Water
33.11 Deaerated Water
3.3.12 Oxygen Free Water
313.13 Water for Bacterial Endotoxins Test
{LYALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND DISTRIBUTION SYSTEMS
441 Validation Requirement
4.2 Validation Approach
“4.2.1 Validation Elements
4.2.2 User Requirements Specification and Design Qualification
4231Q
42409
425Q
43 Operational Use
443.1 Monitoring
43.2 Validation Maintenance
43.3 Change Control
43.4 Periodic Review
S.DESIGN AND OPERATION OF PURIFIED WATER AND WATER FOR INJECTION SYSTEMS
5.1 Unit Operations Considerations
5.1.1 Prefitration
5.1.2 Activated Carbon
5.1.3 Additives
5.1.4 Organic Scavengers
5.15 Softeners
5.1.6 Deionization
5.1.7 Reverse Osmosis
5.1.8 Ultrafiltration
5.1.9 Microbia-Retentive Filtration
5.1.10 Ultraviolet Light
5.1.11 Distillation
5.1.12 Storage Tanks
z
3
rs
Ey
~ 8122 (1231) } General information
5.1.13 Darbutin Stems
5.1.14 Novel/Emerging Technologies snent Selection
5.2 Installation, Materials of Construction, and ComPor
5.3 Sanitization
‘5.3.1 Thermal Sanitization
5.3.2 Chemical Sanitization
5.3.3 UV Sanitization
5.3.4 Sanitization Procedures,
5.4 Operation, Maintenance, and Control
‘5.4.1 Operating Procedures
5.4.2 Process Monitoring Program
5.4.3 Routine Microbial Control
5.4.4 Preventive Maintenance
5.4°5 Change Control
6. SAMPLING
{6.1 Purposes and Procedures
6.1.1 PC Sampling
6.1.2. Q€ Sampling
6.2 Atuibutes and Sampling Locations
6.2.1 Chemical Aitributes
6.2.2 Microbial Attributes
6.3 Validation Sampling Plans
{644 Routine Sampling Plans
6.4.1 Source Water Sampling
6.4.2 Pretreatment and Purification System Sampling
6.4.3 Purified Water Distribution System Sampling
6.4.4 Water for Injection Distribution System Sampling
6.5 Non-Routine Sampling
7. CHEMICAL EVALUATIONS.
7.1 Chemical Tests for Bulk Waters
7.2 Chemical Tests for Sterile Waters
7.3 Storage and Hold Times for Chemical Tests
7.3.1 Containers
7.3.2 Storage Time and Conditions
7.4 Elemental Impurities in Pharmaceutical Waters
8, MICROBIAL EVALUATIONS
8.1 Microorganism Types
8.1.1 Archaeans.
8.1.2 Bacteria
8.1.2.1 Gram-Positve Bacteria
8.1.2.2 Gram-Negative Bacteria
8.1.2.3 Mycoplasma
8.1.3 Fungi
8.1.4 Viruses
8.1.5 Thermophiles
£8.2 Biofilm Formation in Weter Systems
8.2.1 Biofim-Forming Bacteria in Water Systems
8.2.2 Non-Bioflm-Forming Bacteria in Water Systems
8.3 Microorganism Sources
8.3.1 Exogenous Contamination
8.3.2 Endogenous Contamination
‘8.4 Endotoxin
8.4.1 Sources
8.4.2 Removal and Control
8.5 Test Methods
8.5.1 Microbial Enumeration Considerations
8.5.2 The Classical Cultural Approach
85.21 Growth Media
85.2.2 incubation Conditions
8.5.23 Selection of Method Conditions
&
re Pa
yw?
General information [ (1231) 8123
853 Suggested Classica Cut
8.54 Microbial Identification Methods
85.5 Rapid Microbiological Methods
ERT AND ACTION LEVELS AND SPECIFICATIONS
7
9AM Introduction
tet
a
on
8
3.2 Examples of Critical Parameter Measurement
9.3 purpose of he Mensrements
$14 Defining Alert and Action Levels and Speci
‘94.1 Alert Level id Specifications
9.4.2 Action Level
9.4.3 Special Alert and Action Level situ
9.4.4 Specifications i Stuations
9.4.5 Source Water Control
1, INTRODUCTION
eo cand as a rae mata nai ing aa
cay wed 0 mae ate nce, medi hie, an sla ine resin formato,
arr, and anaytal reagents aswel ncening open ‘ah
csi
Sn
aan
ed
i rained ina sale of conte oe aS ey ee lr he capo
Sedan manned Se cent pole suncech pao ey a herr OPSOHY
is), APL intermediates,
a prmational chapter on cleahing applications
formations chapter on Pharmaceutical water ops andiudes me of the chemical and icobilogal
rue owt an preparation and se, The chapter provides oration bout mate quay atrbutes Chat
jiscusses water "m vali yaph) and processing techniques that can be used to improve water
9 scuses water aster vation ad get a dept orf miter water quaity standards tht should be
i %, including sampling and system controls, t's equally important for water systems
pjormational chapter i intended to be educational, and the user should also refer to existing regulations or
that cover US. and international [International Council for Harmonisation of Technical Requirements for
seseeutcals for Human Use (ICH) or World Health Organization (WHO)] good manufacturing practice (GMP) issues, as
Fepeonel
‘Garstaton (DA),
Fan OC Se eh ranton C0) nda
See eee ec ae,
Anclave document on pharmaceutical waters. It contains basic information and points to be considered for the
essing,
holding, monitoring, and use of water. [tis the user's responsibility to ensure that
1 The selection ofthe type and specifications of water is appropriate for its intended use.
1 Water production and quality meet applicable governmental regulations and guidance.
5 The pharmacopeial specifications for the types of water used in monographed articles are met.
4. Water used in the preparation of reagents for analysis or the performance of required tests meets USP requirements.
“nl nd monitoring of the chemical and endotoxin purity of waters are important for complying with the
gute
‘Sona
tes. Basic au
Etsed her in Us chapter
Te of the microbiological quality of waters algo important for many of its uses. This attribute is intentionally not
sed most water monographs
{ison ond Qualification of Water Puritation, Stor
te or Imecton Systems, 6. samping, . Microbial Evlutions, and 9, Aert and Acton Levels ond Specifications.
Tischapter contains various chemical, microbiological processing
ez Water system validation, process con
gates the water hat enes the facily,
‘ndresevors deep bed well wales, sea waters,
‘aon ‘of source water Ths, source water
tonmuncialie seca water sourcing, | Galvey sh os a tuck I's posse tet source water may not be
ns of the monographs in this compendium, Atvibutes listed in USP monographs should be considered the
uirements, More stingent requirements may be needed for some applications to ensure suitability for
idance on the appropriate applications of waters can be found in the monographs and is also
so elcgeal cont dscused troughout ths chapter, but especialy In sections
1a a ont i Datibuton Syslons 5: Design and Operation of buried Woter
dl engingeng concepts of importance to users of
er erclicalgrs ate ao presented ater in this chapter.
2. SOURCE WATER CONSIDERATIONS
origin of his source water can be from natura surface waters tke
‘or some combination of these, potentially Including multiple
ican be supplied from these various origins (public or private),
iy
Ey
2
ite water sourcing, or by external
a a ea Fant to ensure that i meets drinking water standards. Itis the
ble and safe to drink. Such water may require pretea
safe to drink. Such water may recht Kure thatthe water used inthe production of drug substances (APD, as
“psy fe ues of ay source water eM
ito neck ug pret contacto pul
fut ae standards 5 Gee by the requirements
4 ie bythe US EPA nearing water Tega
featon sytem fed wate purposes meets, ata minimum, enki
cat onal mary Dinkng WoterReguatons (NPD) (20
tne te European Union (2) or apan, or he WHO dn
Sha mis on the types and quanties of certain chemical
x c ons es
te Bidlines (ee 3.3.7 Drinking Water). These regulations rer re quantities of chemical and microbial species.
biological contaminants anc
te ate supplies ae from regulated
‘ey be ested regularly and ensred Py
ensure thatthe water Wi
era et mmpanies, ls suingent montoting may be possble because the
et co ee 9.1.3 Soufce Woter Conta). Water Being withdrawn from
ne epopratly at suitable frequency that takes into account local
td Supply should be sampled and teste c
to
8124 (1231) | Genera inormaton ™
epee
land yamnal anges an ote uy wouter ToD ce ng,
tea ian te ged ee epee eras, Cag
systems to only be challenge er the source water tage ENMU es (252))] after the water has been frre! the,
clone chen ontario MOF pte ‘urbe nets
tunity for recontamination, ‘as for non-contact cooling systems. sy i
“Suna ae me eran ec pep a a ay aA Ney
normaly be requed 0 meet ining yo ecto qalty standards stabished y he user and deters a
agencies.
3. WATERS USED FOR PHARMACEUT!
ICAL MANUFACTURING AND TESTING Ppp,
‘UR Ose,
ical purposes. Several are described in us
tt wr
spray uses, cepa methods o preparation. nd UY APC sa and sere waters, which ae produeg ie
Eee cera podcast whee e/a Sea er art evra spon Pa
and striae prone crt quay thous es Fans ander Quay abuts. Menagy D9 ey
‘waters that diet in thelr designated applications, packaging Imitators Sr a ist appearing in those i
mst meet he qu designated appears jaca monographs and any Notes appearing in those mange ae,
should be considered and addressed. Je monographed bulk and sterile waters have a.
Wythe excepon of atest Water for econ, the monographed bul ane ate ae Pa 8 Sten
ingieating thot there are no added substances, or no added antmicTo et AIST re raton, pars ogee
purpose to ensure thatthe serie water product rendered stele based 1 O91 Prepacalon, packaging nga,
Free cae te ar unr steers -n aed bnance ths requrement tended sean Toad
Snes tut wesley eared To speci xmges upper Ns neti, bu here re many
Hert Shanes comer sakes pe ccm ad rages eo trovm leet
wth seam, so technically you ar ang er The sodum ons are eventual removed sufficiently anager’
Peet dmesg th se ae Ya
fen theater sample peste test n Wate” Conducty (648), Anothet speci examples the use of Grane ae
tut oad ote eigen rt a enna oer
lestroyed before use, as is normally the case. Other notable examples include - il bacteria in
revetment ster an of btn ts chenaly reduce clone to corde and protect dowmnsteam equine se
Sfarivogen Banka for protection rem atmosphere contamination. arias
Ter te ab ther pss mh he ro morass be aes it aM hen ee
purpose on Many oes water ran pci aaa metho, The despie es ray yc
Erulbates or fades of preperaon bt thee or monographed waters may not necesanly adhere sticty where?
pled mde preperation o pai tous Waters proce by erento onli by aber x
cre manage way ea ny hentended ues for thes ate, ese urs pos ees
thet such waters efen if prodced snd corto exacly os state, are stable for thel intended use Where ota
‘Mater is used within the compencium without other Gesciptveadecves or clauses, the intents that water ose
purty than Usp ured Weter be wed ce 3.1 uid Wate) Abi! description ofthe various types of wotea coe,
xovated with pharmaceutical sppleaGors and thr significant Uses ratte: follows
Figure 1 ray Be helpl mundestendig sme of tae varous pes of weer, ther propaatlon and uses
les of water used for phi
There ae many diferent gra
Figure 1. Water for pharmaceutical purposes. Complying with U.S
“A NPDV sors)
EPA NPDWR or the drinking water reauit
Japan or WHO. so at tc 2
e General Information | (1231) 8125
3.1
tlk Monographed Waters and Steam
ing waters are generally produced in a
ty estibuted in 2 Piping system for use at the caress U9 2 Multple-unit operation water system. These waters
tre
same site
se
3.1.1 PURIFIED wat
TER
sed ote (ee the HEF Monograph) i used as an ex
ee ea, ue th as the ening of roa the production of anparetera preparations and in
wes inccated (oe venert Notices, 8. 385 be sed asthe minimum water quay for test Sd says mich
‘aes OD ‘a Compendia Procedure. This applies regardless ofthe font and
quality of Source Water forthe product
Sree Tu, Japan, or WHO. This source ome on Pe
ert be validated to reliably and cei "must be protected from microbial contamination. Purified Water
peg Ts hed Water ste that nction under ambient conditions are particularly susceptible to the
Smet De reg beter wales ovale oT
«cect he wate reaching the pls of use ha appopate miei ali ‘microbiological monitoring
eure Wot monegrap abo allows bulk caging fr eammercl ese. fp contrast Serie Ped
su gaan Pred Wate nt equred ob se, acu ee penal for microbalcontamation and oer
ert row, sod beige ony ee ce fara
obi growth, andlor should be ue natin aon blr cil proleraton renders unstable fo
re we Mie depencng onthe matral wed pcg excl cmptuds cid be eating ne
‘rhe paca, though ths artes requedo mathe sume cerica pry tonal te,
oe ms ny even re inert nurs hao pls an he bulk water, Th nature of
insti Se. ak snopes ie por
aio lhe waters mated ‘used in manufacturing, elnical, or analytical applications where the
3.1.2 WATER FOR INJECTION
rr nection (se the USP monograph) is used as an expen in the production of parenteral and ther preparations
ke content mst be contol, an wale phormacetal pistons suchas he Seay
BeeReulpment and parenteral product contact component
27 ualy ef source water forthe production of Water for ction i Drinking Water whose teibutes ae
spy the US. EPA, EU, Japan or WHO. This source water maybe tated to ender it suitabe for subsequent final
pet Paps sich as dston (or whatever oer vated proces sed accoraing tothe monograph). The
EERaPe crak metal ofthe chemical reqrement pected the manog'ah, as wal a an aona bacteria
be tt Meaon Because endotonns re produced bythe kinds of miroarganims that are prone to nhabt ater
sco Psuipment and procedures wed by teste opr, tore, ana datibue Water or jection shout be
Bers te siePs bil cntaminalon and man be designed fo remove naming endtoxs from the source water
ea cept yetems must be valdatd to relably and cnssteny produce and cibute tis quality of water.
Tee er gnograph as ows oukpataping fo: corel sen const to Stere Water fr
aan eer waeckon sok equred fo be wert, However, io preclade sgnfcant changes ns microbial
Ce aa ate erage tis orn! Water for njecton sould be prepared and stored in a manner that
slenditonins content ing ae or soul be used na Uy fashion bore microbial prlieation renders t
eae a cng on he mateal Ue fer ptiagng,extraable compounds could be
Shp ner tombe rng. seh ace peau mat tee PS
Fea ea ae a eeyaging wl ik vende he pactaged vate kes chemical pure than the Duk
Seba wae extractable fom re eel fender te wate’ an inappropriate choice for same applcatons. ts the
a ea o ese mpl oe is pciaged etce when ts red n marten, cnc or aaa
‘pest wher he purer bulk frm ofthe watt indicted.
3.1.3 WATER FOR HEMODIALYSIS
ax ems Go ne USP monagan) ust henodi apts, pinay ihe tone
Heads Ge ne US manage are wate arte proditon of Wate tHe i
gas concentrate solutions Te ribed by the US. EPA EU, japan ot WHO. Water for Hemodialysis hasbeen further
frat iste hese tutes ate oso eas proce and sed on te, Ths ater onan
toed chemcal ond micobo09a SOPOT ater fe Hersh mt eel of he cher
setae agente, and re san atonal batalla seca, The mcobal ins
{roa fee he water ruraque among the -balk” water monographs but usthed on he te ‘of this water’ specific
act water nigus among re etre elated ts sae use, The bacterial endotonns tibute is Wewse
shed at evel related to its safe use. {8126 (1231) / General Information Usp 42
3.1.4 PURE STEAM
referred to a “clean steam”. It is used where the steam or its
vrtact surfaces, such as dating thelr preparation, strization, op
Impurity residues. These Pure Steam applications”
ig sltions heated by diet team
Pe oath muerte ti
eats PS ec ng a we se red by
Svan date urd pe, The oes neat rho cen pode nd aston
(ihe purty atte renin he a ie smh econ bese mls
gratinenmce one ean om oces a
Faee een se ener a eee y fen an agent He pis arse
icy tian ean fica an sine nae in print permeated ae,
(endesatn snot aed to happen eczema ay ele a ray
pricing a tc ay ee prin ated et Seam
of eam stration carr od These aces wuld ery Ce ey contr, There,
carderanionpheran, eventing em ee prac Fae Sen
ate i pec na mentoncd i he Pre Seon
2 ner suiy “plant sean maybe vied he olewngaplcaons 1) sem sein of nongodi
sre tena ia ci heen pr
change nen nd 0 pA a yen tem Senne
3.2 Sterile Monographed Waters
“The following monographed waters are packaged forms of elther Purified Water or Water for Injection that have been
sterilized to preserve thelr microbiological properties. These waters may have specific intended uses as indicated by their
names, and fay also have restrictions on the packaging configurations related to those uses. In general, these stelle waters
nay be used in variety of applications in lieu of the bulk forms of water from which they were derived. However, there isa
Substantial diference between the acceptance criteria for the chemical purities of these bulk waters versus sterile waters. The
Specifications for sterile waters fer from those of bulk waters to accommodate a wide variety of packaging types,
Properties volumes and wes, es the nraanic and organic impr speciation ae not equhalen orb and
Backaged waters. The packaging materials and elastomeric closures are the primary sources of these impurities, which tend
[Slinetease over the shelf fe of these packaged articles. Therefore, due consideration must be given to the chemical purty
Suitability at the time of use ofthe stele forms of water when used in manufacturing, analytical, and cleaning applications in
lieu of the bulk waters from which these waters were derived. Itis the users responsibilty to ensure fitness for use of these
sterile packaged waters in these applications. Nevertheless for the applications discussed below for each sterile water, their
respective purities and packaging restrictions generally render them suitable by definition.
3.2.1 STERILE PURIFIED WATER
raph) is Purified Water, packaged and rendered sterile, It can be used in the
Stere Pure Woter (se the USP manag
preparation of nonparenteral compendial dosage forms or in analytical applications requiring Purified Water where 1) access
{6 F validated Puriled Water system is not practical, 2) only a relatively small quantity is needed, 3) Sterile Purified Waters
Tequired by specie monograph or pharmacy practice, oF 4 bulk paclaged Purfled Waters not suey controle forthe
‘microbiological quality for its intended use.
3.2.2 STERILE WATER FOR INJECTION
ticularly the presence of even small quantities of
ly the prese
Sterile Water for Injection (see the USP monegraph) is Water for Injection packaged and rendered sterile. It is used for
cextemporaneous prescription compounding and as a sterile cluent for parenteral products. It may also be used for other
plications where bulk Water for injection or Purified Water is indicated but access to a validated water system isnot
practical, or where only a relatively small quantity is needed. Sterile Water for Injection is packaged in single-dose containers
fot larger than TL ysr 2
General information | (1231) 8127
eat 3.23 pactenostanc
seriostat Injection (see the
made of OF More suitable amine ea Bh Wate or rection, paca
eon pahage and ered sre 1 whieh
as beet acts, ic rob
wget
WATER FOR INJECTION
3.2.4 STERILE WATER FOR IRRIGATION.
stele Water for lrigation (See the USP monograph is Water or
is Water for In
fod to meet Particulate Matter in inject Of their conte to
sed Se ne i ae St
: or este ot Rad erased Spee 2 oe
7 reas ee ce
™
air ig not practical, or where somewhat lay i
Ke 'at larger quantities are needed than are provided as Sterile Water for Injection
3.2.5 STERILE WATER FOR INHALATION,
see ter naoton Ge te US
nate he USPmonogap i aterto ne
ete lr aneurin
(asain nen pct bcs cnn on ures nd oe a
lection packaged and serlize in single-dose containers
3.3 Nonmonographed Waters
In adtion fo the bulk menographed waters described above, nonmonographed waters can aio be used in
maceutical processing steps such as leaning and symthal eps, and alo as a starting materi fr further purcaton
Ec testing purposes, Unless otherwise spcied in the compendium, the minimum ually of wate! is Pred Water
fire fomnatvo is chapter is not an alkinclusive discussion of all anmonagraphed waters identified in the USP
3.3.1 DRINKING WATER
inking Woter can be referred to as Potable Water (meaning drinkable oft to drink), National Primary Drinking Water
nana Binkng Water, PA Dring Whe cept were gue king cr Naiseation stated (uch asthe”
UP EA NPD, as ced in 0 CFR Part 141, tswater must comply yth te quay atte of eer the NPOW or
ao ee erate regulations ofthe EU or Japan, or the WHO Guldelnes for Drinking Water Quay. Ornking Water may
inking Wate dt sources including ¢ public water supp, private water Supply (ea wel) ora combination of
org
these sources (see 2, Source Water Considerations).
Drinking Water may be used in the early stages of cleaning pharmaceutical manufacturing equipment and product
for the preparation of official
contact components. Drinking Water is also the minimum quality of water that should be used
contact comPercrer bulk pharmaceutical ingredients. Where compatible with the processes, the contaminant levels alowed
HpTeiag water are generally considered sae or use in preparing offical substances and other drug substances, Nowove,
eon red by the processing of the materials to achieve their required final purty, higher qualtes of wate my oe
aE ea vanufacturing steps, perhaps even water as pure as Water for Injection or Punied Water, Suct higher
rected Stes, however, might require only selected attributes tobe of higher purity than Deinng Waves fs Pat 2a and
Fant Soy Drinking Weter the prescribed source or fed wate forthe production of bulk moneoraeres pharmaceutical
Faure 20). Drinking Wate ate specifiations establshes 2 reasonable st of maximum allowable evel of heres
wate egical contaminants with which a water purification system willbe challenged Recass seasonal variations in the
qual tur its important to give due consideration to its uses. The processing
attributes of the Drinking Water supply can occ o
patty auibutes ga pharaceutical waters must be designed to accommodate ths variability. 8128 (1231) / General Information or
SS] Se
Figure 2b. Selection of water for pharmaceutical purposes: Analytical reagents.
3.3.2 OTHER NONMONOGRAPHED WATERS
In addition to Drinking Water, this compendium discusses waters wit various other designations. These include water,
‘vatous qual level for special Uses such as, but not limited to, cleaning and testing purposes,
oth General Notices and Requirements (see General Notices, 8.230.30 Water in a Compendial Procedure) and Reagents,
Indicator, ond Solutions cleary tate that where the term "water is indicated for use in analyses without grammatical
(ualfication or other specification, the quality ofthe water must be Pured Water. However, umerous such qualfiatonséo
iis. Some of these qualifications involve adjectives describing methods of preparation, ranging from specifying the prmay
purtficavon step to spectying addtional purification. Other qualifications call for specific attoute “absences” to be met tt
Fight otherwise intertere wit analytical processes. In most of these cases, the required attbute absences are not spec
ested. Sometimes, a further “purification process” is specified that ostensibly allows the water to adequately meet this
required “absence attribute”,
THowever, preparation instructions for many reagents were caried forward from the innovators laboratories tothe
criginally intoduced monograph Tora particlar USP-NF article or general test chapter. The quality of the reagent water
eeemtbcd in these tests may rellect the water qualty designation of the innovators laboratory. These specific water
Sesignations may have originated without the innovator’s awareness ofthe requirement for Pufed Woter in USP-NF ess
Regardless of the original reason forthe creation ofthese numerous special analytical waters, i fs possible thatthe atrbt,
Of these special waters could now be met by the basic preparation steps and current specifications of Purfed Water. Insom*
discs hohever, some ofthe cited post processing steps are stil necessary to reliably achieve the required atibuts.
‘Geers are not obligated to utiize specific and pethaps archaically generated forms of analytical water where alternates
swith equal or better Gualty, availabilty, or analytical performance may exist. The consistency and reiablty of opeatons
producing these alternative analytical waters should be verified so thatthe desired attributes are produced. n alton 2)
Chernative analytical water must be evaluated on an application-by-applicaion basis by the user to ensure its stabi Pe
{olloning ia semmary ofthe various types of nenmonographed analytical waters that are cited in the USP-NF, This not
fexhaustive listing, Those Isted below are used in multiple locations. Several nonmonographed analytical waters a€ not
Included below because they are only found in ane or perhaps two locations within this compenium. [Note that the names of mi
water” implies that all the oy
Illesuit inthe ingress of con
removal of fons cannot be o
Genera information (1231) 8129
of the waters
showers yl. For example, “on
on die CO) ingen om cases dacred Rt ogee Se |
Omens mina res nad maaan apne Tee
3.3.3 AMMONIA-FREE WATER
cls imply a very low chemical imy
Cotton dow te wate is dtd in the ag
sere tel eA Sn fe nd
Means he abi ced Mater ar anette npn tS
sscesFree Water sree PR carbon case oF NLT 18 megahmcm at 35
once ee Water es arcned aragonite let hep apy ts mos le ue Carbon
Beaentesestve agen orden ™ Prete pce a8 fe ef
The erm “Carbon Donde ee tare
a ge re a mes wed improper, Besides its use for pH or ace
pare xing ts water nt ays eau ad Cauadeosewner a ose
shee remington ds ued Water hain
water protected, Even with protection ates ctN Solved
ready ans though Sealand fine ea
Sep tbon dose ‘Caton done oa
exdange Howes, the ae rot gaa
iar ote donation vac Sroierree Wat doc are
dissolved gases such a5 oxygen (09; oly remover ane E
Depesing on appar, Put Wotermay ee on a bon Diode Free Waters called for
Aen ate sample exposed me The trac oe cen ade ee Mate cal
eyo ore ng redo a ney SS ae os terse a on
pH ange of porns ')intherangeof 4.0% Tos Mio es x 07M
{eidty caused by carbon dloxide ab ‘rpton may be lsignicant compared tothe matrel being snayrca, Te 20d
3.3.5 DisTIuED warer
tse pay 5 swear nce king Wate oa igher ust of water and condensing tt a purer sae
poe para sever rare aren Mae Hoh aed the exciton ost a k
ssfrtnsing an analyte ansering a est materal ashy sa soe a ee anita lnk and fortes
Berbanyte Because non hots Oe Sain nate to be uted fo ming a ee oo
iby aaion water occane eee eet wae ingyen fora pric ON ACT ne
(Setin Zane ely Saenger er Pte rdeey oher nase ene oe
don could be equal stable where Distied Wate i specied. Nis the users operas eee oe
Ped ater or iter or nection” . Soy Fae
yfaaliity tests, the
tat data re of dace a)
ing step. Although Boing is hgh
gasses, these gaes are each re-sbsorbea unless the
3 stoppered con ‘ccur overtime asa il
ainer, e-absorption wil
3.3.6 FRESHLY DIsTILED WaTER
{rely Diled Water o recent dst wate” is prodcedn the sare manna ited Voter and shouldbe wed
soon aris generation. This implies the need a avid endotnn contanaconr ye Geka Se
sean fo at cata cs awn ged sae chy Gl ey or
Pepuing solitons for subcutaneous eam ncons anor agent sen reas oa tobe
ye arene cnt reper tay Sc Stet
xm “rely tiled” and is esting use imply a chemical, enstoun, and mcobiagial pang see
‘she by Wore rho ere made oe chee noone ae a EE
Tetng the reqerent fr PuedWoter dened Sy eer
sutable where ecenty dled water ot Freshy Bsicd
ait of ured Water or Water fonction
3.3.7 DEIONIZED WATER
eas of purcaton andor storage perods coud be caval
Mate spate tthe user's respenty toe Be
Deionized Water can be pr
roduced by starting with ether Ornking Water or Purified Water, depending upon monograph
esting procedures define
Bind gute seca ae so,
ea none of ited uses of this water imply any needed purity attrit ce 4 Last
— {8130 (1231) / General Information Ung
utd be equy sable whee Deonzed Waters pected ts hese esponsiy to erty he sabi og,
3.3.6 DEIONIZED DISTILLED WATER
Dre Dt Waters rote by donna ie 77 Orie ee Dees Woe Mater gy
reapenin' iq hvrntogophy tet ht request ow ionic or organic impr lve, Because ofthe pone
high purity, water thet meets the requirements for Puried Water may not be acceptable. High-Purity Water (see 34
Pun Wore coud be a resonsblesematve to vs mate, the User's esponsbily to very the stably fg.
alterative water use
3.3.9 FILTERED WATER
3.3.10 HIGH-PURITY WATER
ie cn ea ee rN et OS men eae
meeitiartaae gaat i Sen taser cate Keane ease
ime eae aeons ete pts weer waar coupe
Sonal eten ame eras ay ters ea ede a rm
Sou theb nett aemacet sect raat eal one emanate
Sree ma tree joecass Say i Waal oe bi sah
i
3.3.11 DEAERATED WATER
Deaerated Water or “degassed water” is Purified Water that has been treated to reduce the content of disolved a by
“suitable means" such as boiling, sonication, and/or siting during the application of a partial vacuum, followed by
Immediate use or protection trom at reabsorption.
3.3.12 OXYGEN-FREE WATER
COxygen-Free Water is Purified Water that has been treated to remove or teduce dissolved oxygen, Such treatment coud
involve deaerating by boiling or sparging with an inert gas such as nitrogen or helium, fllowed
prevent oxygen reabsorption. Any procedure used for removing oxygen should be verified as reli
Fitfor use.
saa we on hoe eooroms
i me iin i ince Ni i
Seated alae ace ts
4. VALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND
DISTRIBUTION SYSTEMS
a
5
&
4.1 Validation Requirement
Establishing the realty of pharmaceutical water purification, storage, an distribution systems requires demons
contol of the proces through an appropiate period ef monitoring and sbservaton. Fished water ype cor
Produced and used, while product and proces altnbutes may only be periodically asesseo, The uakty ot bus TaN!
‘ater cannot be extablshed by ony testing monograph albus. The unit operons the pharmaceuteal wae 20,
need to demonstrate that they aren contol through monitoring of the process parameters afd water qual, The a4
using conductivity and total organic carbon (TOC) to define chemical purty allows the user to more quantitatively ase
twates chemical purty and its variably asa function of routine eatment system maintenance and fegenesvON.
Treatment processes must aso demonstrate contol of microbial attibutes wit the overall stern Ste uk Opeaeo™
that are needed for chemical treatment may sgaicantly increase microbial and bacterial endotoxin levels Tese oe He oe
msieam i operation Genera information (1231) 8131
yoit9 2 to ensure thatthe phone eo of the te
tdessneed Pharmaceutical waters seater yer process andthe effectiveness of contol
Tate aban tse
eo pani and microbial aout Sel the panacea
eon sn state SUDUUeAypcl water ytem vaio eerste otal through
merit procuce te neon Patter nd tpn oe ees ps
yt proce the capa we ea sang a ein ona Pees a
eo sis fatness She sans ewe
42 Validation Approach
sen Poof decathlon pe cope cre
ee oreo penne at any sats, heals pi ais consistent
eet el eon itt Nog at Spe eran
abv posal nol sae onthe by oe
dais fhe wate
the Bouraies he wae ste and the rica water quay and process
serene har pada rae daria tundey may Sop merle ay cea
‘eto arpied eaubrent connector ned we cul he vr 9 Theater use tcatons (eypicaly either
ro a onnestiont deine sue the water sytem boundary, ren th ater POSS
Beste marebal monitoring tanec the aly ofthe water as is delivered for use, Secause routine qualiy
Sal ei Om a ane oe and componente hess an ea
ee baton stem ake, tee some loge encode te water arses Process
4.2.1 VALIDATION ELEMENTS
se caicealal wang intaluctesig
en ation (OQ), Installation Qualifiatior 3, documented process, ases of this process include,
esi es Sy Seta Seay ere
rtd figs sof eng ei tec hea
Gash ore nly operat aun or oP Paneer eo oo ‘nd commissioning
Seka sain ta heptane srs acd ye mses kan
Figure 3, Water system vaiation ie oe
PECIFICATION AND DESIGN QUALIFICATION
a. use ReQUMOMeN 5
They
cae enemy ect en, en ly es
rms at ten le) ei eh aa vay
peace ten gaan cy ios amo epee 8132 (1231) / General Information
U4
“The review ofthe spectfications, system design, components, functions, and operation should be performed to,
ee ie rec bystem complies with GMPS and very that the design meets the user requirements. This docu,
SGitgrmay be performed a5 part of the overall design process or as a separate DQ. ete
4.23.10
‘an 1Q protocol for a water system confirms that the system has been propery installed and documented. This may
(ee oe ee aents, piping, stalaion, and weld quality, documentation ofthe specifications fra Samay nc
“Sports present inspections to vey tha he craving accra depict thea configuration fhe wate
serra acesar, special tests to very thatthe instalation meets the design requirements. Additional, the wate”
are ed for operational testing, inching caratin of instrament, configuration of alam eel and ahs
Operating parameters (eg, flow rate, pressure) ota
4.2409
fw RAP tO SUA NL ld hee eh
tov atte aime oe et nd ante oe
hed (spe ol ata ay oe
all aspects of water ystem operation, mannan, War
is producing sutable veter eee
‘The 0 phase consisting of tests and inspection
reliably and that appropriate Alert and Action Level
TQ and PQ), During this phase of validation specific testing is
functional checks, and verification of operating ranges. SOPs for.
‘se, water sampling, and testing, etc. should be in place and operator training compl
‘ater system has demonstrated that the components are operational and the systern
4.2.5 PQ
‘Te prospective PQ stage considers two aspects ofthe water sytem: citcal process parameters and crite water
axuibut parameters hess oe evaluated ny paral by monitoring the water qty and demonsiating acceptable qui
aaa Pere demmonavating contol ol tne process parameters (se 6. Voluation Sampling Plans). The nal PQstage
aes raace i rebnement of proce porarete’s 0 yield appropriate water quay, Ths PQ stage includes an incest
Treducney of monitoring for approntmatey 2-4 weeks, of sullen ime to generate adequate data to demonstrate that
sere tha the appapbrte quay atetutes produced and distibuted, One ofthe reasons for this duration i that
Uti the Sguree of planktonic organisms in water samples, takes time to develop and to determine ifthe sanitation unt
aaron a proceses are adetnnteto contol microbial polation. The chemical contol program adequacy ply
eee ae Riou thon takes to see mira control adequacy. However, chemical purcation can be éompromied by
oor microbial control and, oa lesser degree, vice versa
ere i contol of microbial and chemical attbutes has been demonstrated, the next phase of PQs to conthue
tne eqaency of monitoring for approximately 2-4 weeks at somewhat reduced evel that wl stl give adequate data on
Sein bertrnance whe esing the pharmaceutical wate. The water may be used for manufacturing at rsh and the
Bes proaucis maybe released onl after water qualiyattibutes have Been determined to be acceptable and hs
ace roars Deen completed. A te completion ofthe second phase, Ue data should be formally reviewed and he
System approved for operational use.
43 Operational Use
into operational use, monitoring ofthe water quality attributes and the stem
1 frequency (see 6-4 Routine Sampling Plans) to ensure that they remain witha
/Punit operation maintenance,
‘When the water system has been placed
process parameters is performed at a rou!
Sate of Control during long-term variability from seasonal variations in source water qu
System santization processes, and earlierestablished Alert and Action Levels.
1 Sater oysters should continue to be monitored and evaluated on an on-going bass following alte cycle approach
using online instruments or samples fr laboratory-based testing The use of online instruments and process automation
sane sei such as conductivity, TOC, temperature, flow rate, and pressure can facilitate improved operational conta of
crete tes and parameters ad for process release, Manual observation of operating parameters and laboratory-based
{eating is also appropriate and acceptable for monitoring and trend evaluation.
4.3.1 MONITORING
‘The frequency of routine monitoring should be based onthe criticality ofthe finished water, capabilities ofthe procs
and bits to meintain product water qually trends, Monitoring may be adjusted from the inital validation monitoring
program when there is sufficient data to support a change (se 6.4 Routine Sampling Pans).
14.3.2 VALIDATION MAINTENANCE
Maintaining the vldated tte of conta requis aie cycle approach, Alter the completion of the PQ and reese of
water system for use, ongoing activites and programs have to Senptlace to maintain te validated state of corto ae the
yo a ed hao srice Gee 4 Operation Matron and Conte. This inces ot P=
system as been valate and pose yentveantenance, procedures, manuals and Growing, andarzavon ot ,
carton, corectve maintenance rey ature wenn, change conta, deviations corrective and prevent
rye, ecards retention, tagbook, et pa
5 General Information (1231) 8133
4.3.3 CHANGE CONTROL
sion and contol of changes made t
setzaton and laboratory processes ot posed ns NE stem components, operat
rt re reese of pete: need toe sane era eR es ees aa
tomer changes could have an impact on cual tes Thema of
i
Fen et voces parameters and oat
Bessey pore preter and aalty abst ena yee ay
a ‘ongoing state of conta for the system and ably to maintain ete cate
FRE ctalon and preventive maintenance actives mn ene
Se pa ae sa unctonalspeckentnc ee <2
Le eretisons fon Yaar med at risk with the cca specifications
Fesponse factors) havi speci (eg,, material of
:
in, ence le
4.3.4 PERIODIC REVIEW
“eet res hey ee ee ty me tng
iesty Sino) Sen nr tae pon tn mera ps
5. DESIGN AND OPERATION OF PURIFIED WATER AND WATER FOR INJECTION SYSTEMS.
the design instalation, and operation of systems to produce Prtied Water and Wate fr
© produce Puriled Water and Water fr Irecton include sir
nts, contro techniques, and procedures The quay atibute ofthe two waters fle in thei bloburden
ton, the presence acter endotoxin requment or Water fr irecton, andi the methods of preparation.
{tess inthe quay sibs provide considerable common ground nthe design of water stems tometer
cegurement. The citical diference the degre of control ofthe system andthe final purficaion steps needed to ensure
‘Shoot of bacteria and bacterial endotoxins and redetions in opportunites for bon e-development matin hose
funeation steps that could become in stu sources of actea and endotoxin nthe fished water
any specs ol tem desir and operation ete cont and mination of em, Unt operations can cause the