seoul, south korea october 2018 pharmacopeia changes and

Pharmacopeia Changes and Global Industry Trends

Seoul, South Korea

October 2018

Anthony Bevilacqua, Ph.D.

for the Production of Purified Water and

Water for Injection

Disclaimer

I am speaking here today, representing Mettler-Toledo Thornton

All of the presentation points are prepared based on 1) publicly available information, 2)

non-confidential discussions, or 3) my opinions or representation of available information

I am NOT representing the U.S. Pharmacopeia or its policies or opinions

Any specific "USP water-related questions" are encouraged to go to www.usp.org and look

at the FAQs

Or contact USP staff liaison Antonio Hernandez-Cardoso at [email protected]

2

For internal use - Confidential

http://www.usp.org/

mailto:[email protected]

Company Background

Founded by Dr. Thornton 1964

Resistivity/Conductivity, TOC, Silica, Sodium, Microbial Detection, DO, Ozone (O3), pH,

ORP, and Temperature for all fluids, specializing in the detection of contamination in Ultra

Pure Water (UPW)

- Pharmaceutical and Biotech

- Power

- Microelectronics

- Food and Beverage

Extensive research

- Conductivity of ultrapure water

- Temperature compensation

- High temperature UPW

- CO2 and TOC

- Rapid microbial detection methods

- Calibration methods

Active in ASTM, ISPE, PDA, SEMI, EPRI

Acquired by Mettler Toledo 2001

3


Anthony Bevilacqua

Analytical and Physical Chemist, Head of Thornton R&D

Research Papers

- What is the precise conductivity of PURE water as a function of temperature?

- What is affect of specific impurities such as CO2/HCl to the conductivity of pure water?

- Accurate temperature compensation

- What is the impact of measurement error and impurity type on temp compensation?

- Accurate conductivity calibration

Working with USP/PhRMA in 1994

- Develop conductivity methods and limits

- Answer industry questions

Member USP Expert

- Chair USP Pharmaceutical Water Expert Committee 2000-2005, re-elected 2005-2010

- Elected as member of the Chemical Analysis Expert Committee 2010-2015

- Re-elected 2015-2020

- Chair, USP Sterile Water Expert Panel

- Responsible for harmonization for Sterile Waters, instrumentation methods

4


Overview (1/2)

Abstract

Today, more than ever, it is critical for pharmaceutical producers, as well as key suppliers,

to meet quality standards in a global environment. Today, there are different

quality/acceptance criteria and inspection practices for chemicals, APIs, and medicines in

the different markets. This requires pharmaceutical producers to be responsible for testing

their products with different methods and different criteria – increasing the non-value-

added cost to the product.

After the cost of research/development, the single greatest cost of a medicine is the final

testing. Harmonization of tests and acceptance criteria is critical to reducing QC testing

costs. Since Purified Water and WFI are used as an ingredient, solvent, reagent or

cleaning material in EVERY manufacturing plant, it makes sense for industry,

pharmacopeia, and regulators to embrace harmonization of pharmaceutical water tests.

We have been leading to way to create fewer, but smarter tests to assure the quality and

safety of the water in a global environment. The status of key manufacturing and chemical

requirements for pharmaceutical waters globally will be discussed.

5


Overview (2/2)

Topics to be discussed

New global requirements for making WFI

Harmonized chemical impurity tests (Conductivity and TOC)

A new Rapid Microbial Detection technology

The importance of on-line vs off-line impurity detection techniques.

6


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Agenda 7


1 Water, Pharmaceutical Water, and USP

2 Value of Measurements

3 Modern History of Pharmaceutical Water and Harmonization

4 Water Treatment

5 Source Water, Production, and Microbiology

6 Conductivity Measurements and USP 645

7 Total Organic Carbon Measurements and USP 643

8 Ozone, CIP Monitoring, Other Pharmaceutical Waters

9 EP/JP/ChP

7 Special Properties of Pharmaceutical Waters

Water is Unique!

Water is multifunctional

The water monographs are common to all Pharmacopoeia

Water has no test for identity or strength or purity

We tell you how to make these waters

The water is so pure, it gets dirtier when exposed to humans, environment, containers

These waters have the ONLY test perform on-line – and encouraged to be on-line

There are sterile and non-sterile forms of water

8


Why is Water Important?

Water is multi-functional. It is the most widely used excipient in

Pharmaceutical Manufacturing.

Raw material

Solvent

Ingredient

Reagent

Cleaning agent (hot water or steam)

Sterile waters

- Sterile Water for Injection

- Sterile Water for Irrigation and Sterile Water for Inhalation (USP only)

- Sterile Purified Water

- Bacteriostatic Water for Injection

Packaged waters

- Purified Water for small volume use

9



Water is Unique!



What is the test for the identity of Water?





10


Identity, Strength, Purity

Water is the only material in the pharmacopoeia where there is no identity

test!

How do you "identify" water?

- Molecular weight 18.02

- Chemical structure

Strength

- ?

How do you characterize its purity?

- Microbiological

- Organic (non-living)

- Inorganic

- Particulate

- Dissolved Gases

11


O

H H

Characteristics of Impurities in Water

Types of Impurities Characteristics Types of Tests

Chemical

Organic (non-living) non-ionic, carbonaceous Total Organic Carbon

Inorganic ionic Conductivity

Microbial

Bacteria living, mostly organic microbial detection

Bacterial debris dead, mostly organic bacterial endotoxin

Other

Particulates insoluble, non-ionic filter/particle counter

Dissolved Gases ionic (depends), inert? usually benign – not always

12


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Agenda 13





4 Water Treatment





9 EP/JP/ChP

On/Off-Line - General Comments

In-Line

- inside pipe, real-time

- conductivity, pressure, flow

At-Line (Side stream)

- attached to pipe, real-time, flow to drain

- pH, TOC, O2, O3

Off-Line

- batch sample

- "Lab" measurements

- minutes, hours, days

- Microbiological, pH

- TOC, chromatography,

Sampling Type and Speed

- Continuous, batch

- Response time

14


On-Line

What about Pharmaceutical Water?

Regardless of the precise quality of high purity water, it all looks the same

after exposure to air/CO2.

Lab Measurements

- Accurate knowledge of the quality (ppb, S/cm) is obscured

- Interferences

- Atmospheric impurities

- Sampling methods and materials

- Nothing wrong with "lab measurement" technology, it is the sample that is harmed

- 0.055 S/cm (18.2 M-cm) water becomes ~1 S/cm water



Water generation/usage is a continuous process

- Response/Delay time for reporting may be critical

- Real time measurements may be critical

15


How do you know if…

Measurements assure the quality of the PRODUCT and the PROCESS!

… you are removing/controlling ions, TOC, microbes, particulates, etc…?

… each purification step is functioning properly?

… the quality of the product is “suitable for its intended use”?

… the water chemistry has changed (and the water system is not flexible enough)?

measure, measure, measure

16


UPW Make-up & Distribution System

17


Pretreatment

Heat

Exchanger RO

prefilter

2-Pass RO

MB

or

CEDI Degasifier

MB Polisher

0.5 UPW

Storage

Pump Final Filter

0.1

UV Sterilizer

0.2

0.1 POU

filters

More

POU

Feed

water

Cl2 Inj. Acid

Injection

Caustic

Injection

Measurements

Cond/Resistivity

pH

ORP

DO

TOC

Pressure

Flow

Total pts: ~25-40

MB Polisher

Process Analytical Measurements for UPW

Chemical Measurements

Conductivity/Resistivity

- compensated and uncompensated

TOC

Dissolved Gases

- Oxygen

- Ozone

Specific ions

- pH

- Sodium

- Magnesium, Calcium

Specific other

- Bisulfite or free chlorine

- ORP

- Silica

18


Physical Measurements

Temperature

P across filter

Flow rate (for % recovery)

Flow rate and return pressure (through

the distribution system)

Biological Measurements

Number of colonies/mL

Type of bacteria

Endotoxins

What are Critical Measurements?

Measurements of a process or a product that impacts…

Quantity of product

- average, daily, peak

Cost of product

- efficiency

- cost of production

- cost of maintenance

Quality of product

- safety

- purity

- out-of-spec investigations

Consistency of the product

19


Engineering focus Uses in-process measurement tools and

controls while the product is being

manufactured.

Product focus - QA Uses measurement tools after the product is

manufactured.

What are Critical Measurements?

Measurements that are regulated…

for Purified Water and WFI…

Conductivity

Total Organic Carbon

Microbes

Endotoxins (WFI only)

Measurements to verify "No added substances", i.e., ozone

20


Product and Process Control These real time, in-process measurements

permit control of product AND Process while

the product is being manufactured and used.

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Agenda 21





4 Water Treatment





9 EP/JP/ChP

Aqua Distillata (Distilled Water)

Printed in USP I (1820) by the Pharmacopoeia of the United States of

America

Aqua distilleteur vasis permundis, donec ejus duo circiter trientes stillaverint. Aquam

distillatum in lagena vitrea servato.

Let water be distilled in very clean vessels until about two thirds have come over, which is

to be kept in a glass bottle.

22


History of Water Monographs/Chapters

1860s+

- Chemical tests for Ca2+, SO42-, CO2, NH3, Cl-, pH, and oxidizable substances

Prior to 2000

- Water and Parenterals Committee of Revision

1989 – PhRMA stakeholders advocate for improved water quality testing – not improved

water

- Establishes Water Quality Committee (WQC)

1991 – PhRMA/WQC proposes Conductivity and TOC to replace most existing chemistry

tests for BULK Purified Water and WFI

- Proposes deletion of 6 chemical tests

- Proposes on-line (and off-line) instrumentation-based testing and limit-based methods

23


What was the Purpose of these Chemical Tests?

These tests indicate a sense of control by the water purification system

There is nothing harmful about Ca2+, SO4

2-, CO2, NH3, Cl-, and oxidizable substances at

sub-ppm concentrations

- These ions sustain life, with no adverse effects

But at least 2 of these ions are present in ppm concentrations of source drinking waters

- And typically 3 or 4 of these ions are present in source drinking waters

Successful removal of these ions - based on meeting certain chemical limits – is the

indirect assurance that the water purification system is under control

24


Evolution of 643 Total Organic Carbon

500 ppb limit determined

- Survey of industry reveals a typical maximum of 150 ppb TOC, USP establishes limit at

~3x

Determine instrumentation acceptance criteria

- Based on supplier survey - 50 ppb LOD

- Develop System Suitability Test based on oxidation and detection for dissimilar organics

Sucrose and p-benzoquinone selected

- Sucrose C-C single bonds

- p-benzoquinone C=C and C=O double bonds

25


1996-1998

USP 23 Supplement 5, May 1996

- Deleted 5 chemistry tests

- Requires 645 Water Conductivity testing for Purified Water and WFI

- 643 TOC is specified as an alternative to oxidizable substances test for Purified Water

and WFI

USP 23 Supplement 8, November 1998

- 643 TOC is a required test for Purified Water and WFI, deletes Ox Sub Test

26


Relevant Sections of the USP

There are equivalent sections in the other pharmacopoeia.

Pharmaceutical Water Monographs (9)

- Purified Water (bulk and packaged) Sterile Water for Inhalation

- Water for Injection (bulk and packaged) Sterile Water for Irrigation

- Sterile Purified Water Bacteriostatic WFI

- Sterile WFI Water for Hemodialysis

- Pure Steam

Test Chapters (2)

- 645 Water Conductivity 85 Endotoxins

- 643 Total Organic Carbon 71 Sterility

- 644 Conductivity – in process with EP/JP 791 pH

General Information

- 1230 Water for Health Applications - related to Water for Hemodialysis

- 1231 Water for Pharmaceutical Purposes

- 1644 Theory and Practice of Electrical Conductivity Measurements of Solutions

27



Water is Unique!








28


Water Types in Pharmacopoeia

29


Water Type USP EP JP

1 Water for Injection (bulk) + + +

2 Water for Injection/sterilized (containers) + + +

3 Highly Purified Water (bulk) +

4 Purified Water (bulk) + + +

5 Purified Water (containers) + +

6 Sterile Purified Water (bulk) +

7 Sterile Purified Water (containers) +

8 Bacteriostatic Water for Injection (containers) +

9 Sterile Water for Inhalation (containers) +

10 Sterile Water for Irrigation (containers) +

11 Water for Hemodialysis (bulk + containers) + +

12 Water (tap, well) +

13 Pure Steam +

Bulk Water for Injection(s) - Today

30


Attribute1 USP EP JP ChP5 IP

Source Water US/EU/JP/WHO drinking water

Human

consumption Drinking water Purified Water Purified Water

Description Clear and

colorless liquid

Clear, colorless,

odorless liquid

Clear, colorless,

odorless,

tasteless

Clear, colorless,

odorless liquid

Production Method Distillation or

suitable process

Distillation or RO

w/other means

Distillation or

RO/UF from

Water or PW

Distillation Distillation

Total Aerobic (cfu/100 mL)2 10 10 10 10 10

Conductivity (S/cm at 25°C) 1.3 (3 stage)3 Same as USP 2.1 offline6 Same as USP Same as USP

TOC (mg/L) 0.54 0.5 0.5 0.5 0.5

Bacterial Endotoxins (EU/mL) 0.25 0.25 0.25 0.25 0.25

Nitrates (ppm) 0.2 Not detectable 0.06 0.2

Heavy Metals (ppm) 0.1 Not detectable 0.1 Required by PW

Acidity/Alkalinity Indicators - Indicators

pH 5.0-7.0 5.0-7.0

Calcium/Magnesium Indicators

Chloride Not detectable Required Not detectable

Sulfate Not detectable Required Not detectable

Nitrite (ppm) Not detectable 0.02 Required

Ammonium (ppm) 0.5 0.2 0.2

Oxidizable Sub (/100 mL) Not detectable Optional5 Required

Residue on Evaporation (mg/mL) 1.0/100 1/100 Required Note 1. All tests are maximum, unless otherwise stated.

Note 2. Microbiological testing is considered to be harmonized, with the exception noted that the EP test is written into the Production section, and the USP test is contained in a non-compendial general information chapter 1231.

Note 3. Limits are temperature dependent. See 645 Water Conductivity

Note 4. Actual limit is Rs-Rw. See 643 Total Organic Carbon.

Note 5. WFI stored at >80°C and circulated at >70°C.

Note 6. Same as USP Water Conductivity chapter 645 Stage 2, or meets USP 645 any stage.

Effective 2009

Effective

JP 16 Effective

CP 2010 Effective

IP 2012

Same as USP

Bulk Purified Water - Today

31


Attribute1 USP EP JP ChP IP

Source Water US/EU/JP/WHO drinking water

Human

consumption Drinking water Potable Water Potable Water

Description Clear and

colorless liquid

Clear, colorless,

odorless liquid

Clear, colorless,

odorless,

tasteless

Clear, colorless,

odorless liquid

Production Method Suitable process Suitable process

Distillation, RO,

ion-exchange, UF,

or combination

Distillation, RO,

ion-exchange, or

suitable process

Distillation, RO,

ion-exchange, or

suitable process

Total Aerobic (cfu/mL)2 100 100 100 100 100

Conductivity (S/cm at 25°C) 1.3 (3 stage)3 5.1 (1 stage) 2.1 offline6 Same as EP Same as USP

TOC (mg/L) 0.54 Same as USP Same as USP Same as USP Same as USP

Bacterial Endotoxins (EU/mL)

Nitrates (ppm) 0.2 (delete in 2018) Not detectable 0.06 0.2

Heavy Metals (ppm) 0.15 Not detectable 0.1 0.1

Acidity/Alkalinity Indicators Indicators Indicators

pH 5.0-7.0 5.0-7.0

Calcium/Magnesium Indicators Indicators

Chloride Not detectable Not detectable Not detectable

Sulfate Not detectable Not detectable Not detectable

Nitrite (ppm) Not detectable 0.02 Not detectable

Ammonium (ppm) 0.5 0.3 0.2

Oxidizable Sub (/100 mL) Option to TOC Not detectable Option to TOC Option to TOC

Residue on Evaporation (mg/mL) 1.0/100 1/100 1.0/100 Note 1. All tests are maximum, unless otherwise stated.

Note 2. Microbiological testing is considered to be harmonized, with the exception noted that the EP test is written into the Production section, and the USP test is contained in a non-compendial general information chapter 1231.

Note 3. Limits are temperature dependent. See 645 Water Conductivity.

Note 4. Actual limit is Rs-Rw. See 643 Total Organic Carbon.

Note 5. Not required effective Jan 1, 2009 if WFI conductivity requirements are met.

Note 6. Same as USP Water Conductivity chapter 645 Stage 2, or meets USP 645 any stage.

Effective

JP 16

Effective

CP 2010 IP 2012

Same as USP

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Agenda 32





4 Water Treatment





9 EP/JP/ChP

Purified Water - USP39-NF34 official 2016-05-01

33


Water for Injection - USP39-NF34 official 2016-05-01

34


USP Water for Injection – Source Water

35


JP Water for Injection – Source Water

36


EP Water for Injection – Source Water

37


US EPA NPDWR

Removal of these microorganisms assures that Pharmaceutical Waters do

not need to be tested for these objectionable species.

Microorganisms

Disinfectants

Disinfection Byproducts

Inorganic Chemicals

Organic Chemicals

Radionuclides

Complete list at can be found

http://water.epa.gov/drink/contaminants/inde

x.cfm

38


http://water.epa.gov/drink/contaminants/index.cfm

http://water.epa.gov/drink/contaminants/index.cfm

So-Called "No Added Substances Rule"

Nothing wrong with added substances as long as you remove them

Nothing wrong with added substances if you remove them

Examples - sodium bisulfite, softener, and ozone are commonly “added” to protect the

water system and produce high quality water – from 1231 ---

39


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Agenda 40





4 Water Treatment





9 EP/JP/ChP


Water is Unique!








41


WFI Method of Production – USP

42


WFI Method of Production – EP

43


"Method of Manufacture" Requirements

You must Distill to make WFI for a Global product

Purified Water

- USP, EP, JP permits production by distillation, reverse osmosis, de-ionization, filtration,

or equivalent means.

Water for Injection

- USP permits “distillation or a purification process that is equivalent or superior to

distillation in the removal of chemicals or microorganisms”USP27

- EP permits distillation only

- JP permits distillation or RO/UF

- CP permits distillation only – use PW only

Highly Purified Water

- EP only, produced by RO, meets WFI

- Allowed for limited pharmaceutical applications

44


45


Endotoxin Specifications

46


The endotoxin levels from this water system meet...

Looser entodoxin

specifications than

WFI, 0.00%

Tighter endotoxin

specifications than

WFI, 15.87%

WFI specifications

most of the time with

occasionally higher

levels, 19.05%

WFI specifications all

the time, 53.97%

No endotoxin control

expectations, 11.11%

63 respondents

EP WFI Monograph – Official April 2017

47


EP WFI Monograph – Official April 2017

48


Highly Purified Water to be removed from EP

https://www.edqm.eu/en/node/16302

49


https://www.edqm.eu/en/node/16302

"Method of Manufacture" Requirements

You must Distill to make WFI for a Global product

Water for Injection

- USP permits “distillation or a purification process that is equivalent or superior to

distillation in the removal of chemicals or microorganisms”USP27

- EP permits distillation or RO+

- JP permits distillation or RO/UF

- CP permits distillation only – use PW only as supply

Highly Purified Water – to be deleted in 2019

50


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Agenda 51





4 Water Treatment





9 EP/JP/ChP

USP 645 3-Stage Test Method

52


1. Measure in-line, non-temperature-compensated conductivity and temperature. Look

up conductivity limit for that temperature. If measured uncompensated conductivity is

less than conductivity limit, then Pass - Done.

645 Stage 1 Requirements

(for non-Temperature Compensated Conductivity Measurements)

53


Maximum Maximum

Temperature Conductivity Temperature Conductivity

(°C) (S/cm) (°C) (S/cm)

0 0.6

5 0.8 55 2.1

10 0.9 60 2.2

15 1.0 65 2.4

20 1.1 70 2.5

25 1.3 75 2.7

30 1.4 80 2.7

35 1.5 85 2.7

40 1.7 90 2.7

45 1.8 95 2.9

50 1.9 100 3.1

Example: Temperature is 83.7°C and uncompensated conductivity is 1.7 S/cm. The limit is

2.7 S/cm at 80°C. PASS!

USP 645 Water Conductivity Stage 1 Limits

Stage 1 - on line, non-temperature-compensated for USP Purified Water, WFI,

Pure Steam, and Water for Hemodialysis.

54


0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.1

1.8

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

0 10 20 30 40 50 60 70 80 90 100

Temperature (°C)

Un

co

mp

en

sa

ted

Co

nd

uc

tiv

ity

(

S/c

m)

Cl Model

NH3 Model

USP <645> Stage 1 Limit

USP 645 3-Stage Test Method

55


1. Measure in-line, non-temperature-compensated conductivity and temperature. Look

up conductivity limit for that temperature. If measured uncompensated conductivity is

less than conductivity limit, then Pass - Done. If not:

2. Lab Test : Equilibrate water sample with atmospheric CO2 : If

conductivity is less than 2.1 µS/cm at 25°C, Pass – Done.

EP Conductivity Limits - effective July 1, 2004

Separate Conductivity Limits for EP Purified Water, Highly Purified Water,

and WFI – WFI conductivity limits are harmonized.

56


2.4

3.6

4.3

5.15.4

6.5

8.1

9.19.7 9.7 9.7

0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.41.7 1.8 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.1

7.1

10.2

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

11.0

0 10 20 30 40 50 60 70 80 90 100

Temperature (°C)

Un

co

mp

en

sate

d C

on

du

cti

vit

y (

S/c

m)

EP Purified Water Limits

EP WFI & HPW Limits

JP Water Conductivity

Same Limits for JP Purified Water and WFI

57


Advantages of On-line, In-line Stage 1 Testingv

Real-time process (conductivity and temperature!) information.

Immediate alarms and control options.

Data can be logged . . . providing a water history.

Easier and cost-effective.

Eliminates sample collection and transportation errors.

Temperature-compensated conductivity remains an excellent technique to observe water

quality changes.

Maintains the Quality Assurance by improving the integrity of the testing.

58


0.0

0.2

0.4

0.6

0.8

1.0

1.2

0 5 10 15 20 25 30 35 40 45 50

Co

nd

ucti

vit

y (

S/c

m)

off-line 2off-line 1on-line 2on-line 1


Water is Unique!






These waters have the ONLY test performed on-line – and encouraged to be on-line

- Typically >99.9999%


59


645 Bulk (non-sterile) Water, Stage 1

This encourages on-line testing to support real-time measurement,

decisions, and control (PAT).

60


WHO Encouraging On-Line Testing

61


The WHO Expert Committee

on Specifications for

Pharmaceutical Preparations

•WPU – Water for

Pharmaceutical Use

•WHO Recommendation for the

Water System is online testing

for; • Conductivity

• TOC

• Flow

• Pressure

• Temperature

•For the Points-of-Use samples

should be taken for offline testing

Harmonization: Conductivity Methods and Limits

62


Parameter USP EP JP CP Conductivity test required yes yes yes 2010

Eliminate chemistry tests yes no1 yes no3

Purified Water 3-stage test yes no yes

Purified Water test limits2 1.3 S/cm 5.1 S/cm 1.3 S/cm ?

WFI 3-stage test yes yes yes yes

WFI limits2 1.3 S/cm 1.3 S/cm 1.3 S/cm 1.3 S/cm

Instrument requirements yes yes yes

Sensor accuracy ±2% ±2% yes

Sensor calibration method not specific not specific yes

Calibration solutions user selected user selected yes

Calibration Method works works yes

Compensation none none yes

Method tested yes yes yes yes

1 Heavy metals and nitrates tested required for EP; aluminum test required for dialysis solutions

2 at 25°C

3 retained ammonia and heavy metals tests

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Agenda 63





4 Water Treatment





9 EP/JP/ChP

Where does TOC come from?

Leachates and humic acids and other outside sources

- Large molecules

- Complex mixtures

- Some man-made waste… pesticides?

Degradation of the water system

- RO membranes

- Filters

- Ion-exchange resins

Formation within water system

- Biofilm?

64


particulates

most probable

643 Total Organic Carbon (TOC)

Prior to November 1996, the existing test for “oxidizable organics” was the Oxidizable

Substances test. The test is based on the appearance or disappearance of a pink color.

Same goals as Conductivity – Replace existing tests with a better test.

In November 1996, 643 TOC was established as an option to the Total Oxidizable

Substances test.

In May, 1998, the Total Oxidizable Substances was deleted (for bulk water testing).

Only 643 TOC is required.

In the EP, the method is 2.2.44. It is required for Water for Injections and Highly Purified

Water. Optional for Purified Water.

65


Oxidizable Substances Chemistry

All organic carbon is potentially oxidizable to CO2

- Other soluble transition metals are potentially oxidizable – but negligible

Reduction of pink Mn7+ (MnO4-) to Mn2+ by the oxidation of organics

Test passes if the solution remains pink – some MnO4- remaining

The “complete” consumption of MnO4- by chemical reduction is visually detected by a clear

solution

66


Mn7+ + 5e- Mn2+ Heat and H2SO4

Reasons for Development of 643

Oxidizable Substances test is …

- qualitative, not quantitative

- no trend ability

- ineffective

- subject to operator bias

- labor intensive

TOC is …

- semi-quantitative (all oxidizable carbon)

- ideal for trending and process control

- capital intensive

- a reliable tool in Semiconductor, Power and Pharmaceutical facilities

67


What is Total Organic Carbon

68


TOC Measurement

The measurement of TOC typically consists of a 2 step process

- Oxidation to CO2

- Detection of some form of CO2

Oxidation is NOT required – but it is easy to manage the oxidation process

- You could chemically reduce organic carbon

- Or convert it to sucrose or diamond

69


TOC Oxidation Methods

Oxidation of organic carbon

- Chemical combustion TOC + heat → CO2 + H2O

- Chemical oxidation TOC + [O] → CO2 + H2O

- UV light TOC + hv → CO2 + H2O

- Electrochemically TOC – e- → CO2 + H2O

- High voltage TOC + → CO2 + H2O

- Combination

70


TOC Detection Methods

Highly dependent on oxidation method, matrix, and potential interferences

Oxidation and detection methods work together

Common methods

- NDIR : detects CO2 by infrared absorption

- Conductivity : detects H+ and HCO3-

No TOC sensor/analyzer/system measures TOC today

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Oxidation and Detection

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IR-based detection

Conductivity-based detection

CxHyOz + CO2 + H2O H2CO3 H+ + HCO3-

643 TOC - Calibration & Performance

Limit of Detection of 0.050 mg C/L (50 ppb TOC)

Calibrate according to Manufacturer’s recommendations

Must distinguish inorganic carbon, i.e., CO2, HCO3-

Must meet System Suitability testing periodically

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What is System Suitability or SST?

It is required by USP <643> and EP 2.2.44 and ChP, JP, etc…

Question: What is System Suitability Testing?

Answer: The process of challenging a TOC analyzer to convert sucrose and p-

benzoquinone to another detectable species (CO2) equally.

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Raw

Material Stock Solution

(50,000 ppb) Standard Solutions

(500 ppb)

Sucrose and p–Benzoquinone

Sucrose is a simple organic molecule containing only single bonds

- Bonds require less energy to break

p-Benzoquinone is an aromatic organic molecule containing double bonds

- Bonds are harder to break

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643 and 2.2.44. - System Suitability Test

Measure TOC of 0.50 mg C/L (500 ppb C as sucrose), Rs.

Measure TOC of 0.50 mg C/L (500 ppb C as p-benzoquinone), Rss.

Measure TOC of water used to prepare these solutions, Rw. Not to exceed 0.1 mg C/L

(100 ppb).

Response shall be between 85 and 115%!

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ws

ws s

RR

RR100Response

PW, HPW, and WFI TOC Requirements

USP and EP TOC limits officially harmonized effective in EP 6.6.

Procure sample. Measure TOC of test water, Ru.

USP: Water passes TOC test if Ru < Rs - Rw (~500 ppb).

EP: Water passes TOC test if Ru < 500 ppb.

EP: Water passes TOC test if Ru < Rs - Rw (~500 ppb).

- TOC testing required for WFI and Highly Purified Water

- TOC testing optional for EP Aqua Purificata (PW).

JP WFI

- Water passes TOC test if Ru < 500 ppb

- Water passes TOC test if Ru < 400 ppb - off-line (for control)

- Water passes TOC test if Ru < 300 ppb - on-line (for control)

JP Purified Water

- Water passes TOC test if Ru < 500 ppb (recommendation)

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643 Excerpts – Microbial Testing – official Dec 1, 2009

TOC measurement is NOT a replacement for endotoxin or microbial testing.

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How many microbes are in 1 ppb TOC?

PW: 100 cfu/mL is 0.050 ppb WFI: 10 cfu/100 mL is 0.000050 ppb

Assuming the following

- Microbe Density is 1 g/cm3

- 10% of microbe consists of carbon

- Radius of spherical microbe is 0.5 m

Then it follows that

- Microbial volume = (4/3)r3 = (4/3) x 3.14 x (5 x 10-7 m)3 x (100 cm/m)3 = 5.2 x 10-13 cm3

- Carbon volume/microbe = Microbe volume x Microbe density x Carbon content

- Carbon volume/microbe = (5.2 x 10-13 cm3) x (1 g/cm3) x (0.1) = 5.2 x 10-14 g C/microbe

Microbial counts in 1 ppb of TOC carbon

- 1 ppb TOC = 10-9g C/mL

- (10-9g C/mL )(5.2 x 10-14 g C/microbe) 19,000 microbes/mL

Microbial counts in 500 ppb TOC 1,000,000 microbes/mL

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643 – Contamination and Sampling

Strong argument for on-line, real-time testing.

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Agenda 81





4 Water Treatment





9 Elemental Impurities and EP/JP/ChP

EP 2.2.44 Total Organic Carbon

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JP 16 Water Conductivity Control

You can follow USP 645 method to meet conductivity process monitoring

requirements in JP.

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JP 16 Total Organic Carbon Control

You can follow USP 643 method to meet TOC process monitoring

requirements in JP.

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ChP - Conductivity

Introduction

85


ChP - Conductivity

Purified Water Limits

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ChP

WFI - Stage 1

87


Chinese Pharmacopoeia Requirements

Updated in mid 2010 as GMP inspections increase

Conductivity and TOC testing implemented in 2010 officially

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China WFI

monograph

Deleted tests for chloride,

sulfate, calcium, CO2, and

oxidizable substances

Added tests for Aluminum

(for water for hemodialysis

only), conductivity, and TOC

Retained tests for ammonia

and heavy metals

Modified pH test

Status of Harmonization for PW and WFI

Are we harmonized? Close – it has only taken 20 years to get this far!

Preparation

- Source water - harmonized – 100%

- “Method of Production” - harmonized for Purified Water – 100%

- “Method of Production” - harmonized for WFI today – 100% on paper!!!

Microbiology - harmonized on limits/levels – 100%

- Not entirely harmonized on methods

- More USP/EP push towards RMMs

Quantitative tests - harmonized – 90-100%

- 643 TOC – harmonized – 100%

- 645 Conductivity - harmonized for WFI – 100%

- 645 Conductivity - harmonized for Purified Water – EP has higher limits

- Endotoxins (WFI only) – harmonized – 100%

Chemical tests – not completely harmonized for nitrates, heavy metals, pH

- Nitrates test – not changing in EP

- Heavy metals - not required for WFI, sometimes not required for PW

- Elemental impurities – separate discussion

89


Mettler-Toledo Thornton

90


Thank You!

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ありがとう

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Go raibh maith agat

seoul, south korea october 2018 pharmacopeia changes and

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