2 things before we start -...

Interactive Talk on Water PurificationIntroductory to Intermediate LevelWhat’s wrong with using Tap Water anyway??

Brian Hagopian, CPIPChemist and President

Clear Water Consulting, [email protected]

(978) 888-3082

ispeboston.orgConnecting Pharmaceutical Knowledge 2

2 THINGS BEFORE WE START


THE SECOND THING


Where do we start?

ispeboston.orgConnecting Pharmaceutical Knowledge

1.What is the incoming water quality? 2.What is the water quality that we need? 3.What treatment processes are available and what

does each process do? 4.How do I get the water from the point where it is

produced to the points where it is used (without picking up contamination along the way) ?

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Water PurificationAnswer 4 Simple Questions


Question #1: What is our starting water quality?


What public information is available from the local municipality?






What we really need to know

Silt Density Index Organics Content (as TOC, MG/L)


• Particles or Suspended Solids• Dissolved Solids

• Ionized • Non-ionized

• Colloidal Materials• Dissolved Gases• Bacteria and other living organisms

Classify the various contaminants

All Contaminants have the potential to introduce variability !!

Let’s understand what’s in the water to start with


Materials that do not dissolve in water

Can be any shape

Mostly considered as hard, spherical particles

Moving water holds more particles

Larger and more dense particles will settle out by themselves

Smaller particles may never settle

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Particles or Suspended Solids


Materials that dissolve in water

Form free floating ions in solution

• Adds positive and negative charges to a solution

• Solution remains electrically neutral

The ionized solids content changes how much electricity the water can conduct

Direct relationship between the abundance of ions and the conductivity of the water

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Dissolved solids, Ionized


Materials that dissolve in water

Do not form free floating ions in solution

• No charge is added to the solution

No change in the conductivity of the solution

Cannot measure abundance by measuring conductivity

Presence is more difficult to detect

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Dissolved solids, Non-Ionized


Contain carbon

Large in molecular size (10,000-5,000,000 MW)

Slightly negative charge

Somewhere between suspended and dissolved

• Too small to settle by themselves

• Held in solution by size and charge repulsion

Undetectable change in the conductivity

Measure abundance by silt density index

Can quickly clog purification processes

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Colloidal Materials or Suspensions


Nitrogen, oxygen, carbon dioxide, ammonia

Not removed by most purification processes

More dissolved gases in solution at lower temperatures (opposite of dissolved solids)

Least understood and least studied contaminant

Carbon dioxide is troublesome because it adds conductivity when it dissolves into solution

Ammonia can be troublesome to some purification processes in waters treated with chloramine

Measured in clean steam as non condensible gases

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Dissolved Gases

O O

COO

N

H HH


Not uniformly distributed in a water system

Exist in equilibrium with their environment

More food = more bacteria

Less than 1% is free floating (detectable)

Bacteria competes for nutrients with cells we’re growing

Bacteria can replicate every 30 minutes

Mammalian cells replicate every 24 hours

That’s a ratio of 2800 trillion to 1

Vast majority is found in biofilm which we can’t detect

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Bacteria and other living organisms


Attach Colonize Biofilm Development and Growth Send out scouts

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Not uniformly distributed like other contaminants

Regular sterilizations or nutrient deprivation for best control

Understanding How Bacteria Work

Boston Globe, June 29, 2016


Well Water

Low Suspended Solids

High Dissolved Salts

Low Colloidal Content

Some Dissolved Gases

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Surface Water

High Suspended Solids Low Dissolved Salts High Colloidal Content High Dissolved Gases

Where does our water come from?How do it properties vary?


Question #2 What is the end use of the water ??


Where are we in the product’s life cycle ?

What water quality do we really need ?

Drug Discovery

Full Scale Manufacturing

Research

Clinical TrialsPilot Scale

It depends !


CLSI/NCCLSCCCCCCCCLLLLLSSSSSSIII/////NNNNNNNCCCCCCCCCCCCCCCLLLLLLSSSSSSSSS

Labs use CLSI/NCCLS or ASTM specifications for purity


Dialysis has their own requirements


Microelectronics requirements are unbelievable ! Page 1 of 3


Page 2 of 3


Page 3 of 3


Pharmaceutical Water Quality

Hey, Why Is Injectable Grade Water Allowed To Have Bacteria ??


Question #3 What water purification processes are available?

What does each one actually DO?


Particle filters remove contaminants based on their sizeSuspended Solids Removal

Nominally rated filters 80-95% removal efficiency Sizes down to ~ 1 micron

Most are absolute rated filters 95-99.9999% removal efficiency Sterile filtration 0.1 to 0.8 micron size

Ultrafiltration ~99% removal efficiency 5,000-500,000 MWCO

Reverse Osmosis 90-99%% removal efficiency 200-500 MWCO


Ion exchange removes contaminants based on their electric charge in solution


Carbon filters remove small (below 1,000 MW) non polar molecules

Remove disinfectants from drinking water

Protects chlorine sensitive reverse osmosis membranes


Ultraviolet units come in two basic flavors

Single wavelength units (254 nm) for bacterial control

Dual wavelength units (185 & 254 nm) for organics (TOC) and bacteria control

Dual wavelength units (185 & 254 nm) increase the conductivity of the water, so location is extremely important


Commonly Misused Words

Sanitize

Disinfect

Sterilize

These words are used almost interchangeably by equipment manufacturers

But these words mean very different things

103 reduction

105 reduction

106 reduction


Oxidizes organics

Kills bacteria

Consumes biofilm

Ozone is NOT considered an added substance

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Ozone Generators are becoming more popular

Mis-application and misuse of ozone technology has led to compatibility and other under and over dosing problems, making many users reluctant


Distillation is the only water treatment process that removes the water from the contaminants

Considered the gold standard for producing Water-For-Injection (WFI) grade water

Dissolved gases and some chemicals can carry over into distillate (product water)


Summary of Unit Operations


1) Remove Particles first Suspended Solids

Colloidal materials

2) Remove dissolved ions next

3) Remove trace materials Ions, organics, particles

System generated impurities

4) Remove bacteria throughout but definitely as one of the last steps

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Sequencing of Unit Processes Varies between equipment manufacturers


Sand Filter

Carbon Filter

5 micron Filter

Reverse Osmosis

Storage Tank

Pump Dual wavelength UV

Deionization (2) UV Final Filter

To Use Points Recirculating Piping System

SandFilter

CarbonFilter

5 micronFilter

Reverse Osmosis

MAKEUP

StorageTank

STORAGE

Pump Dual wavelength UV

Deionization (2) UV FinalFilter

DISTRIBUTION

DISTRIBUTION

Sequencing of Unit Processes Varies between equipment manufacturers


1) Design to 5 feet per second (FPS) velocity

2) Design to 3 FPS in return with use points active

3) No dead legs (2D to 6D rule)

4) WFI water almost always piped in stainless steel

5) Purified water can be piped in SS, PP, PVDF

6) Distribution piping slopes for drainability

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Design of Distribution Piping Systems


1) We can test it as it is being purified

2) We can test it in the storage tank

3) We can test it as it leaves the mechanical room

4) We can test it at the first and last use points

5) We can test it at every use point

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How do we know if the water quality is OK?


1) In the past, requirements for pure water testing involved qualitative wet chemistry testing for:

•Chlorides

•Sulfates

•Nitrates

•pH

•Calcium

•Carbon dioxide

•Bacteria

•Ammonia

•Heavy Metals

•Oxidizable Substances

•Total Solids

2) These tests were mostly qualitative (look for color change or cloudiness)

3) Some test methods dated back as far as 1890

4) Every test could be done at the pharmaceutical company by Quality Control in the lab

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Let’s take a historical perspective


1) So an expert committee was assembled to simplify the requirements for Pharmaceutical Grade Water

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USP realized that many of these tests were antiquated

Chlorides

Oxidizable Substances

Bacteria

SulfatesNitratespHCalciumCarbon Dioxide

Heavy MetalsAmmonia

Conductivity

T.O.C.

Endotoxin

Bacteria

1) Now there are

2) only 4 attributes


1) Let’s see what everyone thinks!

3) Do you agree with the following statements?

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How do we confirm the water quality?


• It’s a good practice to install sample valves after almost every step in a water purification system.

• If a sample valve has been installed in a particular location, the expectation is that the point will be sampled as part of the water system validation.

• All attributes being tested need to be collected in sample containers and taken to the Quality Control lab (or an outsourced testing company) for testing.

• Some contaminants are uniformly distributed and the number of sampling points can be reduced because samples taken at different points will all yield the same result. This can save $$.

• Validation involves three distinct phases: • Initial - 2-4 weeks in duration, sample all points every day • Intermediary - 2-4 weeks in duration, slightly reduced frequency or number of points sampled. At risk manufacturing can occur. • Extended - the balance of 52 weeks at reduced frequency

• After validation has been completed, sampling should continue at the same frequency used during extended sampling

• Sampling frequency and/or the number of points sampled may be reduced if test results indicate consistently compliant performance

• It’s acceptable to sample at some locations for “Informational Purposes Only”.

• Sampling locations should be determined during the design phase of a project

• The purpose of a sample point should be established during design. Purposes include: • Process Control • Quality Control • Diagnostic/Troubleshooting

• It is acceptable to set different alert and action limits at the same sampling point for “Process Control” and “Quality Control” purposes

• Instruments are to be used for process control purposes only and may not be used to release product

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Do you Agree or Disagree??



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Let’s look into each of these statements in a little more detail

• It’s a good practice to install sample valves after almost every step in a water purification system

• If a sample valve has been installed in a particular location, the expectation is that the point will be sampled as part of the water system validation






• It is acceptable to sample at some locations for “Informational Purposes Only”.






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Brian Hagopian, CPIP

Clear Water Consulting, Inc.

Chelmsford, MA

[email protected]

(978) 888-3082

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THANK YOU

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