Curto Regulatory Requirements Water System

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FUE INTERNATIONAL CONFERENCE ON PHARMACEUTICAL TECHNOLOGIES Future University

CAIRO, EGYPT
March 1-3, 2011 1- ,
WORKSHOP: WORKSHOP: Advances in Sterile Products Technologies
Eng. Paolo CURTO- D.O.C. (Stilmas Group) Managing Director
INTRODUCTION
EMEA NOTE FOR GUIDANCE ON QUALITY OF WATER FOR PHARMACEUTICAL USE Water i W t is one of the major commodities used b th pharmaceutical f th j diti d by the h ti l industry. It may be present as an excipient, or used for reconstitution of products, during synthesis, during production of the finished product or as cleaning agent f rinsing vessels, equipment, primary packaging l i t for i i l i t i k i materials etc. Different grades of water quality are required depending on the different pharmaceutical uses. C t l of the quality of water, i diff t h ti l Control f th lit f t in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification systems systems.
SOURCE: EMEA/CVMP/115/01 CPMP/QWP/158/01

SEMINAR BY DOC PHARMACEUTICAL WATER & STEAM SYSTEMS Pharmaceutical Water Regulatory Requirements
WATER QUALITY CATEGORIES
PHARMACEUTICAL WATER CAN BE DIVIDED INTO TWO MAIN CATEGORIES:

COMPENDIAL WATER NONNON-COMPENDIAL WATER
COMPENDIAL WATER IS USED FOR THE PREPARATION OF MEDICINAL PRODUCTS, AND ITS QUALITY ATTRIBUTES ARE REGULATED BY THE PHARMACOPOEIA (WATER MONOGRAPHS) SUITABLE NON-COMPENDIAL WATER IS USED IN ALL THE OTHER NONPOSSIBLE APPLICATIONS IN THE PHARMACEUTICAL INDUSTRY. ITS QUALITY ATTRIBUTES CAN BE EVEN MORE STRINGENT THAN COMPENDIAL WATER WATER.
WATER QUALITY DECISION TREE
Water Used for . . .
ISPE
Laboratory
Manufacturing
Cleaning
for Manufacture
Analytical
(see note 1)
Research & Pilot

(see note 2)
Sterile Bulk PCI or BPC

Where product is purif fied downstream
Parenteral Dosage Form
NonParenteral Dosage Form
Bulk API or BPC

(see note 5)
Final Rinse
Wash Steps
Note: Commitments made in drug applications override suggestions of the decision tree.
Non cGMP Non-cGMP
cGMP
See Note 1
WFI
See Note 4 N
USP Purified
See Note 1
Suitable NonCompendial
(see note 3)
Notes: 1) By test p ) y procedure definition, some analytical , y methods require USP Compendial waters. Quality should meet the needs of the analytical methods. 2) Labs performing both cGMP and Non-cGMP operations should follow the cGMP path. 3) Non-compendial water may be more highly purified than compendial water. Endotoxin and microbial quality is based on the process and quality standards of the product. Non-compendial water must at a minimum meet EPA (or comparable EU or J t ( bl Japanese standard) t d d) drinking water requirements for microbiological quality. 4) Quality of final rinse water is determined by the type of product and subsequenti processing steps. Where product contact surface is subsequentially sanitized, final rinse with Suitable Non-Compendial water may be acceptable. Such practice may necessitate more stringent qualification criteria for the subsequent sanitization steps steps. 5) Where production is purified downstream.
SOURCE: ISPE Baseline Vol. 4 page 27 - Fig. 3-1. Pharmaceutical Water Quality Decision Tree
This line was deleted from a previous revision, f Because of concerns over misinterpretation s
WATER QUALITY DECISION TREE for Monographed Manufacturing Waters

DRINKING WATER
NON COMPENDIAL
If compatible without further purification
(Complying with US EPA NPDWR or drinking water regulation of EU or JAPAN or WHO Guidelines for Drinking Water)
(See next slide)
WATER FOR SPECIAL PHARMACEUTICAL PURPOSES

( g (e.g. initial cleaning, API g process and ingredient water)
USP
Typical Treatment Steps could include:
Prefiltration Softening Dechlorination D hl i ti Deammonification Organic Scavenging Deionization Reverse Osmosis Distillation Di till ti Ultrafiltration UV Light
COMPENDIAL
WATER FOR HEMODIALYSIS

Unreactive Packaging Distillation or equivalent superior process for removing chemicals and microorganisms g
PURIFIED WATER WATER FOR HEMODIALYSIS (bulk (b lk packaged) k d)

ANALYTICAL REAGENT WATER CLEANING AND INGREDIENT WATER FOR NON PARENTERAL DOSAGE FORMS Sterilization Packaging
WATER FOR INJECTION

Packaging d P k i and sterilization
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
STERILE PURIFIED WATER
PURIFIED WATER (bulk packaged)
STERILE WATER FOR INHALATION
SOURCE: USP 32 - Fig. 1. Water for pharmaceutical purposes

REGULATORY HIERARCHY
PHARMACOPOEIA - USP
- EP - JP
cGMP - EU
- USA - JAPAN - WHO --CHINA --PIC/S
LAW
- ISPE-FDA - Baseline
- FDA-EMEA - Guide to Inspection - CPG (Compliance Policy Guide) ( p y )
GUIDELINES
- PDA Technical Monograph Reports

- ASME BPE 2002 2009 -ISO-14644 -OTHERS
-Other STDs
G.E.P. STANDARD
REGULATORY REFERENCES & STANDARDS
1. 2. 3. 4. 5. 6. 7.
EMEA ICH Q7A (API GMP) EMEA CPMP/QWP/158/01(Note for Guidance on Pharm. Water Quality) ( y) European Pharmacopoeia 7th Ed. (Water Monograph & Tests) European Union / USA / WHO / PIC/S / GMP u opea U o US O C/S G WHO GMP-Annex 3-Water for Pharmaceutical Use GMP3USP 34 <1230>, <1231>, <1232> (pending) USP 34 (Water Monograph & Tests)
REGULATORY REFERENCES & STANDARDS
8. 9. 9 10.
FDA Guide to Inspection of High Purity Water Systems PDA Technical Report No 4 _ Design Concepts for the Validation of a Water for No. Design
Injection System
ISPE Baseline Pharmaceutical Engineering Guide Vol. 4: Water and Steam Systems January 2001- currently under revision 2001-
11. 12.
ASME BPE-2009 Bioprocessing Equipment BPEISPE Commissioning and Qualification of Pharmaceutical Water and Steam Systems-2007 Systems-
13. 13
GAMP 5 G d Automated Manufacturing Practice Good A t t dM f t i P ti
GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS

4.3 4 3 Water
4.30 4.31 4 31 4.32
4.33
4.34
Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use. Unless otherwise justified process water should at minimum meet World justified, should, minimum, Health Organization (WHO) guidelines for drinking (potable) water quality. If drinking (potable) water is insufficient to assure API quality, and tighter 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. 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. Where the manufacturer of a non-sterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) it bl f i f th i t d t il d ( di i l) 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 PHARMACEUTICAL USE
4.1 POTABLE WATER

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.
EP
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.
10
WFI REGULATORY REQUIREMENTS

EUROPEAN UNION
EP WATER FOR INJECTION (01/2009:0169) (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
11

JAPAN
WATER FOR INJECTION-Official Monograph INJECTIONWater f I j ti i W t for Injection is water either prepared b di till ti t ith d by distillation of f Water (*) or Purified Water, or by the Reverse OsmosisUltrafiltration of Purified Water, and used for the preparation of Injections, Injections or preserved in containers and sterilized sterilized
JP
When Water for Injection is prepared by the Reverse OsmosisUltrafiltration, Ultrafiltration 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
12

Peoples Republic of China
WATER FOR INJECTION-Official Monographs INJECTIONWater f I j ti i W t for Injection is prepared b Di till ti d by Distillation of Purified Water. f P ifi d W t ..
ChP
SOURCE: ChP 2010 (Official July 2010) Official Monograph / Water for Injection
13
4.3 PURIFIED WATER

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 y suitable method, from water that complies with the regulations on water intended for human consumption laid down by the competent authority.
EP

14
4.4 HIGHLY PURIFIED WATER

Is intended for use in the preparation of products where water of high biological quality is needed, except where Water for Injections is required.
EP
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 y WFI but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as WFI.
15

United States of America
WATER FOR INJECTION-Official Monograph INJECTION-
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
16

EMEA 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 NOT EMEAWFI RO.NOT ACCEPTABLE!!
The major objections concern range of separation for reverse osmosis, validation and maintenance of devices and microbiological aspects.
17

EMEA REFLECTION PAPER
EMEA Reflection Paper of WFI

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.
18

EDQM SURVEY 2010 Q
PURIFIED WATER Purified Water is water obtained by a suitable process process.
USP
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 or Japan. It contains no added substance substance.
SOURCE: USP 32 Page 1950 OfficialMonographs / Water

19
EUROPEAN UNION GOOD MANUFACTURING PRACTICES
European 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 be taken. b t k
SOURCE: EU GMP Chapter 3: Premises and Equipment - Page 34

20

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 operated b t d beyond th i d i d their designed capacity. W t f I j ti d it 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 70C 70 C.
SOURCE: EU GMP Annex 1: Manufacture of sterile medicinal products

21

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 be b maintained of th results of th monitoring and of any action i t i d f the lt f the it i d f ti taken.
SOURCE: EU GMP Annex 1: Manufacture of sterile medicinal products

22
Chinese Good Manufacturing Practices-1998 PracticesChapter 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 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 p p pp g pipelines shall be cleaned periodically. Vents of tanks of water for injection shall be protected by a non-fiber-releasing hydrophobic microbial air filter. Water for injection s a be s o ed a 80 C minimum, o a 4C a e o jec o shall stored at C u , or at C maximum or maintained in constant circulation at 65C minimum.
23
WATER TYPES IN PHARMACOPOEIA

(source Anthony Bevilacqua-Mettler Toledo) Bevilacqua-
Water T W t Type Water for Injection (bulk) Water for Injection/sterilized (containers) Highly Purified Water (bulk) Purified Water (bulk) 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
EP 7 + + + + +
USP 34 + + +
JP XV + + + +
+ + + + + + + +
24

WATER FOR INJECTION (IN BULK) current limit
WATER FOR INJECTION ( in bulk ) E.P. 7.0 Ed E P 7 0 Ed. QUALITY PARAMETERS
(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 ) It meets the requirements 645 e.g.. 1.1 S/cm (20C) (1) 0.5 mg/l Not considered
Conductivity
It meets the requirements Table 0169.-1. Water Monograph e.g.. 1.1 e g 1 1 S/cm (20C) (1) 0.5 mg/l 0.2 ppm
TOC Nitrates Microbial Counts (action limit) Bacterial Endotoxins (action li it) ( ti limit) < 1,1 S/cm (20C) < 1 8 S/cm (45C) 1,8 (45 C) < 2,4 S/cm (65C)
10 CFU/100 ml 0.25 IU/ml
10 CFU/100 ml 0.25 EU/ml
(1)The Conductivity Limits are indicated in a table as function of Temperature., as follows:
< 1,3 S/cm (25C) < 1 9 S/cm (50C) 1,9 (50 C) < 2,5 S/cm (70C)
< 1,5 S/cm (35C) < 1,7 S/cm (40C) < 2 1 S/cm (55C) 2,1 (55 C) <2,2 <2 2 S/cm (60C) (60 C) < 2,7 S/cm (75 90C) < 2,9 S/cm (95C)
25

WATER FOR INJECTION (IN BULK) current limit
WATER FOR INJECTION ( in bulk ) JP XV QUALITY PARAMETERS Conductivity 1.3 S/cm (3 stage) (1)
0.5 mg/l (0,3 for control) DELETED (By Distillation, or RO-UF from Purified Water)
ChP 2010
(Only by Distillation from Purified Water)
1.3 S/cm (3 stage) (1)

0.5 mg/l Pass the test
TOC
Nitrates (NO3-) Nitrites (NO2-) pH Residue on Evaporation Residue Heavy Metals
Microbial Counts (action limit) Bacterial Endotoxins (action limit)
10 CFU/100 ml 0.25 EU/ml
10 CFU/100 ml 0.25 EU/ml
(1)The Conductivity Limits are indicated in a table as function of Temperature (same as USP/EP)
26
BULK PURIFIED WATER (IN BULK) current limit

Attribute(1)
USP 34
EP 7.0
JP XV Distillation, ionexchange, UF, or combination JP water specification 1.3 (3 stage) 0.5
Production Method Source Water Conductivity (mS/cm at 25C) (2) TOC (mg/L) Oxidizable Substances (/100 mL) Nitrates (ppm)
Note 1 N t 1: All tests are maximum, unless otherwise stated. t t i l th i t t d Note 2: Limits are temperature dependent Note 3: Alternative to TOC
Suitable process US, EU, Japan, WHO drinking water 1.3 (3 stage) <645> 0.5 <643>
Suitable process Human consumption 5.1 (1 stage) 0.5 (optional) <0.1 mL(3) 0.02 KMnO4 0.2
27
BULK PURIFIED WATER (IN BULK) current limit

Attribute(1) Heavy metals (ppm) Aluminum (ppb) Total Aerobic (cfu/mL) Bacterial Endotoxins (EU/mL)
USP 34
EP 7.0 0.1(5) 10 (4)
JP XV
100
100 0.25 (4)
100
Note 1: All tests are maximum, unless otherwise stated. Note 4: Only if water is intended for use in the manufacture of dialysis solutions Note 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.
28
BULK PURIFIED WATER AND WFI
Source Water Requirements

USP: "It is prepared from water complying with the U.S. Environmental 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".
29
Method of Production Requirements

Purified Water USP, EP, JP permits production by distillation, reverse osmosis, deionization, filtration, or equivalent means. Highly Purified Water EP only, produced by RO coupled with other purification methods (like UF), UF) meets WFI t Allowed for limited pharmaceutical applications
30
WFI REGULATORY REQUIREMENTS Methods of Preparation

In the EU, WFI can be produced only by distillation of Drinking Water (*) or Purified Water. In th USA, I the USA WFI can be produced b di till ti or a purification process b d d by distillation ifi ti that is equivalent or superior to distillation in the removal of chemicals and microorganisms of Drinking Water (*). microorganisms ( ).
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
31
Microbiology Requirements
EP limits are ACTION LIMITS in Production section Purified Water100 cfu/mL WFI..10 cfu/100 mL USP limits are recommended in 1231 general chapter S Same limits as EP li it JP limits are enforced in drinking water requirements Same limits as EP
32
Endotoxin Requirements
<0.25 EU/mL Endotoxin (USP and JP) <0.25 IU/ L E d t i (EP) 0 25 IU/mL Endotoxin
Same limits and same tests
33

<645> Water Conductivity
10.0
Current USP <645> Stage 1 and EP Conductivity Limits

Cl Model NH3 Model USP <645> Stage 1 Limit EP PW limit at 20C EP WFI limit at 20C
Uncom mpensate Condu ed uctivity ( S/cm)
9.0 8.0 80 7.0 6.0 5.0 4.0 4.3
3.1 2.7 2.7 2.7 2.7 2.9 2.0 2.5 1.1 2.2 2.4 2.1 1.9 2 1 1.7 1.8 1 9 1.0 1.4 1.5 1.1 1.3 0.9 1.0 0.6 0.8 0.0
3.0
10
20
30
40
50
60
70
80
90
100
34
Temperature (C)

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

Maximum Temperature Conductivity ( C) (C) (S/cm)
0 5 10 15 20 25 30 35 40 45 50 0.6 0.8 0.9 1.0 1.1 1.3 13 1.4 1.5 1.7 1.8 1.9
Maximum Temperature Conductivity ( C) (C) (S/cm)

55 60 65 70 75 80 85 90 95 100 2.1 2.2 2.4 2.5 2.7 27 2.7 2.7 2.7 2.9 3.1
Example: Temperature is 83 7C and uncompensated conductivity is 1 7 S/cm 83.7 C 1.7 S/cm. The limit is 2.7 S/cm at 80C. PASS!
35

Harmonization (?) for Conductivity Limits y

USP <645> has two tables of conductivity limits Permits on-line test from 0-100C. on line 0 100 C. Permits off-line tests and accounts for innocuous CO2 at 25C.
TH
EP 2.2.38 has since EP 5 ED (July 2004) two conductivity vs temperature table (e.g.): 20C 1.1 S/cm at 20 C for WFI. 4.3 S/cm at 20C for Purified Water. Retain nitrate test. Retain Heavy Metals test (only PW).
36

<645> Water Conductivity 645
EP 6th Conductivity Limits

10,0 Unco ompensated Condu uctivity ( S/cm) S 9,0
9,1 9,7 9,7 9,7
8,0 80
8,1
7,0
7,1
6,0 5,0
5,1 5,4
6,5
EP Purified Water Limits EP WFI Limits

3,1 2,7 2,7 2,7 2,7 2,9 2,4 2,5 2,1 2,2 1,7 1,8 , 1 7 1 8 1,9
4,0 3,0 2,0 2,4 1,0 10

3,6
4,3
1,3 1,4 1,4 1,0 1,1 0,9 0,0 0,6 0,8
10
20
30
40 50 60 Temperature (C)
70
80
90
100
37

Total Organic Carbon (TOC)

TOC is a new test method method. Advantages: semi-quantitative, on-line, and process controller. g y Disadvantages: cost and difficulty to calibrate/maintain. On-line capable of sub-ppb detection limits, fewer problems from contamination t i ti N single t h l No i l technology f TOC measurement for t Lab instrumentation Membrane-based conductometric Conductometric Capable of on-line QC, QA
38

<643> TOC
CxHyOz CO2 + H2O H2CO3 H+ + HCO3UV
Hg lamp emits 185 nm and 254 nm UV light g p g Light, chemicals, surfaces, and time move the reaction for ard forward Accurate conversion of temperature and conductivity p y is required
39
THANK YOU FOR YOUR KIND ATTENTION

Any Question p yQ please address to: paolo.curto@docvalidation.it
40

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www.docvalidation.

FUE INTERNATIONAL CONFERENCE ON PHARMACEUTICAL TECHNOLOGIES Future University

WORKSHOP: WORKSHOP: Advances in Sterile Products Technologies

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

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

WATER QUALITY CATEGORIES

PHARMACEUTICAL WATER CAN BE DIVIDED INTO TWO MAIN CATEGORIES:

WATER QUALITY DECISION TREE

Water Used for . . .

Research & Pilot

Sterile Bulk PCI or BPC

Parenteral Dosage Form

NonParenteral Dosage Form

Bulk API or BPC

Non cGMP Non-cGMP

WATER QUALITY DECISION TREE for Monographed Manufacturing Waters

If compatible without further purification

(See next slide)

WATER FOR SPECIAL PHARMACEUTICAL PURPOSES

WATER FOR HEMODIALYSIS

PURIFIED WATER WATER FOR HEMODIALYSIS (bulk (b lk packaged) k d)

WATER FOR INJECTION

CLEANING AND INGREDIENT WATER FOR PARENTERAL DOSAGE FORMS

STERILE PURIFIED WATER

PURIFIED WATER (bulk packaged)

STERILE WATER FOR INHALATION

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

- PDA Technical Monograph Reports

REGULATORY REFERENCES & STANDARDS

REGULATORY REFERENCES & STANDARDS

GAMP 5 G d Automated Manufacturing Practice Good A t t dM f t i P ti

GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS

QUALITY OF WATER FOR PHARMACEUTICAL USE

4.1 POTABLE WATER

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

WFI REGULATORY REQUIREMENTS

SOURCE: EP 6.3 Official Monographs / Water for Injection

WFI REGULATORY REQUIREMENTS

WFI REGULATORY REQUIREMENTS

QUALITY OF WATER FOR PHARMACEUTICAL USE

4.3 PURIFIED WATER

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

QUALITY OF WATER FOR PHARMACEUTICAL USE

4.4 HIGHLY PURIFIED WATER

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

WFI REGULATORY REQUIREMENTS

WATER FOR INJECTION-Official Monograph INJECTION-

SOURCE: USP 32 Official Monographs / Water for Injection

WFI REGULATORY REQUIREMENTS

London, 5 March 2008 Doc. Ref. EMEA/CHMP/CVMP/QWP/28271/2008

WFI REGULATORY REQUIREMENTS

EMEA Reflection Paper of WFI

WFI REGULATORY REQUIREMENTS

PURIFIED WATER Purified Water is water obtained by a suitable process process.

SOURCE: USP 32 Page 1950 OfficialMonographs / Water

EUROPEAN UNION GOOD MANUFACTURING PRACTICES

European Union Good Manufacturing Practices

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

EUROPEAN UNION GOOD MANUFACTURING PRACTICES

European Union Good Manufacturing Practices

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

EUROPEAN UNION GOOD MANUFACTURING PRACTICES

European Union Good Manufacturing Practices