ISPE Sep 2016 7000RMS Bioburden Analyzer - NemTilmeld · 7000RMS Bioburden Analyzer ISPE Sep 2016...

7000RMS Bioburden Analyzer

ISPE

Sep 2016

Real Time Microbial Detection

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Agenda

1 Introduction Thornton and 7000RMS

2 Why On-line Microbial Monitoring

3 7000RMS Technology and Key Features

4 Test Points for 7000RMS

5 Pharmacopeia acceptance of Alternative Methods

6 Validation Guidelines

2

THORNTON – Leading Pure Water Analytics

1964 Dr. Richard Thornton, an MIT professor, founded Thornton Inc.

2001 Acquired by Mettler-Toledo and integrated into Process Analytics Division

Widely considered as the leader in the production of high quality

resistivity / conductivity sensors and the Thornton/Light Curve

Long history of community marketing successful at establishing brand

recognition at key international organizations such as USP (A.

Bevilacqua), EP, JP, FDA, SEMI & PV (J. Cannon) and ASTM (D. Gray)

Strong working relationships at system fabricators

3

THORNTON Innovation Highlights

Long Tradition in Pure Water Analytical Measurements

1989 1948 1964 1992 2000 1996 1994 2003 2005 2008 2010 2007

Multiparameter

2-Channel

Portable TOC Concentric Ti

C/R Cell for

UPW

Sodium and

Silica Analyzers

1st TOC

Sensor

Ozone

Sensor

UniCond®

Multiparameter

4/6 Channel

4000 TOC

2012 2013

1st Integrated

Multiparameter

Instrument

Sanitary C/R

Sensor

Cost Effective

2-Channel

Broad-range 4-e

Conductivity

Sensor

Pure Water pH

Sensor

M300 ½

Channel

M800

Transmitter and

TOC 5000i

Pure Water

Optical DO

Ozone Digital

ISM sensor

2015 2014

Microbial

Analysis

CIP

Monitoring

4

Goals of the Introduction

7000RMS is a "game changer" for microbial detection in pure water

Past: Measuring the bioburden in Purified Water

and Water for Injection has almost exclusively

depended on time-consuming and error-prone

culture-based lab measurements.

Now: Our new 7000RMS analyzer offers

accurate, continuous, on-line determination of

microbial and inert particle contamination in

pharmaceutical water systems.

Introduce the new 7000RMS

(Real Microbiology System)

for Real-Time Bioburden

Detection

5

Value Proposition

7000RMS answers the market need for real-time bacterial detection

Don't miss a bug! With real-time microbial detection.

Don’t Miss A Bug!

Continuous Measurement

Compliant with USP Recommendations/Regulations

Economic On-line Alternative to Sampling

6

A few of our new best friends 7

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1 Introduction






8

Why On-line Microbial Monitoring?

Off-line method of bioburden

detection:

Unreliable results (human errors)

High risk of false-positive results

Costly

Time consuming

Delay of product release

On-line method of bioburden

detection:

Reliable, real-time results

Allows real-time release of water

Eliminates sampling error

Cost-effective

No delay of product release

9

Drivers for Alternative Methods

Global organizations support development of on-line bioburden analysis

Online Water Bioburden Analysis

Workgroup

- Established as an Industry

workgroup to promote

development and

implementation of online

bioburden analyzers

- Members from Merck,

Novartis, Amgen, Fresinius,

Baxter, P&G, Roche, Sanofi

and Pfizer

OWBA FDA

FDA PAT (Process Analytical

Technologies) Initiative

FDA Aseptic Processing

Guidance - cGMPs

FDA Strategic Plan for

Regulatory Science

FDA Senior Microbiologist

Supports RMMs

10

Traditional Microbial Detection

A colony-forming unit (CFU) is a unit used to estimate the

number of viable bacteria or fungal cells.

Counting with CFU’s requires culturing the microbes and counts

only viable cells.

Duration and temperature of incubation are also critical aspects of

a microbiological test method.

Classical methodologies using high-nutrient media are typically

incubated at 30°–35° for 120 – 168 hours.

Because of the flora in certain water systems, incubation at lower

temperatures (e.g., 20°–25°) for longer periods (e.g., 7–14 days)

can recover higher microbial counts when compared to classical

methods.

Low-nutrient media are designed for these lower temperature and

longer incubation conditions (sometimes as long as 14 and up to

21 days to maximize recovery of very slow-growing oligotrophs or

sanitant-injured microorganisms), but even high-nutrient media can

sometimes increase their recovery with these longer and cooler

incubation conditions.

11

https://en.wikipedia.org/wiki/Bacteria

https://en.wikipedia.org/wiki/Fungal

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12

7000RMS - Features

Instant AFU Counts

Real-time display of microbial

contamination

Easy operation

No sample preparation or reagents

required.

Touchscreen

At-Line or Grab Sample

Wide measurement range

Dependable measurements from 1

cell / 100 mL to 2000 / mL.

Multiple communication options

SCADA connectivity with ModBus TCP

Multiple analog outputs

Ethernet standard RJ45/Wi-Fi capable.

13

7000RMS – Product Specifications 14

More 7000RMS Benefits

Higher product quality at a lower cost The 7000RMS eliminates the need for routine lab

testing, with no sample preparation required. Instant

notification of microbial excursions allows for rapid

remediation, preventing product from being affected.

The reduction in lab measurements and savings in

energy through optimized sanitization cycles results in

markedly lower operating costs

Reliable optical technology Light-induced fluorescence (LIF) and sophisticated

algorithms are used to detect and quantify microbes

and inert particles. Particle sizing is achieved using Mie

scattering. The 7000RMS is also able to measure

organisms that can be missed in growth-based

methods

Easy to use throughout your facility Whether in your RO system, pure water storage or

distribution loop the 7000RMS can be utilized on-line or

off-line. It can also be used in the laboratory for rapid

testing of grab samples. The analyzer's touchscreen

interface displays all critical data and controls in a user-

friendly manner

15

Metabolites Fluorescence Spectra for 7000RMS

By detection of these two metabolites we can identify viable bacteria and do

not need to fluoresce other metabolites

Fluorescence of metabolites with

the 405nm laser used in

7000RMS

(Hill et al, Field Ana. Chem. & Tech, 3(4-5), 221,1999)

405nm Laser in 7000RMS

16

16

Flowchart

Online / sample mode

17

Inside 7000RMS 18

Example of 7000RMS User Interface 19

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20

Bacterial detection as an At-Line measurement

Bring the Microbiology Lab to the System – eliminate sampling !

In-Line

- inside pipe, real-time

- conductivity, pressure, flow

At-Line (Side stream)

- attached to pipe, real-time,

flow to drain

- Microbiological

- TOC, pH, O2, O3

Off-Line

- batch sample

- "Lab" measurements

- minutes, hours, days

- pH, chromatography

Now all 3 USP regulated parameters measured in-line/on-line are available in Thornton's

portfolio!

On-Line

21

Application Example: Storage/Distribution

Validate PW and WFI quality with on-line

Real-time Microbial System – 7000RMS

Reduce false-positive tests from sampling

errors

Reduce lab testing costs and analysis

delays

No delay in product release

Real time microbial detection provides

faster analysis, eliminates delays and

reduces costs

Monitor and trend the water quality thereby

allowing for accurate risk assessment

Reduce testing and insure proper and

timely sanitization

User Objective

Pure Water

or WFI

Why the 7000RMS?

5000TOCi

O3

7000RMS

can also

be installed

after the

purification

unit

22

Application Example: Point of Use Testing

Rapidly validate water at point-of-use

Expand distribution monitoring to include

all Points of Use

Eliminate sampling errors and costs

Sample points-of-use real time

Reduce sample analysis time and eliminate

risk associated with grab samples

See measurement results in seconds

Bring the measurement to the sample

User Objective Why the 7000RMS?

UPW

23

Thornton's Answers to Regulations

Thornton's 5000TOCi

& 450TOC Sensors

USP <643>: established standards

for TOC measurements and the

equipment used to monitor TOC

METTLER TOLEDO

Service

USP <643>, USP <645>, EP 2.2.44

and JP16 - System Suitability

Test, TOC calibration and

conductivity calibration

Thornton's UniCond

Conductivity Sensors USP <645> for in-line or off-line

conductivity testing

Thornton's 7000RMS

Bioburden Analyzer

USP <1231>: monitor UPW at a

frequency that ensures the system is

in control and continues to produce

water of acceptable quality

Now available

on-line

24

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25

Relevant Sections of the USP

Pharmaceutical Water Monographs

- Purified Water (bulk) Sterile Water for Inhalation

- Water for Injection (bulk) Sterile Water for Irrigation

- Sterile Purified Water (packaged) Bacteriostatic WFI

- Sterile WFI (packaged) Water for Hemodialysis

- Pure Steam

Test Chapters

- 645 Water Conductivity 85 Endotoxins

- 643 Total Organic Carbon 71 Sterility

- 644 Conductivity – planned for the future 791 pH

General Information

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

- 1231 Water for Pharmaceutical Purposes (contains microbial limits)

- 1233 Instrumentation for Pharmaceutical Water – planned for future?

- 1644 Theory and Practice of Electrical Conductivity Measurements of Solutions

- 1223 Validation of Alternative Microbiological Methods – 2nd Supplement USP 38

26

USP Recommendation for Microbial Monitoring

7000RMS enables real-time, continuous measurement according to USP

recommendations

USP < 1231 > Water for Pharmaceutical Purposes recommendation:

- Pharmaceutical water systems should be monitored at a frequency that ensures the

system is in control and continues to produce water of acceptable quality.

The general information chapter endorses operating monitoring instruments

continuously in order that historical in-process data can be recorded for

examination

The new USP <1223> promotes and encourages the validation and

development of alternative microbial technologies

27

Revised Chapter for Alternative Microbial

General Information

- 1223 Validation of Alternative Microbiological Methods – 2nd Supplement USP 38

28

European Pharmacopeia Alternative Microbial

Information

- 5.1.6 Alternative Methods for Control of Microbiological Quality

5.1.6. ALTERNATIVE METHODS FOR CONTROL OF MICROBIOLOGICAL QUALITY

The following chapter is published for information.

1. GENERAL INTRODUCTION

The objective of this chapter is to facilitate the implementation and use of alternative

microbiological methods where this can lead to cost-effective microbiological control and

improved assurance for the quality of pharmaceutical products. These alternative methods

may also find a place in environmental monitoring.

The microbiological methods described in the European Pharmacopoeia have been used for

almost a century and these methods - for enumerating and identifying micro-organisms - still

serve microbiologists well. Over the years, these methods have been invaluable to help

control and secure the production of microbiologically-safe pharmaceutical products.

Nevertheless conventional microbiological methods are slow, and results are not available

before an incubation period of typically up to 14 days. Thus the results from the conventional

microbiological methods seldom enable proactive, corrective action to be taken.

Alternative methods for control of microbiological quality have been introduced in recent

years, and some of these methods have shown potential for real-time or near-real-time

results with the possibility of earlier corrective action. These new methods can also offer

significant improvements in the quality of testing.

29

European Medicines Agency EMA 30

• Questions and answers on production of water for injections

by non-distillation methods – reverse osmosis and biofilms

and control strategies.

• This set of questions and answers is intended to provide preliminary

guidance until such time the ongoing revision of Annex I of the GMP guide

is complete.

• 6. What testing should be employed during initial qualification and routine operation sampling? • Testing should be conducted in line with Ph.Eur. Monograph 169 ‘Water for Injections’

• Use of rapid microbiological methods should be employed as a prerequisite to the control strategy to aid with rapid

responses to deterioration of the system.

• Article 23 of Directive 2001/83/EC states: “...the authorization holder must, in respect of the methods of manufacture and

control...take account of scientific and technical progress...”

• Quantitative microbiological test methods – in line with Ph.Eur. 5.1.6 monograph ‘Alternative Methods for control of

Microbiological Quality’.

• Due consideration should be given to employing alternate methods for the rapid quantitative determination of the

contamination levels existing within the water system. The validation of such system should be in line with the above

referenced monograph.

• Use of alternative/ rapid microbiological test methods should be employed as part of the overall control strategy for the

system.

• Taking into account the speed at which organisms can proliferate, the use of rapid microbiological test methods and

systems should be employed in order to improve or increase the probability of early detection and allow timely action to

be taken.

USP Adoption of New Technology

1840 - 1994

Chemistry/Organic tests

are;

- Qualitative,

- Subject to bias

- Off-line.

- Carbon dioxide

- Calcium

- Ammonia

- Chloride

- Sulfate

- Oxidizable

Substances

- Heavy Metals

1840 - 1994 1994 - 1996 > 1996

1994 – 1996

Thornton asked

to prove

instrumentation

versus wet

chemistry

Chemistry tests

- VS.

Conductivity

Instrument

Oxidizable

Substances

- VS.

TOC Instrument

1996 to present

USP Accepted

as Compedial

Tests

Conductivity

Instrument

TOC Instrument

2003 –

2006

Adoption by

EP

JP

ChP

IP

31

USP Adoption of New Technology

1890 - 2016

Bacteria tests are;

- Plate Count

- Qualitative,

- Subject to bias

- Off-line.

- Sampling errors

- Poor growth

1890 - 2016 2016 to 20?? 20??

2016 – ?

Traditional Plate

Counts

-VS.

On-Line Real Time

Instruments

USP <1223> now

encourages validation

of alternative

microbial methods

Ph.EUR. 5.1.6.

“Alternative Methods

for Control of

Microbiological

Quality”

Accepted by USP

as a Compendial

Test?

On-Line Real Time

Instruments

20??

Accepted by the

other Global

Pharmacopeia’s

32

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33

Online vs. Plate Counts – Why the difference?

CFU Versus AFU

34

Proposed Methods for Validation – Method 1

Method 1 is the fastest validation approach while minimizing risk for the

customer without requiring live bacteria inoculation.

Method 1: Proposed method for validation utilizing side-by-side testing

Method 1 is likely to be the preferred option for many customers as it:

- does not involve bringing live bacterial cultures into their facility

- provides a direct correlation in their process between the 7000RMS and their current

plate count method

Method 1 compares the direct at-line microbial readings from the 7000RMS to the

laboratory results from standard sampling and plate counting in combination with review

of historical data.

This method does not require the inoculation of a water system with bacterial samples

that maybe non-native or non-existent in the water system.

If the PW and/or WFI distribution systems have been monitored over time and historical

records demonstrate that the system is under microbial control then this side-by-side

validation method eliminates the risk of bacterial introduction.

35

Correlation Sample 1 "Ideal"

Plate Count (CFU) 7000RMS AFU

To validate the alternative method (RMS), the customer needs to demonstrate to

the validation officer the correlation of the RMS values vs. the plate count.

36

Correlation Sample 3 "Wrong"

Alternative methods must show correlation but more important they must not show inferior

(lower) like in sample 3 in the chart below.

- Highlights importance of ensuring good lab technique and sample handling!

Plate Count (CFU) 7000RMS AFU

37

Correlation Sample "USP 1223"

0

10

20

30

40

50

60

70

80

90

100

110

1 2 3 4

Plate Count

7000RMS

Note:

If the bacteria cells in a water

sample are low, you would

typically see 0 CFU with plate

count

If the bacteria in the water

sample is low, you would

typically see proportionally

small difference between the

plate count and RMS AFU

count

The more bacteria in the

sample you will see higher

proportional difference

between the plate count and

RMS AFU count

Bacteria

cells/sample

Plate Count

(CFU)

7000RMS

Biocount

1 0 ≈ 1

10 0 ≈ 10

50 - 100 25 - 40 ≈ 50 - 100

100 - 200 50 - 75 ≈ 100 - 200

Comparison test per USP<1223>

38

Online vs Plate Counts – Why the Difference?

The USP is proactively managing customer expectations that online results

will be different. Help manage this upfront in the sales process!

‘Why do I have higher counts online versus my plate counts?”

USP <1223> “It is important to understand that the cfu has always been an estimation of

microorganisms present, rather than an actual count.”

“Studies on the recovery of microorganisms have demonstrated that traditional plate-count

methods reporting cell count estimates as colony-forming units (cfu) may recover 0.1%–

1% of the actual microbial cells present in a sample.”

“Higher cell counts must not be considered as necessarily indicative of greater risk given

the inherent variability of standard growth methods.”

The CFU (Colony Formation Unit) has always been an estimation of microorganisms

present, rather than an actual count – colony may be from 1 cell or 1,000 cells (plate

count)

Rapid microbiological methods are direct cell count methods, therefore a higher count is

expected

39

Conclusions

Traditional plate count method has been performed for 125 years and is

recognized as only an estimate of the actual microbial cells present

“Alternative microbial detection methods will in most applications report higher

counts”. USP<1223>

“Higher counts should not be interpreted as an increased microbial safety risk

for previously controlled and monitored systems.” USP<1223>

“Any alternative microbial detection methods may be used provided it has been

demonstrated they are equivalent or superior to the compendial Pharmacopeia

method”. FDA Senior Microbiologist

Online vs Plate Counts – Why the difference? 40

Mettler-Toledo Thornton

Thank You!

Thank You!

Merci

Grazie

謝謝

ありがとう

Danke

고맙습니다

Gracias

Tak

Terima kasih

Dziękuję

Tack

Cảm ơn bạn

Cпасибо

Obrigado

Go raibh maith agat

σας ευχαριστώ

धन्यवाद

ודה

41

ISPE Sep 2016 7000RMS Bioburden Analyzer - NemTilmeld · 7000RMS Bioburden Analyzer ISPE Sep 2016...

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