Sanitization Methods for Pharmaceutical Water Systems

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©2018 Evoqua Water TechnologiesConfidential | Page 1

TRANSFORMING WATER. ENRICHING LIFE.©2018 Evoqua Water Technologies

Sanitization Methods forPharmaceutical Water Systems

Presented by Gary ZoccolantePlymouth Rock Water Consulting


Gary Zoccolante

• Technical Director, Plymouth Rock Water Consultants• Over 45 years of experience in the design, operation and

and trouble-shooting of pharmaceutical water systems• B.S. degree in Mechanical Engineering from Northeastern

University• Pharmaceutical Technical director at Evoqua Water Technologies

for over 35 years• Committee member of the original ISPE Baseline® Water and

Steam Systems Guide• Authored and co-authored many papers on pharmaceutical water

production and system operation and maintenance• Holds several patents for pharmaceutical water processes

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How to Ask a Question

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Sanitization Methods for PharmaceuticalWater Systems

A comparison of heat, ozone or chemicals to sanitize pharmaceuticaland other ultrapure water systems.

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Agenda

• Sanitization Overview– Sanitization versus Sterilization

– Why Do Biopharm Water Systems Need Sanitization?

– Where is Sanitization Required?

– How Can Sanitization Be Performed?

– Sanitization Frequency

– Sanitization Time Out of Service Impact


Agenda (Continued)

• Sanitization Process and Design– Chemical– Heat– Ozone

• Generation System Sanitization• Storage & Distribution Sanitization• Regulatory Impact• Sanitization Safety• Summary

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Sanitization versus Sterilization

• Sanitization– Generically: “Eliminate most harmful microorganisms capable of

reproduction”– Pharmaceutical water context: “Reduce contact surface biofilm

contamination to level sufficient to facilitate consistent production of watermeeting microbial/endotoxin requirements”

• Sterilization– 21 CFR – Sterility of equipment… “The condition achieved by

application of heat, chemical sterilant(s), or other appropriate treatmentthat renders the equipment…free of viable organisms…capable ofreproducing…”


Why Do Biopharm Water Systems NeedSanitization?

• Sanitization of equipment is a Good Manufacturing Practice(GMP) requirement

• Some microorganisms can survive low nutrient environments• System microbial contamination can cause:

– Product failure– Production interruption– Equipment failure/maintenance– Investigations– Additional testing costs

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GMP 21 CFR 211.67a

• “Equipment shall be cleaned, maintained, and sanitizedat appropriate intervals to prevent malfunctions orcontamination that would alter the safety, identity,strength, quality, or purity of the drug product beyond theofficial or other established requirement”


Biofilm Formation

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Mark Wiencek, Rohm & Haas Company, Spring House, PA 19477

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Where is Sanitization Required?Risk of Microbial Contamination

Generation System Low Moderate High

Depth filtration X

Water Softeners X

Activated Carbon X

Break Tank X

Reverse Osmosis X

Electrodeionization X

Sub-micron Filter & Ultrafilter X

Risk of Microbial Contamination

S&D and Loop Purified Water Water for Injection

Chemical Sani Moderate Not Recommended

Heat Sani (Intermittent) Low Risk Low / Moderate*

Heat (Continuous) Low Risk Low Risk

Ozone (Continuous in tank) Low Risk Low / Moderate*


How Can Sanitization Be Performed?

• Hot water• Steam• Ozone• Chemical

• Sanitizing agents can be applied;– Intermittently– Continuously

• Component replacement/offsite sanitization

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Continuous Sanitization

• Only possible with ozone or high temperature• High temperature (65OC – 80OC) generally best with hot

generation and/or use points are hot• Ozone may be best for ambient generation and/or use• No flush required• Most Water for Injection (WFI), heat in most cases• Some Purified Water (PW)

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• Higher frequency improves consistent performance• Automation leads to increased convenience and frequency• Extracellular Polymeric Substance (EPS) issue

– Heat can easily penetrate– Ozone must oxidize and diffuse through– Chemical penetration varies with chemical

• Crevice issue• Not common in WFI applications

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Intermittent Sanitization

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Sanitization Frequency

• Should be established from risk based analysis– Product risk– Micro/endotoxin data– Production impact– History– Regulatory expectation

• Sanitization frequency must be sufficient to maintainsystem microbial control


Sanitization Frequency

• FDA has stated that erroneous micro data may costpharma more $$$ than any other item

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Effective Sanitization Concepts

• Subject organisms to lethal conditions• Often inadequate

– Infrequent– Concentration– Time– Temperature– Must penetrate

• Remove biofilm if possible

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Sanitization Time Out of Service Impact

Hot Water: Typically 3-6 hr.*Steam: Typically 3-6 hr.*

Ozone: 20m – 2 hr.

Chemical: 2-4 hr. contact time, 12hrs+ total time* May be less with some designs & processes.

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Risk Based Sanitization Method Selection

• Product risk• Personnel risk• Production risk

– Water failure• Micro• Endotoxin• Conductivity• TOC

– Time out of service• Equipment risk


Generation System Sanitization Methods

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Generation System Sanitization Options

• Chemical• Hot water• Steam (limited)

• Intermittent sanitization for most unit processes• Continuous hot sanitization for some processes• Ultraviolet light (UV), filters and other continuous

physical means help


Generation System Hot Water Sani

• All processes can be hot water compatible• Can impact media life

– Reverse Osmosis (RO) elements– Ion Exchange (IX) resin– Filter cartridges– More benign than chemicals

• Can have significant $$$ capital impact• Most effective option for low micro, endotoxin

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Hot Water Sanitization

• Sanitization typically 80OC with 60 minute hold• Total cycle typically 3 to 4 hours• Rapid cycle technology* can shorten cycle to 40 minutes

with superior micro control

*proprietary technology


Purified Water Product

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TAC

CFU

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ml 16 detections over an 810 day period,

never higher than 2 CFU/100ml

Short Cycle Micro Performance

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Generation system - Chemical Sanitization

• Generally lowest capital cost– System materials of construction– Sanitization equipment

• Typically highest cost per sanitization with labor• Typically not as effective as heat• Typically not automated, but can be• Peracetic acid/hydrogen peroxide dominant


Storage & Distribution Sanitization Methods

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Storage and Distribution Sanitization Options

• Chemical• Hot Water• Steam• Ozone

• Chemical sanitization intermittent• Steam sanitization intermittent• Ozone and hot water intermittent or continuous


Chemical Sanitization

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• Generally lowest capital cost– System materials of construction– Sanitization equipment

• Typically highest cost per sanitization with labor• Typically not as effective as heat or ozone• Typically not automated



• Most flexible for material selection• Good match for PP, PE and PVC• Time consuming

– Long contact time typically required– Must prove presence at all ports (manual)– Must prove absence at all ports (manual)

• Highest rinse water requirement to remove residualchemical

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• Tight microbial level requirement greatest risk– No pseudomonads– No gram negatives– No B. cepacia– No pseudomonas aeruginosa

• Once biofilm is established removal is very difficult


Sanitization Chemicals

• Peracetic acid/hydrogen peroxide mixture most common• Chlorine dioxide

– Gas phase helps in biofilm penetration• Sodium hypochlorite

– Excellent low cost choice for plastic– Not compatible with SS– Not compatible with most media

• Sodium hydroxide – best for biofilm removal

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Hot Water Sanitization

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Ambient Storage – Hot Water Sani

• Common in Purified Water applications• Logical in ambient WFI production applications• Historically favored by regulatory agencies• Lethal to all microbes indigenous to pure water

systems• Some biofilm removal• Excellent penetration and conduction into

problematic areas


Ambient Storage – Hot Water Sani

• Lengthy history of success• Easily verified• Easily automated• Can require significant time• Can tax utilities• Minimal tank level for sani energy/time efficiency• Cooling heat exchanger eliminates water dump

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Three Ways to Introduce Heat


Ambient Loop (Operation)

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Ambient Loop (HW Sanitization)


Steam Sanitization

• Not recommended by ISPE• Losing favor in pharma• Pure/clean steam required• Design for extreme temperature delta production versus sanitization• Complete drainability• Continuous sloping• Sanitary air venting• Condensate drainage• Utility impact• Rouge impact• Elastomer/seal impact

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Continuous Hot Storage – Self-Sanitizing


Continuous Hot Storage

• FDA views 65OC or higher as self-sanitizing

– Continuous 80OC not required

• Periodic elevation to 80OC recommended as needed

• EU views 70OC as self-sanitizing

• High temperature is possible rouge factor

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Hot Water Storage & Loop


HW Storage / Ambient Loop

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HW Storage / Dual Loop


Ozone Sanitization

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Ozone

• Allotrope of oxygen - three atoms• Relatively unstable• Half-life varies - 10 to 120 minutes• Solubility about 13 x O2

• OSHA atmosphere limit = 0.1 ppm• Potentially explosive at O3/O2 mixtures >20% -

impossible in water

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Ozone Sanitization ofStorage/Distribution

• Use began much later than chemical and thermalsanitization

• Relatively slow growth in implementation until recently– Release of ISPE Ozone Guide stimulated interest and

knowledge– EP recommending consideration for alternative WFI

systems• Can be more energy efficient than thermal sanitization• Can have shorter cycles than thermal or chemical

sanitization

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Why is ozone use rapidlyincreasing?

• Microorganism kill several logs faster than chlorine• Most planktonic bacteria killed in seconds• Lyses cell wall - not dependent on diffusion through cell

wall• Decomposes to oxygen – no water waste necessary• Regulatory acceptance generally good


Ozone Sanitization Advantages

• Easily automated• Easily verified• Extremely effective• Ozone easily removed with UV• No rinse concerns with regular use• Effective at continuous levels as low as 20 ppb

(50 – 100 ppb typ)

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Ozone Sanitization

• Sanitization levels typically 0.1 ppm to 0.5 ppm• Sanitization duration as short as 20 minutes• Tank typically continuously sanitized• Use point flush should be performed as needed

– Based upon use point micro data– Observe OSHA atmospheric ozone level requirements– Ozone removal methods available if necessary

• Ozone can remove biofilm with sufficient contact time


Ozone versus Thermal Sanitization

• Heat may have advantages for dead leg penetration• Must use zero dead leg valves for best performance• Half life versus diffusion rate• Must consider use point flush

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Ozone Sanitization

• Few WFI systems – discouraged by original ISPE Waterand Steam Guide

• New EP regulations for WFI (April 2017)– No longer distillation only– Ozone implementation recommended several times

• Degrades water conductivity via TOC oxidation– Oxidation byproducts primarily carbon dioxide

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Ozone Generator Types

• Corona discharge oldest – most placements– Gas as feed source– Gas feed must be >95% O2, <-60OC dew point

(to minimize nitric acid formation)

• Electrolytic more costly but gaining popularity– Pure water as feed source

Both can work effectively

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Ozone Removal

• Dissolved– Ultraviolet light 254 nm (3X germicidal dose)– Activated carbon– Heat– Time

• Gas– Manganese dioxide catalytic device– Heat

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Ozone Measurement

• Chemical testing– Indigo trisulfonate solution decolorization

• Absorbance change of 600 nm light• Linear with ozone level• Preferred method

– Excellent way to confirm monitor readings

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Ozone Measurement On-line

• Electrolytic membrane amperometer– Electrochemically converts ozone to oxygen– Measures current required for conversion - proportional

to O3– Good sensitivity– Membrane minimizes electrode fouling and oxidant

interference• All monitors have significant maintenance/calibration

requirements• All monitors present some level of issues

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Ozonated Loop (Operation)

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Ozonated Loop (Sanitization)


Maintenance/Regulatory/Summary

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Sanitization Maintenance Impact

• Typically automated• May increase rouging in SS• Instrument calibration• Heat exchangers• Boilers/chillers• Component removal?

• Typically automated• Generators/oxygen generators• Monitors• Possible rouge formation in SS• Component removal

• Chemical preparation• Chemical introduction• Chemical circulation• Use point verification• Chemical rinse out• Use point verification


Regulatory Impact

• WFI nearly all hot water/steam– Long accepted by agencies– Ozone promoted by new EU WFI recommendations– Chemical discouraged by most SMEs

• Purified Water– Hot water promoted in many critical applications– Ozone accepted in many applications– Chemical sanitization in majority of total pharma market applications

• Production• Quality labs• R&D labs• API• Not a regulatory favorite, but generally accepted

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Sanitization Safety

• All sanitization methods have safety concerns• Personal protective equipment required if any contact

possible• Temperature concerns with hot water and steam• Chemical exposure• Atmospheric ozone exposure


• Sanitization capability is a GMP requirement• Sanitization method and design are critical to quality• Sanitization selection should be risk based• Sanitization method must be decided early in system design,

– affects material and specifications• Chemical, Heat and Ozone all have advantages and disadvantages

• Heat and Ozone can be most effective method, can be automated,but can cost more.– Usually selected for more critical applications

• Chemical can be less expensive, but can also require extensivelabor, water volume and time

Sanitization Method Comparison Summary

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• Continuous sanitization is almost always more effective thanintermittent

• Intermittent sanitization frequency is risk based,– more frequent results in better control

• No sanitation method or frequency can replace proper systemdesign, operation and sampling procedures



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Parameter Chem Sanitization Heat Sanitization Ozone Sanitization Continuous Hot Continuous OzoneSafety - Personnel risks ◍ ◍ ◍ ◍ ◍Equipment risks ● ● ◍ ● ◍Sanitization effectiveness ◍ ● ● ● ● ●Sanitization frequency ○ ● ◍ n/a n/aSanitization Automation ○ ● ● ● ●Up-time availability ○ ◍ ● ● ● ● ●Cost to purchase (small system) ● ◍ ○ ◍ ○Cost to purchase (large system) ● ○ ○ ○ ○Cost to sanitize Generation (labor/materials) ◍ ○ ● ○ ◍Cost to sanitize S&D (labor/materials) ○ ○ ● ○ ●Cost to maintain ● ◍ ○ ◍ ○Sanitization parameter attainment verification ◍ ● ● ● ●Suitability to 'return to service' ○ ● ● n/a n/aTraining requirements and complexity ◍ ◍ ◍ ◍ ◍Equipment complexity ● ◍ ◍ ◍ ◍Repeatability ◍ ● ● ● ● ● ●Regulatory acceptance - Purified Water ◍ ● ● ● ● ●Regulatory acceptance - Water-For-Injection ○ ● ● ● ●

Legend○ = Weakest Choice◍ = Medium Choice● = Strong Choice

●● = Strongest Choice

Biopharm Sanitization Design Comparison


Gary ZoccolantePlymouth Rock Water Consulting

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Sanitization Methods for Pharmaceutical Water Systems