curto regulatory requirements water system

www.docvalidation.it www.stilmas.com

FUE INTERNATIONAL CONFERENCE ON FUE INTERNATIONAL CONFERENCE ON PHARMACEUTICAL TECHNOLOGIESPHARMACEUTICAL TECHNOLOGIESPHARMACEUTICAL TECHNOLOGIESPHARMACEUTICAL TECHNOLOGIES

FutureFuture UniversityUniversityFuture Future UniversityUniversityCAIRO, EGYPTCAIRO, EGYPT

March 1March 1--3, 20113, 2011,,

WORKSHOPWORKSHOP: : Advances in Sterile Products Technologies

Eng. Paolo CURTO’- D.O.C. (Stilmas Group) Managing Director

INTRODUCTIONINTRODUCTION

EMEANOTE FOR GUIDANCE ON QUALITY OF WATER FOR NOTE FOR GUIDANCE ON QUALITY OF WATER FOR

PHARMACEUTICAL USEPHARMACEUTICAL USEW t i f th j diti d b th h ti l

EMEA

Water is one of the major commodities used by the pharmaceutical industry. It may be present as an excipient, or used for reconstitution of products, during synthesis, during production of the finished product

l i t f i i l i t i k ior as cleaning agent for rinsing vessels, equipment, primary packaging materials etc.Different grades of water quality are required depending on the diff t h ti l C t l f th lit f t idifferent pharmaceutical uses. Control of the quality of water, in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification systemsdevelopment and maintenance of water purification systems.

SOURCE: EMEA/CVMP/115/01 – CPMP/QWP/158/01

SEMINAR BY DOC – PHARMACEUTICAL WATER & STEAM SYSTEMS – Pharmaceutical Water Regulatory Requirements 2

WATER QUALITY CATEGORIES WATER QUALITY CATEGORIES

PHARMACEUTICAL WATER CAN BE DIVIDED INTO PHARMACEUTICAL WATER CAN BE DIVIDED INTO TWO MAIN CATEGORIES:TWO MAIN CATEGORIES:

COMPENDIAL WATERCOMPENDIAL WATER-- COMPENDIAL WATERCOMPENDIAL WATER-- NONNON--COMPENDIAL WATERCOMPENDIAL WATER

COMPENDIAL WATERCOMPENDIAL WATER IS USED FOR THE PREPARATION OF MEDICINAL IS USED FOR THE PREPARATION OF MEDICINAL PRODUCTS, AND ITS QUALITY ATTRIBUTES ARE REGULATED BYPRODUCTS, AND ITS QUALITY ATTRIBUTES ARE REGULATED BYPRODUCTS, AND ITS QUALITY ATTRIBUTES ARE REGULATED BY PRODUCTS, AND ITS QUALITY ATTRIBUTES ARE REGULATED BY THE PHARMACOPOEIA (WATER MONOGRAPHS)THE PHARMACOPOEIA (WATER MONOGRAPHS)

SUITABLE NONSUITABLE NON COMPENDIAL WATERCOMPENDIAL WATER IS USED IN ALL THE OTHERIS USED IN ALL THE OTHERSUITABLE NONSUITABLE NON--COMPENDIAL WATERCOMPENDIAL WATER IS USED IN ALL THE OTHER IS USED IN ALL THE OTHER POSSIBLE APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY. POSSIBLE APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY. ITS QUALITY ATTRIBUTES CAN BE EVEN MORE STRINGENT THAN ITS QUALITY ATTRIBUTES CAN BE EVEN MORE STRINGENT THAN COMPENDIAL WATERCOMPENDIAL WATERCOMPENDIAL WATER.COMPENDIAL WATER.


WATER QUALITY WATER QUALITY DECISION TREEDECISION TREEDECISION TREEDECISION TREE

ISPEWater Usedfor . . .

Manufacturing Laboratory Cleaningfor Manufacture

Analytical Research & Sterile Bulk Parenteral Non- Bulk

Notes:1) By test procedure definition, some analytical

Note: Commitments made in drugapplications override suggestionsof the decision tree.

Analytical (see note 1) Pilot

(see note 2)

Sterile Bulk PCI or BPC

Non-cGMP cGMP

Parenteral Dosage Form Parenteral

Dosage FormAPI or BPC

(see note 5)Wash StepsFinal Rinse

fied

dow

nstre

am

) y p , ymethods require USP Compendial waters. Qualityshould meet the needs of the analytical methods.2) Labs performing both cGMP and Non-cGMPoperations should follow the cGMP path.3) Non-compendial water may be more highly purifiedthan compendial water. Endotoxin and microbial qualityis based on the process and quality standards of theproduct. Non-compendial water must at a minimum

t EPA ( bl EU J t d d)

Non cGMP cGMP

WFISee Note 1

Whe

re p

rodu

ct is

pur

if

Not

e 4

from

a p

revi

ous

revi

sion

,s

over

mis

inte

rpre

tatio

n

meet EPA (or comparable EU or Japanese standard)drinking water requirements for microbiological quality.4) Quality of final rinse water is determined by the typeof product and subsequenti processing steps. Whereproduct contact surface is subsequentially sanitized,final rinse with Suitable Non-Compendial water may beacceptable. Such practice may necessitate morestringent qualification criteria for the subsequentsanitization steps

USP Purified

Suitable Non-Compendial

See Note 1

See

N

This

line

was

del

eted

fB

ecau

se o

f con

cern

s

sanitization steps.5) Where production is purified downstream.

SOURCE: ISPE Baseline Vol. 4 – page 27 - Fig. 3-1. Pharmaceutical Water Quality Decision Tree

Compendial(see note 3)


WATER QUALITY DECISION TREE WATER QUALITY DECISION TREE for Monographed Manufacturing Watersfor Monographed Manufacturing Watersfor Monographed Manufacturing Watersfor Monographed Manufacturing Waters

DRINKING WATER(Complying with US EPA NPDWR or

drinking water regulation of EU or JAPAN or WHO Guidelines for Drinking Water)

If compatible without further

purificationNON COMPENDIAL

USPor WHO Guidelines for Drinking Water)

WATER FOR SPECIAL PHARMACEUTICAL

PURPOSES(e.g. initial cleaning, API

Typical Treatment Steps could include:Prefiltration DeionizationSoftening Reverse OsmosisD hl i ti Di till ti

(See next slide) ( g g

process and ingredient water) Dechlorination DistillationDeammonification UltrafiltrationOrganic Scavenging UV Light

WATER FOR HEMODIALYSIS

COMPENDIALslide)

WATER FOR HEMODIALYSIS (b lk k d)

PURIFIED WATERWATER FOR INJECTION

Distillation or equivalent superior

process for removing chemicals and

microorganisms P k i d

Unreactive Packaging

(bulk packaged)

WATER FOR INJECTION (bulk packaged)

g Packaging and sterilization

ANALYTICAL REAGENT WATER

CLEANING AND INGREDIENT WATER FOR NON PARENTERAL

CLEANING AND INGREDIENT WATER FOR PARENTERAL DOSAGE FORMS WATER FOR INJECTION (bulk packaged)

STERILE WATER FOR INJECTION

STERILE WATER FOR IRRIGATION

BACTERIOSTATIC WATER FOR INJECTION

WATER FOR NON PARENTERAL DOSAGE FORMS

Sterilization Packaging

SOURCE: USP 32 - Fig. 1. Water for pharmaceutical purposes

STERILE PURIFIED WATER PURIFIED WATER (bulk packaged) STERILE WATER FOR INHALATION


REGULATORY HIERARCHYREGULATORY HIERARCHYREGULATORY HIERARCHYREGULATORY HIERARCHY

PHARMACOPOEIA cGMPPHARMACOPOEIA

LAW

cGMP

- USP- EP

- EU- USA

JAPAN- JP

- JAPAN- WHO--CHINA--PIC/S

GUIDELINES- ISPE-FDA - Baseline- FDA-EMEA - Guide to Inspection- CPG (Compliance Policy Guide)

PDA Technical Monograph

( p y )

PDA Technical Reports- PDA – Technical Monograph- ASME – BPE 2002-OTHERS

G.E.P. STANDARD

- PDA – Technical Reports- ASME – BPE 2009-ISO-14644-Other STDs


REGULATORY REGULATORY REFERENCES & STANDARDSREFERENCES & STANDARDSREFERENCES & STANDARDSREFERENCES & STANDARDS

1.1. EMEA EMEA –– ICH Q7A (API GMP)ICH Q7A (API GMP)

2.2. EMEA EMEA –– CPMP/QWP/158/01(Note for Guidance on Pharm. Water Quality)CPMP/QWP/158/01(Note for Guidance on Pharm. Water Quality)( y)( y)

3.3. European Pharmacopoeia European Pharmacopoeia –– 7th Ed. (Water Monograph & Tests)7th Ed. (Water Monograph & Tests)

4.4. European Union / USA / WHO / PIC/S / GMPEuropean Union / USA / WHO / PIC/S / GMPu opea U o / US / O / C/S / Gu opea U o / US / O / C/S / G

5.5. WHO GMPWHO GMP--Annex 3Annex 3--”Water for Pharmaceutical Use””Water for Pharmaceutical Use”

6.6. USP 34 <1230>, <1231>, <1232> (pending)USP 34 <1230>, <1231>, <1232> (pending)6.6. USP 34 <1230>, <1231>, <1232> (pending)USP 34 <1230>, <1231>, <1232> (pending)

7.7. USP 34 (Water Monograph & Tests)USP 34 (Water Monograph & Tests)


REGULATORY REGULATORY REFERENCES & STANDARDSREFERENCES & STANDARDSREFERENCES & STANDARDSREFERENCES & STANDARDS

8.8. FDA FDA –– Guide to Inspection of High Purity Water SystemsGuide to Inspection of High Purity Water Systems

99 PDAPDA –– Technical Report No 4Technical Report No 4 “Design Concepts for the Validation of a Water for“Design Concepts for the Validation of a Water for9.9. PDA PDA –– Technical Report No. 4 _ Technical Report No. 4 _ Design Concepts for the Validation of a Water for Design Concepts for the Validation of a Water for Injection System”Injection System”

10.10. ISPE Baseline Pharmaceutical Engineering Guide ISPE Baseline Pharmaceutical Engineering Guide –– Vol. 4: “Water and Vol. 4: “Water and Steam Systems” Steam Systems” –– January 2001January 2001-- currently under revisioncurrently under revision

11.11. ASME BPEASME BPE--2009 2009 BioprocessingBioprocessing EquipmentEquipment

12.12. ISPE ISPE –– Commissioning and Qualification of Pharmaceutical Water and Commissioning and Qualification of Pharmaceutical Water and Steam SystemsSteam Systems--20072007

1313 GAMP 5GAMP 5 G d A t t d M f t i P tiG d A t t d M f t i P ti13.13. GAMP 5 GAMP 5 –– Good Automated Manufacturing PracticeGood Automated Manufacturing Practice


GMP FOR ACTIVE GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTSPHARMACEUTICAL INGREDIENTSPHARMACEUTICAL INGREDIENTSPHARMACEUTICAL INGREDIENTS

4 34 3 WaterWater4.34.3 WaterWater4.30 Water used in the manufacture of APIs should be demonstrated to be suitable

for its intended use.4 31 Unless otherwise justified process water should at minimum meet World4.31 Unless otherwise justified, process water should, at minimum, meet World

Health Organization (WHO) guidelines for drinking (potable) water quality.4.32 If drinking (potable) water is insufficient to assure API quality, and tighter

chemical and/or microbiological water quality specifications are called for,chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms and/or endotoxins should be established.

4.33 Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

4.34 Where the manufacturer of a non-sterile API either intends or claims that it is it bl f i f th i t d t il d ( di i l)suitable for use in further processing to produce a sterile drug (medicinal)

product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

SOURCE: EMEA – ICH Q7A: Good Manufacturing Practices for active pharmaceutical ingredients – CPMP/ICH/4106/00


QUALITY OF WATER FOR QUALITY OF WATER FOR PHARMACEUTICAL USEPHARMACEUTICAL USEPHARMACEUTICAL USEPHARMACEUTICAL USE

4.14.1 POTABLE WATERPOTABLE WATER

Is not covered by a pharmacopoeial monograph but must comply with the

EP

Is not covered by a pharmacopoeial monograph but must comply with the regulations on water laid down by the competent authority. Testing should be carried out at the manufacturing site to confirm the quality of the water.

Potable water may be used in chemical synthesis and in the early stages of cleaning pharmaceutical manufacturing equipment unless there are specific technical or quality requirements for higher grades of water.

It is the prescribed source feed water for the production of pharmacopoeial grade water.



WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSEUROPEAN UNION

WATER FOR INJECTION (01/2009 0169)WATER FOR INJECTION (01/2009 0169)

EP

WATER FOR INJECTION (01/2009:0169)WATER FOR INJECTION (01/2009:0169)

Water for Injection is obtained from water that complies with the regulation on water intended for human consumption laid down by the competent authority, or from purified water, by distillation

SOURCE: EP 6.3 – Official Monographs / Water for Injection


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSJAPAN

WATER FOR INJECTIONWATER FOR INJECTION--Official Monograph Official Monograph

W t f I j ti i t ith d b di till ti f

JP

Water for Injection is water either prepared by distillation of Water (*) or Purified Water, or by the Reverse Osmosis-Ultrafiltration of Purified Water, and used for the preparation of Injections or preserved in containers and sterilizedInjections, or preserved in containers and sterilized……

When Water for Injection is prepared by the Reverse Osmosis-Ultrafiltration take precaution against microbial contaminationUltrafiltration, take precaution against microbial contamination of the purifying system to get confortable quality being equivalent to that of water prepared by distillation.

(*) Water, specified in JP monograph, means tap water and well water for human consumption

SOURCE: JP XV – Official Monographs / Water for Injection


WFI REGULATORY REQUIREMENTS WFI REGULATORY REQUIREMENTS People’s Republic of China

WATER FOR INJECTIONWATER FOR INJECTION--Official Monographs Official Monographs

W t f I j ti i d b Di till ti f P ifi d W t

ChP

Water for Injection is prepared by Distillation of Purified Water.…………..

SOURCE: ChP 2010 (Official July 2010)– Official Monograph / Water for Injection



4.34.3 PURIFIED WATERPURIFIED WATER

Is water for the preparation of medicinal products other than those that

EP

Is water for the preparation of medicinal products other than those that require the use of water which is sterile and/or apyrogenic. Purified Water which satisfies the test for endotoxins may be used in the manufacture of dialysis solutions. y

Production:Purified Water is produced by distillation, by ion exchange or by any other p y , y g y ysuitable method, from water that complies with the regulations on water intended for human consumption laid down by the competent authority.




4.44.4 HIGHLY PURIFIED WATERHIGHLY PURIFIED WATER

Is intended for use in the preparation of products where water of high

EP

Is intended for use in the preparation of products where water of high biological quality is needed, except where Water for Injections is required.

Production:Production:… Current production methods include, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration and deionization. Highly Purified Water meets the same quality standards as g y q yWFI but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as WFI.



WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSUnited States of America

WATER FOR INJECTIONWATER FOR INJECTION--Official MonographOfficial Monograph

Water for Injection is water purified by distillation or a purification

USP

Water for Injection is water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.

It is prepared from water complying with the U.S. Environmental Protection Agency National Primary Drinking Water Regulations or comparable regulations of the European Union, Japan, or with p g p , p ,the WHO Guidelines for Drinking Water Quality. It contains no added substance.

SOURCE: USP 32 – Official Monographs / Water for Injection


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSEMEA REFLECTION PAPER

London, 5 March 2008 Doc. Ref.

EMEA/CHMP/CVMP/QWP/28271/2008

Reflection Paper on Water for Injection Prepared by Reverse Osmosis

Conclusion by EMEA WFI by RO NOTConclusion by EMEA…WFI by RO….NOT ACCEPTABLE!!

The major objections concern range of separation for reverse osmosis,

validation and maintenance of devices and microbiological aspects.


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSEMEA REFLECTION PAPER

EMEA Reflection Paper of WFIEMEA Reflection Paper of WFIEMEA Reflection Paper of WFIEMEA Reflection Paper of WFI

CONCLUSION CONCLUSION

Today it is not possible to assume that the quality of WFI prepared by reverse-osmosis is as safe as water prepared by distillation according to the requirement of the European Pharmacopoeia.


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSEDQM SURVEY 2010Q

PURIFIED WATERPURIFIED WATER

Purified Water is water obtained by a suitable process

USP

… Purified Water is water obtained by a suitable process.

It is prepared from water complying with the U.S. Environmental Protection Agency National Primary Drinking Water Regulations orProtection Agency National Primary Drinking Water Regulations or comparable regulations of the European Union or Japan.

It contains no added substanceIt contains no added substance.

SOURCE: USP 32 – 50– OfficialMonographs / Water


EUROPEAN UNION GOOD EUROPEAN UNION GOOD MANUFACTURING PRACTICESMANUFACTURING PRACTICESMANUFACTURING PRACTICESMANUFACTURING PRACTICES

European Union Good Manufacturing PracticesEuropean Union Good Manufacturing Practices

Chapter 3: Premises and Equipment

Equipment

3.43 Distilled, deionized and, where appropriate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to b t kbe taken.

SOURCE: EU GMP – Chapter 3: Premises and Equipment - Page 34




Annex 1: Manufacture of sterile medicinal products

Equipment

35. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be

t d b d th i d i d it W t f I j tioperated beyond their designed capacity. Water for Injections should be produced, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°Ctemperature above 70 C.

SOURCE: EU GMP – Annex 1: Manufacture of sterile medicinal products




Annex 1: Manufacture of sterile medicinal products

Equipment

44. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should b i t i d f th lt f th it i d f tibe maintained of the results of the monitoring and of any action taken.

SOURCE: EU GMP – Annex 1: Manufacture of sterile medicinal products



Chinese Good Manufacturing PracticesChinese Good Manufacturing Practices--19981998Chapter 4: Equipment

Article 34: The preparation, storage and distribution of purified water and water for injection shall be protected from microorganism breeding and contamination. Storage tanks and delivery pipelinesbreeding and contamination. Storage tanks and delivery pipelines shall be made from non-toxic and corrosion resistance materials. Inaccessible places and dead spots shall be avoided in design and installation of pipelines.Storage tanks and pipelines shall be p p g p pcleaned periodically. Vents of tanks of water for injection shall be protected by a non-fiber-releasing hydrophobic microbial air filter.Water for injection shall be stored at 80 °C minimum, or at 4°C a e o jec o s a be s o ed a 80 C u , o a Cmaximum or maintained in constant circulation at 65°C minimum.


WATER TYPES IN PHARMACOPOEIAWATER TYPES IN PHARMACOPOEIA(source Anthony Bevilacqua(source Anthony Bevilacqua--Mettler Toledo)Mettler Toledo)

W t T EP 7 USP 34 JP XVWater Type EP 7 USP 34 JP XVWater for Injection (bulk) + + +Water for Injection/sterilized (containers) + + +Highly Purified Water (bulk) +Purified Water (bulk) + + +Purified Water (containers) +Purified Water (containers)

Sterile Purified Water (bulk) +

Sterile Purified Water (containers) +Bacteriostatic Water for Injection (containers) +Sterile Water for Inhalation (containers) +Sterile Water for Irrigation (containers) +Water for Hemodialysis (bulk + containers) + +Water (tap, well) +Pure Steam +Pure Steam +


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSWATER FOR INJECTION (IN BULK) current limit

WATER FOR INJECTION ( in bulk )E P 7 0 Ed USP 34

QUALITY PARAMETERSE.P. 7.0 Ed.

(Only By Distillation)USP 34

(By Distillation or a purification process equivalent or superior to distillation in the removal of chemicals and micro-organisms)g )

Conductivity It meets the requirements Table 0169.-1.

Water Monographe g 1 1 S/cm (20°C) (1)

It meets the requirements 645

e.g.. 1.1 S/cm (20°C) (1)

e.g.. 1.1 S/cm (20°C) (1)

TOC 0.5 mg/l 0.5 mg/l

Nitrates 0.2 ppm Not considered

Microbial Counts(action limit)

10 CFU/100 ml 10 CFU/100 ml

Bacterial Endotoxins ( ti li it)

0.25 IU/ml 0.25 EU/ml(action limit)

(1)The Conductivity Limits are indicated in a table as function of Temperature., as follows:< 1,1 S/cm (20°C) < 1,3 S/cm (25°C) < 1,5 S/cm (35°C) < 1,7 S/cm (40°C)< 1 8 S/cm (45°C) < 1 9 S/cm (50°C) < 2 1 S/cm (55°C) <2 2 S/cm (60°C)< 1,8 S/cm (45 C) < 1,9 S/cm (50 C) < 2,1 S/cm (55 C) <2,2 S/cm (60 C)< 2,4 S/cm (65°C) < 2,5 S/cm (70°C) < 2,7 S/cm (75 ÷ 90°C) < 2,9 S/cm (95°C)


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSWATER FOR INJECTION (IN BULK) current limit

WATER FOR INJECTION ( in bulk )JP XV ChP 2010

QUALITY PARAMETERSJP XV

(By Distillation, or RO-UF from Purified Water)

ChP 2010(Only by Distillation from Purified

Water)

Conductivity 1.3 S/cm (3 stage) (1) 1.3 S/cm (3 stage) (1)

TOC 0.5 mg/l (0,3 for control) 0.5 mg/l

•Nitrates (NO3-)•Nitrites (NO2-)•pH•Residue on Evaporation

DELETED Pass the test

Residue on Evaporation•Heavy Metals

Microbial Counts(action limit)

10 CFU/100 ml 10 CFU/100 ml

Bacterial Endotoxins (action limit)

0.25 EU/ml 0.25 EU/ml

(1)The Conductivity Limits are indicated in a table as function of Temperature (same as USP/EP)


BULK PURIFIED WATER (IN BULK) BULK PURIFIED WATER (IN BULK) current limit current limit

(source Anthony Bevilacqua(source Anthony Bevilacqua Mettler Toledo)Mettler Toledo)(source Anthony Bevilacqua(source Anthony Bevilacqua--Mettler Toledo)Mettler Toledo)

Attribute(1) USP 34 EP 7.0 JP XV

Production Method Suitable process Suitable processDistillation, ion-exchange, UF, or

combinationcombination

Source Water US, EU, Japan, WHO drinking water Human consumption JP water specification

Conductivity (mS/cm at 25°C) (2) 1.3 (3 stage)<645>

5.1 (1 stage) 1.3 (3 stage)<645>

TOC (mg/L)0.5

<643>0.5 (optional) 0.5

Oxidizable Substances (/100 mL) <0.1 mL(3) 0.02 Oxidizable Substances (/100 mL) KMnO4

Nitrates (ppm) 0.2

N t 1 All t t i l th i t t dNote 1: All tests are maximum, unless otherwise stated.Note 2: Limits are temperature dependent Note 3: Alternative to TOC


BULK PURIFIED WATER (IN BULK) BULK PURIFIED WATER (IN BULK) current limitcurrent limit


Attribute(1) USP 34 EP 7.0 JP XV

Heavy metals (ppm) 0.1(5)

Aluminum (ppb) 10 (4)

Total Aerobic (cfu/mL) 100 100 100

Bacterial Endotoxins (EU/mL) 0.25 (4)

Note 1: All tests are maximum, unless otherwise stated.Note 4: Only if water is intended for use in the manufacture of dialysis solutionsNote 5: If purified water in bulk complies with the requirement for conductivity prescribed for Water for Injection (0169) in bulk, it is not necessary to carry out the test for heavy metals prescribed.


BULK PURIFIED WATER AND WFIBULK PURIFIED WATER AND WFI

Source Water RequirementsSource Water Requirements• USP: "It is prepared from water complying with the U.S. Environmental Protection Agency National Primary Drinking Water Regulations or with the

Source Water RequirementsSource Water Requirements

Protection Agency National Primary Drinking Water Regulations or with the drinking water regulations of the European Union, Japan, or with the World Health Organization's Guidelines for Drinking Water Quality.“

• EP: "from water that complies with the regulations on water intended for human consumption laid down by the competent authority.“

• JP: "prepared from Water".



Method of Production RequirementsMethod of Production RequirementsMethod of Production RequirementsMethod of Production Requirements

• Purified WaterPurified Water– USP, EP, JP permits production by distillation, reverse osmosis, de-

ionization, filtration, or equivalent means.

• Highly Purified Water– EP only, produced by RO coupled with other purification methods (like

UF) t WFIUF), meets WFI– Allowed for limited pharmaceutical applications


WFI REGULATORY REQUIREMENTSWFI REGULATORY REQUIREMENTSMethods of PreparationMethods of Preparation

In the EU, WFI can be produced only by distillation of Drinking Water (*) or Purified Water.

I th USA WFI b d d b di till ti ifi tiifi ti In the USA, WFI can be produced by distillation or a purification process a purification process that is equivalent or superior to distillation in the removal of chemicals that is equivalent or superior to distillation in the removal of chemicals

and microorganisms”and microorganisms” of Drinking Water (*).and microorganisms and microorganisms of Drinking Water ( ).

In Japan, WFI can be produced by distillation of Drinking Water (*) or Purified Water or by the Reverse Osmosis – Ultrafiltration of Purified Water.

In China WFI can be produced only by distillation of Purified Water

(*) suitably pre-treated



Microbiology RequirementsMicrobiology RequirementsMicrobiology RequirementsMicrobiology Requirements• EP limits are ACTION LIMITS in Production section

– Purified Water…100 cfu/mLPurified Water…100 cfu/mL– WFI……………..10 cfu/100 mL

• USP limits are “recommended” in 1231 general chapterS li it EP– Same limits as EP

• JP limits are enforced in drinking water requirements– Same limits as EP



Endotoxin RequirementsEndotoxin RequirementsEndotoxin Requirements Endotoxin Requirements

• <0.25 EU/mL Endotoxin (USP and JP)

0 25 IU/ L E d t i (EP)• <0.25 IU/mL Endotoxin (EP)

Same limits and same tests


BULK PURIFIED WATER AND WFIBULK PURIFIED WATER AND WFI<645> Water Conductivity

(source Anthony Bevilacqua(source Anthony Bevilacqua Mettler Toledo)Mettler Toledo)

Current USP <645> Stage 1 and EP Conductivity Limits

(source Anthony Bevilacqua(source Anthony Bevilacqua--Mettler Toledo)Mettler Toledo)

Conductivity Limits

8 0

9.0

10.0

S/cm

)

Cl ModelNH3 Model

6.0

7.0

8.0

uctiv

ity ( USP <645> Stage 1 Limit

EP PW limit at 20°CEP WFI limit at 20°C

4.3

4.0

5.0

6.0

ed C

ondu

1 9 2 1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.11.12.0

3.0

mpe

nsat

e

0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.9 2.1 2.21.8

0.0

1.0

0 10 20 30 40 50 60 70 80 90 100

Unco

m

0 10 20 30 40 50 60 70 80 90 100Temperature (°C)




Stage 1: Temperature/Conductivity Requirements(for non-Temperature Compensated Conductivity Measurements)


( p p y )Maximum Maximum

Temperature Conductivity Temperature Conductivity(°C) (µS/cm) (°C) (µS/cm)

0 0.65 0.8 55 2.1

( C) (µS/cm) ( C) (µS/cm)

10 0.9 60 2.215 1.0 65 2.420 1.1 70 2.525 1 3 75 2 725 1.3 75 2.730 1.4 80 2.735 1.5 85 2.740 1.7 90 2.745 1.8 95 2.950 1.9 100 3.1

Example: Temperature is 83 7°C and uncompensated conductivity is 1 7 µS/cmExample: Temperature is 83.7 C and uncompensated conductivity is 1.7 µS/cm. The limit is 2.7 µS/cm at 80°C. PASS!




Harmonization (?) for Conductivity Limitsy

• USP <645> has two tables of conductivity limits – Permits on-line test from 0-100°C.Permits on line test from 0 100 C.– Permits off-line tests and accounts for innocuous CO2 at 25°C.

• EP 2.2.38 has since EP 5TH

ED (July 2004) two conductivity vs temperature table (e.g.):– 1.1 S/cm at 20°C for WFI.1.1 S/cm at 20 C for WFI.– 4.3 S/cm at 20°C for Purified Water.– Retain nitrate test.– Retain Heavy Metals test (only PW).



EP 6th Conductivity Limits645 Water Conductivity

9,19,7 9,7 9,7

8 0

9,0

10,0

S/c

m)

6,5

8,1

7,16,0

7,0

8,0

uctiv

ity (

S

4,3

5,1 5,4

6,5

4,0

5,0

ed C

ondu EP Purified Water Limits

EP WFI Limits

2,4

3,6

1 7 1 8 1,9 2,1 2,2 2,4 2,5 2,7 2,7 2,7 2,7 2,9 3,1

1 0

2,0

3,0

ompe

nsat

0,6 0,8 0,9 1,0 1,1 1,3 1,4 1,41,7 1,8 ,

0,0

1,0

0 10 20 30 40 50 60 70 80 90 100

Unc

o

Temperature (°C)


BULK PURIFIED WATER AND WFIBULK PURIFIED WATER AND WFI(source Anthony Bevilacqua(source Anthony Bevilacqua--Mettler Toledo)Mettler Toledo)

Total Organic Carbon (TOC)TOC is a new test methodTOC is a new test method.

– Advantages: semi-quantitative, on-line, and process controller.– Disadvantages: cost and difficulty to calibrate/maintain.g y

• On-line capable of sub-ppb detection limits, fewer problems from t i ticontamination

N i l t h l f TOC t• No single technology for TOC measurement– Lab instrumentation– Membrane-based conductometric– Conductometric

• Capable of on-line QC, QASEMINAR BY DOC – PHARMACEUTICAL WATER & STEAM SYSTEMS – Pharmaceutical Water Regulatory Requirements 38

BULK PURIFIED WATER AND WFIBULK PURIFIED WATER AND WFI<643> TOC


C H O CO + H O H CO H+ + HCO


• CxHyOz CO2 + H2O H2CO3 H+ + HCO3-

• Hg lamp emits 185 nm and 254 nm UV lightUV

g p g

• Light, chemicals, surfaces, and time move the reaction for ardreaction forward

• Accurate conversion of temperature and conductivity p yis required


THANK YOU FOR YOUR KIND ATTENTIONAny Question please address to:y Q p

[email protected]


curto regulatory requirements water system

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